Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=[O:5])C.O.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CN(C=O)C.[Pd](Cl)Cl.[Cu]Cl>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:22][CH2:23][CH2:24][C:25](=[O:5])[CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CCCCOc1cccc(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Product: CC(=O)CCCOc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Palladium(II) chloride (112 mg) and copper(I) chloride (628 mg) were added to DMF-water (7:1, 8 mL), followed by stirring at room temperature under oxygen atmosphere for 1 hour. A solution of 1-(benzyloxy)-3-(pent-4-en-1-yloxy)benzene (1.70 g) in DMF (7 mL) was added dropwise to the reaction mixture, followed by vigorous stirring at room temperature for 2 hours. 0.5M Hydrochloric acid (60 mL) was added to the reaction mixture, followed by extraction with diethyl ether (100 mL). The organic layer was washed sequentially with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 5-[3-(benzyloxy)phenoxy]pentan-2-one (1.65 g).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][N:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C)CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Temperature: 210 °C
Yield: 40.5 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.3 mmol) in NMP (10 mL) is added 4-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 8.6 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22% 45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (0.64 g, 41%).
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:37])[CH2:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=2)[C:13]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:12]=2[NH:11][C:10]1=[O:36]>O>[C:27]([O:26][C:24]([NH:23][CH2:22][C:18]1[CH:17]=[C:16]([C:14]2[C:13]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:12]=3[NH:11][C:10](=[O:36])[CH:9]([CH2:8][C:7]([OH:37])=[O:6])[N:15]=2)[CH:21]=[CH:20][CH:19]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)CC1N=C(c2cccc(CNC(=O)OC(C)(C)C)c2)c2cc(Cl)ccc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(C2=NC(CC(=O)O)C(=O)Nc3ccc(Cl)cc32)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
A 1N aqueous solution of sodium hydroxide (1.5 ml) was added to a methanol solution (6 m.) of 5-(3-tert-butyloxycarbonylaminomethylphenyl)-7-chloro-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester (0.6 g), the compound produced in Example 97-(1). The mixture was stirred for 2 hours at 60° C. The reaction mixture was diluted with water (50 ml), which was acidified, followed by extraction with ethyl acetate (50 ml) twice. The extracts were combined and washed with a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5-(3-tert-butyloxycarbonylaminomethylphenyl)-7-chloro-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid (0.64 g) as a colorless amorphous solid product.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[OH:13])[CH:8]=[O:9])[CH2:3][CH2:2]1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[O:9])[CH2:2][CH2:3]1
Reactant: CCCCCCCCCI
Reactant: O=Cc1ccc(O)c(OC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCCCCCCOc1ccc(C=O)cc1OC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
To a solution of 1.78 g (10.0 mmol) of 3-(cyclopropyloxy)-4-hydroxybenzaldehyde and 2.54 g (10.0 mmol) of 1-iodononane in 20 mL acetonitrile was added 3.58 g (11.0 mmol) of Cs2CO3. The slurry was stirred at rt for 12 h. The reaction was quenched with 30 mL of water and extracted with ethyl acetate (50 mL×2). The combined extractions were washed with water, dried with sodium sulfate and concentrated to a solid. Flash chromatography on a Biotage 40M cartridge using 10% ethyl acetate/hexanes afforded 2.9 g (95%) of the title compound as a white solid. 1H NMR (500 Mhz) δ 0.87-0.91 (m, 7H), 1.30-1.90 (m, 14H), 3.85 (m, 1H), 4.10 (t, J=6.9, 2H), 6.98 (d, J=8.2, 1H), 7.48 (dd, J=8.5, 1.8, 1H), 7.77 (d, J=1.8, 1H), 9.89 (s, 1H); LC-1: 4.6 min; ESI-MS 305 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>C(O)CC(C)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:21]=[C:20]([NH2:19])[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=3)[CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(NC2CCNCC2)nc1N
