Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:31][O:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:31][O:32][N:33]([CH3:34])[C:19]([C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[CH:17]=1)=[O:21]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(3-nitrophenyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (637 mg, 1.54 mmol), methoxy(methyl)amine hydrochloride (298 mg, 3.06 mmol), was added N,N-dimethylformamide (20 mL), HATU (701 mg, 1.84 mmol) and DIPEA (793 mg, 6.14 mmol). The resulting solution was stirred for 2 hours at 25° C. and then quenched by the addition of water (50 mL). The reaction solution was extracted using ethyl acetate (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography using silica gel, eluting with 50% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford N-methoxy-N-methyl-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide as a white solid. LRMS (ESI) calc'd for C21H28N5O5Si [M+H]+: 458, found 458. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.59 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.18 (d, 8.4 Hz, 1H), 7.95 (s, 1H), 7.70 (t, J=7.8 Hz, 1H), 5.78 (s, 2H), 3.64 (t, J=8.2 Hz, 2H), 3.49 (s, 3H), 3.09 (s, 3H), 0.98 (t, J=8.2 Hz, 2H), 0.04 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>COC(O)C.CCOCC>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Reactant: Nc1cccc(Br)c1
Agent: COC(C)O
Solvent: CCOCC
Product: COc1ccc2c(Nc3cccc(Br)c3)c(C#N)cnc2c1
Yield: 33.2 %

Procedure:
A solution of 2.97 g (13.6 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile and 4.67 g (27.2 mmol) of 3-bromo aniline in 76 ml of methoxyethanol was refluxed under nitrogen for 5 hours. The solution was cooled and diluted with ether. Solid was collected and washed with ether. The solid was stirred with a hot mixture of ethyl acetate and sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was recrystallized from a chloroform-ethyl acetate mixture giving 1.6 g of 4-[(3-bromophenyl)amino]-7-methoxy-3-quinolinecarbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 354.1, 356.1.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Cl-].[Zn+2].[Cl-].C(OCC(C)C)(=O)C>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:32][CH2:31][C@:29]([CH2:28][CH2:27][CH2:26][C@@H:24]([CH2:23][CH2:22][CH2:21][C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OCC(C)C
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 35 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a mixture consisting of 69.9 g (0.460 mol) of 2,3,5-trimethylhydroquinone, 52.5 g (0.386 mol) of zinc chloride, 150 ml of isobutyl acetate and 7.5 g of concentrated hydrochloric acid, 138.3 g (0.459 mol) of isophytol (purity: 98.3%) was added dropwise under stirring at 30-40° C. over 3 hours. At the same temperature, the reaction mixture was stirred for an additional 2 hours. After the reaction mixture was washed with 30 ml of water, the solvent was distilled off. Toluene (300 ml) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 202.0 g of the title compound was obtained as a brown oil (yield 99.6%, GLC purity: 97.5).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]1[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][C:22]=1[OH:34].[OH-].[Na+]>>[CH:21]1[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][C:22]=1[O:34][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc2c(c1)Cc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)Cc2ccccc2-3)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 9H-Fluoren-2-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26O5 [M+Na]+: 441.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].O.NN.[C:16]([O-])(=O)C.[Na+].IC>C1COCC1.CCCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CC(=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCCCCCC
Product: CS(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 4-bromo-3-fluorobenzene sulphonyl chloride (10 g, 36.56 mmol) in THF (100 mL) was cooled to 0° C. and hydrazine monohydrate (6.2 mL, 127.96 mmol) was added dropwise. After the addition, the reaction was left to stir at room temperature for 1 hour before adding heptane (500 mL). The precipitate formed was filtered off and re-dissolved in industrial methylated spirit (200 mL). Sodium acetate (18 g, 219.36 mmol) was added followed by iodomethane (11.38 mL, 182.8 mmol). The reaction mixture was stirred at reflux for 18 hours. The reaction was cooled to room temperature and the solvent was concentrated to half of the initial volume. Water (300 mL) was added and the product was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL) and dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting from 15% to 35% EtOAc/heptane to afford the title compound as a colourless solid in 48% yield, 4.40 g.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([C:27]3[CH:39]=[CH:38][C:30]4[O:31]C(C)(C)[O:33][C:34](=[O:35])[C:29]=4[CH:28]=3)[C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[C:27]3[CH:39]=[CH:38][C:30]([OH:31])=[C:29]([CH:28]=3)[C:34]([OH:35])=[O:33])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)cyclohexanecarboxamide and NaOH (1N) in the presence of EtOH as a white powder (42%). 1H NMR (DMSO-d6, 300 MHz) δ 7.44 (m, 5H), 7.27-7.16 (m, 5H), 6.95 (d, J=8.7 Hz, 1H), 4.79 (s, 2H), 2.59 (t, J=7.8 Hz, 2H), 2.12 (m, 1H), 1.63-0.89 (m, 14H), 0.88 (t, J=7.4 Hz, 3H). M− (ESI): 508.3; M+ (ESI): 509.7. HPLC, Rt: 5.58 min (Purity: 99.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][CH2:18][Cl:19])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 79.6 %

