Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:21][C:22]([OH:24])=O.[NH2:25][C:26]1[N:31]=[CH:30][C:29]2[CH2:32][C:33]3([CH2:43][C:28]=2[CH:27]=1)[C:41]1[C:36](=[N:37][CH:38]=[CH:39][CH:40]=1)[NH:35][C:34]3=[O:42].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:42]=[C:34]1[NH:35][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:41]2[C:33]21[CH2:32][C:29]1[CH:30]=[N:31][C:26]([NH:25][C:22](=[O:24])[CH2:21][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:18])([F:19])[F:20])[CH2:12][CH2:11]4)[C:2]3=[O:1])=[CH:27][C:28]=1[CH2:43]2
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetic acid (79 mg, 0.23 mmol, described in Intermediate 11), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:7]([OH:11])=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:7](=[CH:8][C:9]=1[CH3:10])[O:11][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Cc1cc(O)c(C=O)c(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(cc(C)c(Cl)c2C)OC1C(F)(F)F
Temperature: 65 °C
Yield: 110.2 %

Procedure:
To a solution of 3-chloro-6-hydroxy-2,4-dimethylbenzaldehyde (6.9 g, 37.4 mmol) in 80 mL of DMF was added dried finely powdered K2CO3 (11.36 g, 82.2 mmol). With mechanical stirring, the reaction was heated to 65° C. To the suspension was added dropwise ethyl trifluorocrotonate (7.54 g, 44.9 mmol). The stirring reaction was heated at 90° C. for 1.5 h. K2CO3 was filtered from the cooled reaction. From the reaction under vacuum, DMF was removed. The resulting residue was dissolved in 400 mL EtOAc. The organic solution was washed with 100 mL 1 M KHSO4, 70 mL of satd. KHCO3, 100 mL brine, followed by drying over MgSO4, and concentrating under vacuum. The crude desired product (13.8 g) of was isolated. After employing flash chromatography conditions, pure compound (9.8 g, 78%) of was isolated and its structure confirmed by NMR and LC-MS.
Reaction SMILES: [O-:1][CH2:2][CH2:3][CH3:4].[Na+].Cl[C:7]1[N:16]([CH2:17][CH2:18][CH3:19])[C:15](=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=2)[N:8]=1>O>[I:21][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:1][CH2:2][CH2:3][CH3:4])[N:16]([CH2:17][CH2:18][CH3:19])[C:15]2=[O:20]
Reactant: CCCn1c(Cl)nc2ccc(I)cc2c1=O
Reactant: CCC[O-]
Agent: [Na+]
Solvent: O
Product: CCCOc1nc2ccc(I)cc2c(=O)n1CCC
Temperature: 1 °C
Reaction time: 2.5 h

Procedure:
A portion of the sodium propoxide solution prepared above (87 g) was cooled to 1° C. and treated dropwise with the solution of 2-chloro-6-iodo-3-n-propyl-4(3H)-quinazolinone prepared in Step 2B above. The temperature was maintained at or below 0° C. and the addition took 2.5 h. After stirring at 0° C. for an additional 1.5 h, the reaction mixture was poured into 250 mL water. The phases were separated and the organic phase was washed two times each with 250 mL water. The organic phase was then evaporated under reduced pressure to give 53.4 g of a light yellow oil which solidified upon standing to a white solid. mp 60-62° C.; 1H NMR (CDCl3): δ8.49 (d,1H), 7.87 (dd,1H), 7.19 (d,1H), 4.43 (t,2H), 4.05 (m,2H), 1.85 (m,2H), 1.70 (m,2H), 1.05 (t,3H), 0.96 (t,3H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32](Cl)=[O:33].N1C(C)=CC=CC=1C>ClCCl.CCOCC>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:7])=[CH:26][CH:25]=1)=[O:33]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Product: O=C(Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1)c1c(Cl)cccc1Cl
Reaction time: 4 h
Yield: 48.5 %

Procedure:
4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (67 mg, 0.176 mmol) and 2,6-dichlorobenzoyl chloride (50 mg, 0.23 mmol) were dissolved in 5 mL of dichloromethane and 2,6-lutidine (50 μL, 0.43 mmol) were added. After 4 hours, the mixture was diluted with ether and dichloromethane and washed with 1 N HCl, water, and saturated NAHCO3 and was dried (MgSO4). The crude product was dissolved in 4 mL of methanol and treated with 4 N NaOH (0.1 mL). After 2 hours, the excess base was quenched with 0.1 mL of acetic acid, the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 30 min. The peak eluting at 87% acetonitrile was concentrated and lyophilized to give 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine (46 mg), LR(+)LSIMS: m/z 539 (M+H) (2 Cl).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([C:37]3[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cccc2c(-c3cccc(Br)c3)c(Cc3ccccc3)cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)CCc1ccc(-c2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Yield: 67 %