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COC(=O)c1ncc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1N
Temperature: 120 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
Compound (38) (2.5 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (0.6 g, 2.5 mmol) in isoamyl alcohol (20 mL) at 25° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.70 g (65%) of the title compound: TLC (Rf =0.30; 10% CH3OH/CH2Cl2); 1H NMR (DMSO) δ 7.59 (d, 1H, J=7.7), 7.41 (s, 1H), 7.22 (s, 1H), 7.15 (br s, 4H), 6.73 (s, 1H), 4.63 (d, 2H, J=13.2), 4.10 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H), 2.99 (t, 2H, J=9.8), 1.90 (d, 2H, J=10.0), 1.39 (m, 2H); 13C NMR (DMSO) δ 167.0, 31.2; HRMS (FAB) m/z 455.2143 (M+H)+ (C21H26N8O4 requires 455.2155); Anal. (C21H26N8O4 ·1/2H2O·1/2CH3OH) C, H, N.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:34]=[CH:33]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:35]3[CH:34]=[CH:33][C:32]4[C:37](=[C:28]([Cl:27])[CH:29]=[CH:30][CH:31]=4)[N:36]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1cccc2ccc(N3CCNCC3)nc12
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Cl)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:27])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([N+:24]([O-])=O)=[CH:14][CH:13]=2.[Cl-].[NH4+]>O.CO.[Zn]>[NH2:24][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:27])/[C:9]/2=[CH:8]\[C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccccc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccccc3)c21
Yield: 100 %

Procedure:
Using Method L above, (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-phenyl-2H-indol-2-one (30 mg, 0.08 mmol) (from Example 38 supra) was reduced with zinc (48.9 mg, 0.75 mmol) and ammonium chloride (9.4 mg, 0.18 mmol) in 10% water in methanol (10 mL) at reflux for 1 day to give (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-phenyl-2H-indol-2-one (yield: 26.5 mg, 100%).
Reaction SMILES: [C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1.O>[C:1]1([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]([C:26]([OH:28])=[O:27])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N2c3ccccc3Cc3ccccc32)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1c2ccccc2N(c2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
A solution of N-phenylacridan (14.15 g, 55 mmol) in 200 mL of dry THF under inert atmosphere was cooled to −78° C. and 33.0 mL of 2.5 M n-butyllithium in hexanes (82.5 mmol) was added dropwise over 20 minutes. The solution was stirred at −78° C. for 30 minutes and then warmed to room temperature over 35 minutes. The reaction mixture was again cooled to −78° C. and 350 g of crushed dry ice was added causing a precipitate to form. The reaction was allowed to slowly warm to room temperature causing the reaction to become homogeneous. Stirring under argon was continued at room temperature. The resultant precipitate was collected by suction filtration. The solid was dissolved in 100 mL of water, which was acidified to pH 3 with 2N HCl and extracted with 4×200 mL of ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to dryness to afford 8.72 g of crude product. The reaction mixture filtrate was also concentrated to dryness to afford a solid that was taken up in 300 mL of water. The aqueous solution was acidified, extracted with 3×200 mL of methylene chloride and the combined organics were dried over sodium sulfate and concentrated to afford a second crop of 3.44 g of N-phenylacridan-9-carboxylic acid (73.4%).