Procedure:
A mixture of 1-(4-chlorobenzyl)piperazine (6.32 g; 0.03 mole), 1-bromo-3-chloropropane (4.75 g; 0.03 mole), anhydrous potassium carbonate (6.25 g; 0.045 mole) and butanone (75 ml) was stirred at reflux for 3 hr, cooled and filtered. The filtrate was evaporated in vacuo, and the residue dissolved in ether and washed with water (3x). The solvent solution dried over magnesium sulphate, filtered and evaporated to yield 6.86 g (80%) of the title compound. G.L.C. (5% Dexsil 300, 100°-350° at 15°/min) showed the sample to be 99% pure. A sample was distilled b.p.0.5 150°, and the distillate had the following spectral and analytical characteristics: νmax (film) 2900, 2760, 1480, 1450, 1435 cm-1. δ (CDCl3), 1.95 (2H,m); 2.43 (10H,m); 3.42 (2H,s); 3.56 (2H,t,J 7 Hz); 7.25 (4 H,s) (Found; C, 58.32; H, 7.07; Cl, 24.37; N, 9.79; C14H20Cl2N2 requires; C, 58.34; H, 7.02; Cl, 24.69; N, 9.75%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH:25]=[C:26]([CH3:27])[CH3:28])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
The mixture 5-fluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (148) (245 mg, 0.62 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (149) as white solid (230 mg, 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>Cl.CCOCC>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[O:11])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CC(=O)O)cc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: CCOCC
Product: C=Cc1ccc(CC(=O)OC2CCCCO2)cc1
Temperature: 45 °C
Yield: 70.8 %

