Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:35][CH:36]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:51][CH:50]=1)[C@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>C(Cl)Cl>[CH2:56]([O:55][C:52]1[CH:53]=[CH:54][C:49]([C@@H:36]([NH:35][C:8](=[O:10])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:11])[C@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[CH:50][CH:51]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)c1ccc(OCc2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)N[C@H](c1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
(S)-2-Phenylpropanoic acid (107 mg, 0.713 mmol), EDC (137 mg, 0.713 mmol), HOBt (109 mg, 0.713 mmol), and Hunig's base (249 μL, 1.426 mmol) in DCM (6480 μL) were stirred at room temperature for 10 min. (2R)-tert-Butyl 2-(amino(4-(benzyloxy)phenyl)methyl)pyrrolidine-1-carboxylate (248 mg, 0.648 mmol) was added and the solution stirred at room temperature for 4 h. The reaction was quenched with 10% aqueous citric acid and extracted with DCM (3×). The combined organic layers were washed with 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10%→60% ethyl acetate in hexanes). Two diastereomers were obtained. (R)-tert-Butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (78 mg, 0.114 mmol, 17.54% yield) was obtained as a colorless oil (peak 1). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=6.29 Hz, 1H), 7.33-7.43 (m, 6 H), 7.11-7.23 (m, 4H), 7.06 (d, J=8.56 Hz, 2H), 6.82 (d, J=8.56 Hz, 2H), 4.99 (s, 2H), 4.50 (dd, J=10.83, 6.04 Hz, 1H), 4.01-4.11 (m, 1H), 3.28-3.49 (m, 3H), 1.76-2.07 (m, 2H), 1.53-1.68 (m, 2H), 1.50 (s, 9H), 1.40 (d, J=7.05 Hz, 3H); LRMS (ESI) m/e 515.40 [(M+H)+, calcd for C32H39N2O4 515.29]; m/e 513.60 [(M−H)−, calcd for C32H32N2O4 513.28]. (R)-tert-Butyl 2-((S)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (122 mg, 0.183 mmol, 28.2% yield) was obtained as a colorless oil (peak 2). 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=6.30 Hz, 1H), 7.23-7.44 (m, 10H), 7.02 (d, J=8.56 Hz, 2H), 6.84 (d, J=8.56 Hz, 2H), 5.01 (s, 2H), 4.68-4.76 (m, 1H), 4.02-4.09 (m, 1H), 3.54 (q, J=7.13 Hz, 1H), 3.09-3.22 (m, 1H), 2.41-2.54 (m, 1H), 1.94-2.07 (m, 1H), 1.64-1.74 (m, 1H), 1.49 (d, J=7.05 Hz, 3H), 1.47 (s, 9H), 1.30-1.40 (m, 2H); LRMS (ESI) m/e 515.30 [(M+H)+, calcd for C32H39N2O4 515.29]; m/e 513.50 [(M−H)−, calcd for C32H32N2O4 513.28].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[CH2:16][C:15](=[N:17]C(OC)=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])C.[OH-:23].[Na+].Cl>O>[CH2:12]([N:10]1[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7](=[O:22])[C:8]2[CH2:16][C:15](=[N:17][O:23][CH2:6][C:4]([OH:5])=[O:3])[S:14][C:9]1=2)[CH3:13]
Reactant: [OH-]
Reactant: CCOC(=O)c1cn(CC)c2c(c1=O)CC(=NC(=O)OC)S2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c1SC(=NOCC(=O)O)C2
Reaction time: 3 h
Yield: 40 %

Procedure:
To the solution obtained in Example V containing 4,7-dihydro-7-ethyl-2-carbomethoxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was added 0.15 g (3.7 mmols) of sodium hydroxide in 5 ml of water. The medium was maintained under stirring for 3 hours at room-temperature. The precipitate formed was filtered out, washed with ethanol and then with ethyl ether. The product so obtained was then taken up in 20 ml of water and the solution was acidified with concentrated hydrochloric acid. The precipitate so formed was filtered out, washed with water and then with ethanol. After drying, 4,7-dihydro-7-ethyl-2-carboxymethoxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid was obtained in a yield of 40%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[N:30]1.C1(B(O)O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:33]3[N:29]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][O:23]4)[N:30]=[CH:31][CH:32]=3)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: OB(O)c1ccccc1
Product: FC(F)(F)c1nc2c(c(-c3ccnn3C3CCCCO3)n1)CCN(Cc1ccccc1)C2