Reaction SMILES: CO[C:3](=[C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][C:21]1=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[CH:33][CH:32]=1>CN1C(=O)N(C)CCC1.C(OCC)(=O)C>[CH3:42][N:40]1[CH:41]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:3](=[C:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[O:29])[C:4]3[CH:9]=[CH:8][C:7]([C:10]4([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:12]4)=[CH:6][CH:5]=3)=[CH:32][CH:33]=2)[N:38]=[CH:39]1
Reactant: C=CCOC(=O)NC1(c2ccc(C(OC)=C3C(=O)Oc4ccccc43)cc2)CC1
Reactant: Cn1cnc(-c2ccc(N)cc2)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: C=CCOC(=O)NC1(c2ccc(C(Nc3ccc(-c4cn(C)cn4)cc3)=C3C(=O)Oc4ccccc43)cc2)CC1

Procedure:
1.05 g of allyl (1-{4-[methoxy-(2-oxobenzofuran-3-ylidene)methyl]phenyl}cyclopropyl)-carbamate and 0.47 g of 4-(4-aminophenyl)-1-methylimidazole in 3 mL of DMPU were reacted in the microwave reactor at 180° C. After cooling, the mixture was diluted to 150 mL with ethyl acetate, extracted 2× with water, and the organic phase was dried over MgSO4 and evaporated down to the residue with silica gel. The substance was chromatographed with dichloromethane/methanol (97:3) on silica gel 70 at a flow rate of 30 mL/min Residue: 0.6 g of yellow oil.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C(OC([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCNCC2)nc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
Ethyl 6-chloronicotinate (1.12 g) was dissolved in DMF (30 mL), and 1-tert-butoxycarbonylpiperazine (1.24 g) and potassium carbonate (1.00 g) were added thereto. The mixture was stirred at 80° C. for 18 hr. Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added thereto at room temperature. The mixture was stirred for 2 hr and the reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was basified with aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform. The extract was dried and the mixture was concentrated under reduced pressure to give 1-(5-ethoxycarbonyl-2-pyridyl)piperazine (1.17 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[S:11][CH2:12][CH2:13][CH2:14][Cl:15].O.O.[Sn](Cl)Cl.[OH-].[NH4+:22]>C(O)C.Cl>[Br:1][C:2]1([NH2:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[S:11][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: O=[N+]([O-])c1cccc(Br)c1SCCCCl
Reactant: [NH4+]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC1(Br)C=CC=CC1SCCCCl
Temperature: 0 °C
Yield: 93.2 %

Procedure:
1-Bromo-2-[(3-chloropropyl)thio]-3-nitrobenzene (6.78 g, 21.9 mmol) was dissolved in ethyl alcohol (125 mL) and cooled in an ice bath to 0° C. Tin (II) chloride dihydrate (7.4 g, 32.8 mmol) was dissolved in concentrated hydrochloric acid (25 mL) and then added to the first solution over 20 minutes. The reaction was then allowed to warm to room temperature and stirred over night. Reaction mixture was cooled to 0° C. in an ice bath and another (1.5 eq, 7.4 g) of tin (II) chloride dihydrate in concentrated hydrochloric acid (25 mL) was added. This was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature and stirred until loss of starting material. Reaction was then basified to pH 12 with ammonium hydroxide and then filtered. The filtrate was then concentrated to a aqueous slurry, the slurry was then diluted with water (100 mL) and extracted with ethyl acetate (3×300 mL). Organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated to give 1-bromo-2-[(3-chloropropyl)thio]-benzenamine (5.7 g, 93.2%). 1H NMR (CDCl3, 300 MHz): δ7.02-60.87 (m, 2H), 6.65 (dd, 1H, J=7.7, 1.9 Hz), 4.63 (s-broad, 2H), 3.68 (t, 2H, J=6.4 Hz), 2.92 (t, 2H, J=6.95 Hz), 2.04-1.95 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].C(=O)(O)[O-].[Na+]>ClCCl>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])([O-:17])=[O:16]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of aniline (17 g, 180 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (100 mL) was added a solution of 3-nitrobenzoyl chloride (30 g, 160 mmol) in dichloromethane (60 mL). The mixture was stirred for 15 min at 0° C. then overnight at room temperature. It was then poured into saturated sodium bicarbonate (1 L) and stirred vigorously for 15 min. The precipitate was collected, washed with water and dried (40 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([CH:12]=O)[CH2:9]2)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:12]/[C:8]1[CH2:9][C:10]2[C:6]([C:7]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: CCCCCC1=C(C=O)Cc2cc(OC)ccc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCCC1=C(/C=C/C(=O)OC)Cc2cc(OC)ccc21