Procedure:
A mixture of 7 g (43 mmol) of 4-vinylphenylacetic acid, 12.0 g (142 mmol) of 3,4-dihydro-2H-pyran and 2 drops of 32% hydrochloric acid is warmed at 45° C. for 90 minutes in a 50 ml three-necked round-bottom flask fitted with magnetic stirrer and nitrogen blanketing system. 100 ml of ether are then added. The organic phase is then washed twice with 50 ml of 1 N sodium hydroxide solution in each case and twice with 50 ml of water in each case, dried over magnesium sulfate and evaporated, giving a colourless oil, which is recrystallized from three times the amount of n-hexane, giving 7.5 g (70% of theory) of tetrahydro-2H-pyran-2-yl 4-vinylphenylacetate having a melting point of 34° C. 1H-NMR (CDCl3, 300 MHz): δ [ppm] 7.4-7.1/m/4H 6.68/dd/1H 5.98/dd/1H 5.73/dd/1H 5.22/dd/1H -3.7/m/2H 3.64/s/2H 1.9-1.5/m/6H
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:24]([O:33][CH2:34][C:35]#[C:36][CH2:37][OH:38])[N:23]=[C:22]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[N:21]=2)(=[O:18])=[O:17])=[N:14][CH:15]=1)([CH3:9])[CH3:8].[CH3:45][O:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[N:50]=[C:49](S(C)(=O)=O)[N:48]=1>CN(C=O)C>[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[C:24]([O:33][CH2:34][C:35]#[C:36][CH2:37][O:38][C:49]3[N:50]=[C:51]([O:53][CH3:54])[CH:52]=[C:47]([O:46][CH3:45])[N:48]=3)[N:23]=[C:22]([C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)[N:21]=2)(=[O:18])=[O:17])=[N:14][CH:15]=1)([CH3:9])[CH3:8]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)C)cn3)nc(-c3ccncc3)nc2OCC#CCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OCC#CCOc2nc(-c3ccncc3)nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c2-c2ccc(C)cc2)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 243 mg of K2CO3 in 15 ml of DMF 450 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 11) was added. After stirring for 0.5 h at 90° C., 192 mg of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added and stirring was continued for 16 h at 90° C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous acetic acid and 50 ml of DCM. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of DCM. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with DCM:methanol 20:1 to give 88 mg of 5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige foam. LC-MS: tR=5.54 min, [M+1]+=668.38, [M−1]+=666.39.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+]>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:11]
Reactant: O=CC1CC2C=CC1C2
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Product: N#CCC=C1CC2C=CC1C2
Yield: 72.1 %

Procedure:
A stirred solution of 100 g (0.82 mol) of 2-formyl-5-norbornene (Aldrich Chemical Co.), 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58% ), 132 ml of diemthylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 79.6 g (68% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]hept-5-ene: b.p. 76-78° C/1 mm; ir 3060, 2260, 1420, 1330, 915, 840, 755, 720; nmr 1.3-2.5 (4H, m), 2.9-3.4 (4H, m), 5.0-5.5 (1H, m), 5.9-6.2 (2H, m); ms 145.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br.C(O)(=O)C.C([O-])(O)=O.[Na+]>O>[NH2:13][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(O)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 81 %

Procedure:
To a round bottom flask was added 3-methoxy-5-trifluoromethyl-phenylamine (1.0 g, 5.23 mmol), 10 ml HBr (49% aq.), and 8 mL glacial acetic acid. A reflux condenser was attached and the solution heated to 140° C. for 20 h. The reaction was then diluted with water and neutralized to ˜pH 7 by slow addition of saturated NaHCO3. The aqueous solution was then extracted into EtOAc twice. The organic layers were combined, washed once with brine, dried over Mg2SO4, filtered, and concentrated in vacuo to yield the title compound as a tan solid (750 mg). MS (M+H)+=178; Calc'd 177.12 for C7H6F3NO.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C.ClCCl>[Cl:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[CH2:8][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.50 g (74.452 mmol) potassium carbonate was added to a solution of 7.400 g (29.543 mmol) of 1-bromomethyl-2-chloro-4-nitro-benzene and 5.00 mL (59.300 mmol) pyrrolidine in 150 mL acetonitrile and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with 200 mL dichloromethane, filtered and the filtrate evaporated down i. vac. The residue was taken up in EtOAc, the org. phase was washed with water, dried over magnesium sulphate and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:29][C@H:30]2[O:32][CH2:31]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:29][C@@H:30]3[CH2:31][O:32]3)[C:7]=2[N:13]=1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(C[C@@H]3CO3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
In dimethylformamide (140 ml) was dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (5.0 g, 28.22 mmol), and sodium hydride (1.35 g, 31.04 mmol) was then added to the solution under cooling on ice. The obtained mixture was stirred at room temperature for 1.5 hours. The reaction solution was cooled on ice again, and (S)-glycidyl 3-nitrobenzenesulfonate (8.78 g, 33.86 mmol) was then added thereto. While slowly raising the temperature to room temperature, the mixture was stirred for 15 hours. Thereafter, water was added to the reaction solution, and it was then extracted with ethyl acetate. The resultant was washed with saturated sodium chloride solution, and it was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate) to yield 4.98 g (76%) of the above-captioned compound in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]=[C:16]=[S:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N:18]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.C1(C)C=CC=CC=1.C(N(CC)CC)C>O>[F:1][C:2]1[C:14]([NH:15][C:16]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][N:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[S:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCCCN1
Reactant: C=CCn1c(=O)sc2cc(F)c(N=C=S)cc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCn1c(=O)sc2cc(F)c(NC(=S)N3CCCCN3C(=O)OCC)cc21
Yield: 105.1 %