Procedure:
To a solution of 3-benzyl-4-(3-bromophenyl)-8-(trifluoromethyl)quinoline (0.30 g, 0.7 mmol), 4-(2-carboxyethyl) benzene boronic acid (0.15 g, 0.75 mmol) in 15 ml DME under a nitrogen atmosphere is added terakistriphenyl phosphine palladium (0.08 g, 0.07 mmol) followed by sodium carbonate (0.22 g, 2.04 mmol) dissolved in 5 ml water. The reaction mixture was heated to reflux for 12 hr. The reaction was cooled, poured into 1N HCl and extracted with EtOAc. The organic layer was dried and concentrated to provide the title compound as a tan solid (0.24 g, 70%): MS (ES) m/z 509.9; HRMS: calcd for C32H24F3NO2+H+, 512.18319; found (ESI, [M+H]+), 512.1842;
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)COCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
(2S)-1-(Benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylpropan-2-amine (3.02 g, 5.62 mmol) was dissolved in 60 mL of anhydrous CH2Cl2 and 9.1 mL of glacial acetic acid. The reaction mixture was cooled to 0° C. under an atmosphere of N2 and boron trifluoride diethyl etherate (0.75 mL, 5.92 mmol) was added dropwise over several minutes. After stirring for 5 hours, the reaction mixture was treated with 85 mL of cold, aqueous 10% NaOH solution. The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×20 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-5% methanol/CHCl3) gave 1.57 g of (2S)-1-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-amine as a white solid.
Reaction SMILES: [OH:1][N:2]=[CH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CN(C=O)C.[Cl:22]N1C(=O)CCC1=O>[Cl-].[Na+].O>[Cl:22][C:3](=[N:2][OH:1])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C=NO)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(Cl)=NO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A 250 mL flask was charged with tert-butyl 4-((hydroxyimino)methyl)piperidine-1-carboxylate (2.0 g, 8.8 mmol) and DMF (100 mL). 1-chloropyrrolidine-2,5-dione (1.2 g, 8.8 mmol) was added and stirred at ambient temperature overnight. The reaction was poured into 1:1 brine:water and extracted with EtOAc. The organic layer was washed twice with water, dried over sodium sulfate, filtered and concentrated to afford tert-butyl 4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (2.3 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5]2.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:31][C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([C@H:44]3[CH2:46][C@H:45]3[CH2:47][CH:48]=O)[CH2:40][CH2:39]2)=[N:36][CH:37]=1>ClCCCl.CCOC(C)=O>[Cl:31][C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([C@H:44]3[CH2:46][C@H:45]3[CH2:47][CH2:48][NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([F:11])[CH:10]=3)[NH:7][C:6](=[O:12])[CH2:5]4)[CH2:40][CH2:39]2)=[N:36][CH:37]=1
Reactant: O=CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C1Cc2cc(NCC[C@@H]3C[C@@H]3C3CCN(c4ncc(Cl)cn4)CC3)cc(F)c2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-amino-7-fluoro-1,3-dihydro-2H-indol-2-one from step 2 of this example (33 mg, 0.20 mmol) was slurried in DCE (0.9 ml) and acetic acid (51 uL, 0.89 mmol) and NaBH(OAc)3 (76 mg, 0.36 mmol) added. {(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}acetaldehyde (50 mg, 0.18 mmol) from Example 3 was added and the mixture stirred at RT for 2 hours. The mixture was diluted with EtOAc (30 ml), and partitioned across 4:1 water:saturated sodium bicarbonate (50 ml). The layers were separated, the aqueous phase extracted with EtOAc (2×30 ml), the organic fractions combined, dried over Na2SO4, filtered, and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 40% acetone:hexanes. This was followed by a second purification using chromatography on SiO2 eluting with 30% acetone:hexanes to give the titled compound. LRMS calc: 429.17; obs: 430.19 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.Br[C:24]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>>[F:33][C:30]1[CH:31]=[CH:32][C:24]([NH:1][C:4]2[C:5]3[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]4[O:20][C:16]([CH3:15])=[CH:17][CH:18]=4)=[N:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[C:25]2[C:29]=1[NH:28][CH:27]=[CH:26]2
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Fc1ccc(Br)c2cc[nH]c12
Product: Cc1ccc(CNc2ccc3c(Nc4ccc(F)c5[nH]ccc45)cccc3n2)o1