Procedure:
The title compound was prepared in a manner analogous to Intermediate 12 substituting 7-benzyl-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine for Intermediate 11 and 1-(tetrahydropyran-2-yl)-1 h-pyrazole-5-boronic acid pinacol ester for phenylboronic acid. MS (ESI): mass calcd. for C23H24F3N5O, 443.2. m/z found, 444.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10][CH3:11].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=O.[C:50]([O:53][CH2:54]C)(=[O:52])C>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CO>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:50]([O:53][CH3:54])=[O:52])=[C:3]([CH2:9][O:10][CH3:11])[CH:4]=1
Reactant: COCc1cc(F)ccc1Br
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: COCc1cc(F)ccc1C(=O)OC
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Under an argon atmosphere, to a solution of 3.45 g of 1-bromo-4-fluoro-2-(methoxymethyl)benzene in 20 mL of dimethylsulfoxide were added 353 mg of palladium acetate, 650 mg of 1,3-bis(diphenylphosphino)propane, 4.4 mL of triethylamine, and 10 mL of methanol in this order, and the atmosphere in the reaction container were replaced with carbon monoxide, followed by stirring at 70° C. for 6 hours. The reaction mixture was poured into a mixed liquid of water and ethyl acetate. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 1.75 g of methyl 4-fluoro-2-(methoxymethyl)benzoate.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[NH:41]1[CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[N:41]1([CH:27]2[CH2:28][CH2:29][N:23]3[N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:12]5[CH:13]=[C:9]([Cl:8])[N:10]=[CH:11]5)=[C:15]([O:39][CH3:40])[CH:16]=4)[N:38]=[C:24]3[CH:25]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:26]2)[CH2:44][CH2:43][CH2:42]1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC(N2CCC2)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (50 mg, 0.107 mmol, from example 137) was added to a mixture of azetidine (6.11 mg, 0.107 mmol), and sodium cyanoborohydride (1.0M in THF, 428 μL, 0.428 mmol) in ethanol (0.535 mL). The mixture was stirred at rt for 16 h and then concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (18.7 mg, 27% yield) as a TFA salt. LC-MS (M+H)+ 508.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.63 (1 H, d, J=3.7 Hz), 7.89-7.98 (1 H, m), 7.31-7.38 (1 H, m), 7.07-7.22 (5 H, m), 7.01 (2 H, dd, J=8.5, 4.9 Hz), 4.92 (2 H, d, J=4.6 Hz), 4.64-4.77 (1 H, m), 4.42 (2 H, br. s.), 3.98-4.10 (1 H, m), 3.66-3.97 (5 H, m), 2.58-2.90 (2 H, m), 2.14-2.44 (4 H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[NH:3][C:4]([C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[O:26])=[CH:18][C:17]=2[F:37])[CH:7]=1)=[O:5].N[C:40]1C=CC(OC2C=CN=C3C=C(C(N(C)N(C)C)=O)SC=23)=C(F)C=1>>[F:37][C:17]1[CH:18]=[C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[O:26])[CH:20]=[CH:21][C:16]=1[O:15][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:7]=[C:6]([C:4]([N:3]([CH3:40])[N:2]([CH3:1])[CH3:38])=[O:5])[S:14][C:13]=12
Reactant: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)NN(C)C)sc23)c(F)c1
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N(C)N(C)C)sc23)c(F)c1
Yield: 43 %

Procedure:
Following the procedure described above for compound 236 (step 4, example 95, scheme 63) but replacing amine 239 with 7-(4-amino-2-fluorophenoxy)-N,N′,N′-trimethylthieno[3,2-b]pyridine-2-carbohydrazide (244), title compound 241 was obtained in 43% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.79 (d, J=13.3 Hz, 1H), 7.67 (s, 1H), 7.62-7.31 (m, 7H), 6.62 (d, J=5.4 Hz, 1H), 3.40 (s, 9H), 3.23 (s, 2H), 3.21 (s, 3H). MS (m/z): (M+1) 536.2 (100%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][OH:20])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][O:20][C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)(C)CN(CCCOc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (ESI) m/z 409 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(#N)C>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:11][CH2:12]1
Reactant: N#Cc1cccc(F)c1
Reactant: C1COCCN1
Solvent: CC#N
Product: N#Cc1cccc(N2CCOCC2)c1
Temperature: 110 °C
Reaction time: 72 h
Yield: 26.6 %