Yield: 61.2 %

Procedure:
As in Example 111, 6-methoxy-3-pentyl-1H-2-indenecarboxaldehyde (8.5 g) and (carbomethoxymethylene)triphenylphosphorane (18.8 g) in dichloromethane (75 mL) was stirred at room temperature for 42 hours. The crude reaction product from the normal work up was purified by HPLC (diethyl ether-hexane; 1:3) to provide 6.4 g of (E)-3-(6-methoxy-3-pentyl-1H-inden-2-yl)-2-propenoic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: CC(C)c1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 77° C. and MS: m/e=347 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-isopropyl-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C@H:27]([OH:32])[C@@H:28]([OH:31])[CH2:29][OH:30]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][CH2:26][C@H:27]([OH:32])[C@@H:28]([OH:31])[CH2:29][OH:30])=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC[C@H](O)[C@@H](O)CO
Product: COc1ccc(C(=O)NC[C@H](O)[C@@H](O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (2S,3S)-4-amino-1,2,3-butantriol (CAS registry number: 168113-19-7) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:28])[CH:6]([S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16]O)=[CH:10][CH:9]=1.[CH3:31][S:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:37]=1)(=[O:34])=[O:33]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][S:18][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][O:44][C:43](=[O:45])[CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:41][CH:40]=3)=[CH:12][CH:13]=2)[C:5]([OH:28])=[O:4])=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCCO)cc1)SCCc1ccc(F)cc1
Product: CS(=O)(=O)Oc1ccc(CC(=O)OCCCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-[4-(3-hydroxy-propyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (45 mg, 0.091 mmol) and (4-methanesulfonyloxy-phenyl)-acetic acid (19 mg, 0.083 mmol) in the same manner as described for example 1. The crude product was purified by HPLC (yield: 3.0 mg, 4.2%). 1H NMR (400 MHz, CDCl3): δ 7.30-7.32 (d, 2H), 7.21-7.23 (d, 2H), 7.05-7.08 (m, 4H), 6.98-7.00 (d, 2H), 6.90-6.94 (t, 2H), 4.04-4.07 (t, 2H), 3.63 (m, 2H), 3.46 (m, 2H), 3.08 (s, 3H), 2.79-2.90 (m, 5H), 2.54-2.58 (t, 2H), 1.87-1.90 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(O)=O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:23])[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cc2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 3 h
Yield: 192.3 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 3-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]azetidine-1-carboxylate (325 mg, 1.07 mmol) in DMF (5 mL) and AcOH (1 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (153 mg, 0.54 mmol) in 3 portions over 10 min. The mixture was stirred at −20° C. for 3 h. Aqueous K2CO3 (5%, 20 mL) was added and the mixture was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide 397 mg (97%) of the desired product, which contained minor impurities. ES-MS m/z 382.08 [M+H]+, HPLC RT (min) 3.05.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(F)cc2)CC1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccc(F)cc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(4-fluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.23 g, 0.93 mmol) and hydrazine hydrate (0.046 g, 0.91 mmol) was heated at 120° C. for 3.5 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.22 g, 96%) as white solid, which was used in the next step without further purification. MS m/e: 253 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@H:4]([OH:11])[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]=1[CH3:8].[H-].[Na+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.O>COCCOC>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:11][C@@H:4]1[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC1=C(C)C(C)(C)C[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1=C(C)C(C)(C)C[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
2 g (13 mmol) of (1S)-3,4,5,5-tetramethyl-3-cyclohexen-1-ol prepared in Examples 2A and 2B were dissolved in 10 ml of DME and added dropwise to a suspension of 965 mg (38.9 mmol) of NaH in 10 ml of DME at RT. After evolution of gas had ceased, 14 mmol of 2-bromomethylnaphthalene were added dropwise. Reaction was complete after stirring at RT for 12 h. 50 ml of water were added to the mixture, which was then extracted twice with 50 ml of ether. Chromatography of the residue as in Example 3A resulted in 3.7 g (97%) of the abovementioned product.