Procedure:
6-Fluoro-3-(2propenyl)-2(3H)-benzothiazolon-5-yl isothiocyanate (3.1 g) and ethyl hexahydropyridazine-1-carboxylate (1.17 g) were added to toluene (15 ml). A catalytic amount of triethylamine was added thereto, and the resultant mixture was stirred at 25° C. for 12 hours. Water was added thereto, and the resultant mixture was extracted with toluene. The extract was washed with water, dried and concentrated to give ethyl 2-[6-fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-ylaminothiocarbonyl]-hexahydropyridazine-1-carboxylate (3.3 g). m.p., 40°-42° C.
Reaction SMILES: C([NH:8][CH2:9][C:10]([NH:12][C:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:11])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[NH2:8][CH2:9][C:10]([NH:12][C:13]([CH3:19])([CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:11]
Reactant: CCCCCC(C)(C)NC(=O)CNCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCC(C)(C)NC(=O)CN

Procedure:
A solution of 2-benzylamino-N-(1,1-dimethylhexyl)acetamide (15.8 g, 57 m mol) in acetic acid (160 ml) was hydrogenated over 10% palladium on charcoal (3.16 g) for 2 hours at atmospheric pressure and 80° C. The mixture was filtered and the filtrate evaporated to a viscous liquid (15 g). This was dissolved in water (40 ml), basified with 10 N sodium hydroxide solution and extracted with ether (3×50 ml). The combined extracts were dried over magnesium sulphate then evaporated and distilled to give 2-amino-N-(1,1-dimethylhexyl)acetamide as a colourless oil, b.p. 92°-94° C. at 0.1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:9]([C:11](O)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.Cl.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27].C(N(CC)CC)C.C1COCC1>S(Cl)(Cl)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:9]([C:11]([NH:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(C(=O)O)c(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Nc1ncnn2cc(C(=O)NCC(F)(F)F)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (495 mg, 1.73 mmol) in thionyl chloride (15 mL) was heated (50° C.) for 3 h. Upon cooling to rt the reaction mixture was concentrated to dryness. The resulting acid chloride intermediate was combined with 2,2,2-trifluoro-ethylamine hydrochloride salt (587 mg, 4.33 mmol), triethylamine (1.15 ml, 8.66 mmol), and THF (8 mL). The reaction was stirred for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and then washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was tritureated with ethyl acetate and methanol to afford the desired product (490 mg, 74%). 1H-NMR (300 MHz, DMSO-d6) 8.77 (t, J=6.2 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J=8.9 Hz, 2H), 7.97 (s, 1. H), 7.59 (d, J=8.9 Hz, 2H), 3.91-3.99 (m, 2H); ES-MS m/z 381.1 (MH)+; HPLC RT (Method B) 2.33 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH:11]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]1
Reactant: COc1ccc(C)cc1C1=CC(C)(C)CC(C)(C)C1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C)cc1C1CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
To a solution of 1-methoxy-4-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1.0 g, 3.87 mmol) produced in Example (104a) in methanol (30 mL) was added 10% palladium on carbon (0.6 g, wet), followed by stirring for 12 hours at room temperature and atmospheric pressure under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 1.0 g of a crude product of the title compound as a yellow oil.