Procedure:
3-Fluorobenzonitrile (4.35 g, 36.0 mmol) was dissolved in acetonitrile (40 ml), and morpholine (110 ml, 1.25 mol) was added thereto followed by stirring at 110° C. for 3 days and nights. The reaction mixture was concentrated to give oily substances which were then purified by silica gel chromatography (eluent: chloroform) to give the title compound (1.80 g, 27%) as oily substances.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2.[C-:14]#[N:15].[Na+].O.CCOCC>CS(C)=O>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: Cc1ccc2cccc(CBr)c2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2cccc(CC#N)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 8-(bromomethyl)-2-methylquinoline (1.50 g, 6.35 mmol) in DMSO (20 mL) was added NaCN (0.62 g, 12.7 mmol). The mixture was stirred at ambient temperature for 10 minutes. Water (100 mL) and ether (100 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give 2-(2-methylquinolin-8-yl)acetonitrile (0.75 g, 58.3%) as a solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f38) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18].O>C(O)CCC>[N+:12]([O-:15])([OH:14])=[O:13].[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][C:17]([NH2:18])=[NH:16]
Reactant: N#CN
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: CCCCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Temperature: 0 °C

Procedure:
To 2-amino-4-nitro toluene 1 (0.033 mol) in n-butanol (29 mL) is added nitric acid (2.1 g, 65% in water) followed by cyanamide solution in water (2 mL, 0.047 mmol). The resulting mixture is heated at reflux for 25 h. After cooling to 0° C., filtration and washing with 1:1=ethanol:diethyl ether (30 mL), 2-methyl-5-nitrophenyl guanidine nitrate 2 is obtained. To 2-methyl-5-nitrophenyl guanidine 2 (0.0074 mol) in isopropanol (15 ME) is added 3 (0.0074 mol) and sodium hydroxide flakes (0.008 mol). The resulting mixture is heated at reflux for 12 h. After cooling to 0° C., the product is collected by filtration and washed with isopropanol (6 mL) and methanol (3 mL) to afford 4. 1H NMR (400 MHz, d6-DMSO) δ 9.31 (s, 1H), 9.24 (s, 1H), 8.78 (m, 1H), 8.70 (m, 1H), 8.61 (m, 1H), 8.47 (m, 1H), 7.88 (m, 1H), 7.55 (m, 3H), 2.39 (s, 3H). MS (m/z) (M+1)+: 278.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:13][CH2:14]O>C(Cl)(Cl)(Cl)Cl.[Cl-].C[N+](C)(C)CC1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[C:6]([C:13]2[CH:14]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:7]#[N:8])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#CCc1ccc(F)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(=C(C#N)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-fluorobenzyl cyanide (30 g; 0.222 mol.) in carbon tetrachloride (100 ml) was added slowly, over a period of 30 minutes, to a rapidly stirring mixture of 40% aqueous sodium hydroxide (100 ml; 1 mol), carbon tetrachloride (100 ml) and trimethylbenzylammonium chloride (TMBA; 0.6 g; 0.003 mol). The mixture was maintained at room temperature overnight, after which time a precipitate had formed which was collected by filtration and washed with water and chloroform. The organic layer of the mother liquor was washed successively with dilute hydrochloric acid, 5% aqueous sodium bicarbonate and water and then dried over magnesium sulphate. The dried solution was filtered and then evaporated to a paste which was triturated with ethanol to give a second crop of product, which was combined with the first. The material was recrystalised form ethanol to yield small white needles. Yield=50%.: m.p. 194°-195° (EtOH); 1H NMR (200 MHz, CDCl3) d 7.17-7.29 (m, 4H), 7.78-7.89 (m, 4H); 13C NMR (50 MHz, DMSO-d6) d 116.74 (d, |J|=22.4 Hz), 116.76 (s), 124.81 (s), 128.59 (d, |J|=3.4Hz), 131.73 (d, |J|=9.1 Hz), 163.87 (d, |J|=250.6 Hz); MS (El) m/e 266 (100, M+·); Analysis calc'd for C16H8N2F2: C, 72.17; H, 3.03; N, 10.52; found: C, 71.98; H, 2.80; N, 10.48.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][C@H:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@@H]2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: C[C@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (S)-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.32 g, 1.02 mmol), cyclohexene (0.26 mL, 2.54 mmol), and 1.0 M boron tribromide in dichloromethane (6.1 mL, 6.1 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by column chromatography on silica gel, eluting with dichloromethane, to yield 4-{[(S)-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.25 g, 0.72 mmol, 71%) as a white, solid, single enantiomer, m.p. 176-178° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[CH:15]=[C:14]([CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[NH2:16]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Yield: 65.2 %

Procedure:
A mixture of 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (26.5 g, 0.10 mol, 1.00 equiv), iron powder (25.2 g, 0.43 mol, 4.28 equiv) and ammonium chloride (72.24 g, 1.35 mol, 13.5 equiv) in ethanol (600 ml) was stirred mechanically under refluxed for 2 hours. The reaction was allowed to cool down; the mixture of the reaction was filtered and the filtrate was taken to dryness in vacuum. The resulted solid was dissolved in methylene chloride (500 ml) and filtered. Removal of the solvent from the filtrate in vacuum gave 15.3 g of the product. MS (ESI) m/z: 235 (M+1).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].CCC[CH2-].[F:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12](OC)=[O:13].Cl>O1CCCC1>[F:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12](=[O:13])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1F
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC#N)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 4.4 g (108.6 mmol, 5.7 ml) of acetonitrile diluted in 50 ml of anhydrous tetrahydrofuran are added dropwise at −78° C. under argon 27.1 ml of a N-butyllithium solution (2.5M in hexane, 67.8 mmol), the reaction mixture is stirred 30 min at −78° C., then 5 g (27.15 mmol) of methyl 2-fluoro-4-methoxybenzoate diluted in 30 ml of tetrahydrofuran are added dropwise at −78° C. to the reaction mixture. This mixture is stirred 2 h at −78° C., then a 1M hydrochloric acid solution is added, and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The solid is triturated in 15 ml of methanol to yield 4.4 g (84%) of 3-(2-fluoro-4-methoxyphenyl)-3-oxopropanenitrile in beige solid form.
Reaction SMILES: Cl.O.FC(F)(F)C(O)=O.[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[N:21](C3CCCCO3)[CH:20]=[N:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[C:28]1[N:33]=[C:32]2[NH:34][C:35]3([CH2:40][CH2:39]3)[C:36](=[O:38])[NH:37][C:31]2=[N:30][CH:29]=1>C(O)C>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[NH:21][CH:20]=[N:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[C:28]1[N:33]=[C:32]2[NH:34][C:35]3([CH2:39][CH2:40]3)[C:36](=[O:38])[NH:37][C:31]2=[N:30][CH:29]=1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Temperature: 80 °C
Yield: 38.5 %

Procedure:
6 N Hydrochloric acid in water (0.171 mL, 1.025 mmol) was added to a stirred mixture of 7′-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one trifluoroacetate (0.109 g, 0.205 mmol) in ethanol (4 mL) at 80° C. The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 30 min. The resulting mixture was filtered and purified using reverse-phase preparatory HPLC (10-60% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and most of the solvent removed under reduced pressure. Solids were collected by vacuum filtration, washed thoroughly with water and dried under high vacuum at 45° C. to give the desired product (0.027 g, 0.079 mmol, 39% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.22 (br. s., 1H), 8.63 (br. s., 1H), 7.93 (s, 1H), 7.89 (d, J=7.81 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.47 (br. s., 1H), 2.43 (s, 3H), 1.29-1.38 (m, 2H), 0.95-1.04 (m, 2H); MS (ESI) m/z 334.2 [M+1]+.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([CH3:19])[CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=2[O:4][C:3]1=[O:20].S(Cl)(Cl)=O.Cl>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:19][C:8]1[CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:5]2[O:4][C:3](=[O:20])[C:2](=[C:2]3[C:6]4[CH:7]=[C:8]([CH3:19])[CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:5]=4[O:4][C:3]3=[O:20])[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(c(C(C)(C)CC(C)(C)C)c1)OC(=O)C2O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(c(C(C)(C)CC(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C)cc2C(C)(C)CC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
7.1 g of 3-hydroxy-5-methyl-7-(1,1,3,3-tetramethylbutyl)-3H-benzofuran-2-one (U.S. Pat. No. 5,614,572, Column 35, Compound No. 111) are introduced into 12.5 ml of toluene as initial charge and admixed with 3 drops of DMF and 2.7 ml of thionyl chloride. The solution is then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively but still controllable. Thereafter the reaction mixture is stirred at 100° C. for a further 1 h. About 12 ml of liquid are subsequently distilled off to remove excess thionyl chloride. The residue is diluted with 37.5 ml of toluene and admixed at room temperature with 3.5 ml of triethylamine added dropwise. The thick red reaction mixture is then refluxed for 30 min. The precipitated triethylamine hydrochloride is filtered off after cooling to room temperature and the filtrate is concentrated in a rotary evaporator to an oily consistency. The isoxindigo is crystallized out by addition of 25 ml of acetonitrile, filtered off, washed with acetonitrile and dried to leave 3.45 g (53% of theory) of 5,5′-dimethyl-7,7′-bis(1,1,3,3-tetramethylbutyl)[3,3′]bibenzofuranylidene-2,2′-dione of the formula