Procedure:
The title compound, MS: m/e=387.1 (M+H+), was prepared in accordance with the general method of example 38 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-bromo-7-fluoroindole.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][NH2:12])[CH2:2]1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH2:2]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCC1COc2ccccc2C1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCC3COc4ccccc4C3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using chroman-3-ylmethanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 545 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:32]#[N:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]4=[O:30])=[CH:16][C:15]=3[F:31])[CH2:10][CH2:9]2)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:32]#[N:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:43])[CH3:28])[O:22][C:21]4=[O:30])=[CH:16][C:15]=3[F:31])[CH2:10][CH2:9]2)[CH:2]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccnc4)CC3)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccnc4)CC3)c(F)c2)C(=O)O1
Yield: 58 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)-N-{3-[4-(4-(pyridin-3-ylamino)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 58% yield.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].N>CC(C)=O.O>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][C:8]2=[O:13])=[CH:6][CH:5]=1)([O-:21])=[O:20]
Reactant: O=C1COCCN1c1ccccc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 2-liter flask, 177 g (1.0 mol) of 4-phenyl-3-morpholinone (VIII) are introduced at internal temperature 10° C. in 4 portions into 728 g (7.4 equivalents) of concentrated sulphuric acid. The mixture is then heated to 25° C. and stirred at this temperature for 30 minutes. The solution is cooled to −5° C. and admixed within one hour with 101.8 g (1.05 equivalents) of 65% nitric acid. The mixture is stirred at −5° C. for one hour. 1300 ml of demineralized water are metered into this solution at 10° C. Subsequently, a pH of 7.4 is established, likewise at 10° C., with 25% aqueous ammonia solution. The suspension is admixed with 2000 g of acetone and heated to 40° C. In the course of this, the product goes into solution, so that the phases can be separated. 1500 g of acetone/water mixture are distilled off at standard pressure from the organic phase, in the course of which the product precipitates out. The suspension is cooled to 10° C. and stirred for a further 30 minutes, and the product is isolated. The moist product is washed with 320 g of cold acetone and dried at 50° C. under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C1([SH:18])C=CC=CC=1.N1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)C=CC=1>>[CH3:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[S:18])=[CH:3][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: Sc1ccccc1
Reactant: c1ccc2ncccc2c1
Product: Cc1ccc(C(O)=S)cc1-c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A 22 liter 3-necked round bottom flask, fitted with an overhead stirrer, thermometer, and a distillation head was placed in a heating mantle and charged with quinoline (6 liter), 3-bromo-4-methylbenzoic acid (2.75 kg, 12.79 mole), thiophenol (1.75 kg 15.22 mole) and cuprous oxide (958 g, 6.7 mole). The red slurry was placed under a nitrogen blanket and heated with stirring to 180°-200° C. over a 1 hour period collecting the water as it distills. This temperature was maintained for 0.5 hours. The mixture was cooled to 110° C. and then transferred to a stirred solution of 6N hydrochloric acid. After stirring overnight, the product was collected by suction filtration, washed with 6N hydrochloric acid (19 liters) and then with water until neutral (alk-acid paper). The filter cake was washed with isopropanol and dried at 40° C. in vacuo to yield the title compound as a tan solid (2.97 kg, 95% yield, 91% purity).
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[C:9]([O:13][C:14]([C@@:16]12[CH2:32][O:31][CH:30]=[C:17]1[C:18](=[O:29])[N:19]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:20]2)=[O:15])([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([O:13][C:14]([C:16]12[CH2:32][O:31][C@H:30]3[CH2:1][C:17]13[C:18](=[O:29])[N:19]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:20]2)=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC[Zn]CC
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)COC=C2C1=O
Solvent: ClCCl
Solvent: ICI
Product: C[C@H](c1ccccc1)N1CC2(C(=O)OC(C)(C)C)CO[C@H]3CC32C1=O
Reaction time: 0.25 h

Procedure:
To a solution of diethyl zinc (1M hexane solution, 22.3 ml) in dichloromethane (75 mL) was added dropwise diiodomethane (1.79 mL, 22.3 mmol) at −10° C., and the mixture was stirred for 15 min at the same temperature. A solution of (S)-6-oxo-5-[(R)-1-phenylethyl]-5,6-dihydro-4H-furo[3,4-c]pyrrole-3a-carboxylic acid tert-butyl ester in dichloromethane was added at −10° C., and the resulting mixture was stirred for 8 h at room temperature. The reaction mixture was quenched with 10% aq. citric acid. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% AcOEt in hexane to afford the title compound (1.96 g) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].N1CCCCC1>CCO.O>[CH3:11][C:10]1[NH:19][C:17](=[O:18])[C:16]([C:14]#[N:15])=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=1.[CH3:11][C:10]1[CH:9]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:19][C:17](=[O:18])[C:16]=1[C:14]#[N:15]
Reactant: CC(=O)CC(=O)Cc1ccccc1
Reactant: N#CCC(N)=O
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(Cc2ccccc2)[nH]c(=O)c1C#N
Product: Cc1cc(Cc2ccccc2)c(C#N)c(=O)[nH]1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 103.4 %

Procedure:
1-Phenyl-2,4-pentanedione (18.32 g, 104 mmol) and cyanoacetamide (8.74 g, 104 mmol) were dissolved in EtOH (104 mL) and heated until homogenous (ca. 75° C.). Piperidine (8.86 g, 104 mmol) was added and the reaction mixture heated at reflux for 15-30 min. followed by cooling to room temperature, during which time precipitation occurred. The heterogenous contents were filtered to give a solid which was suspended in 200 mL water and stirred vigorously for 20 min. The heterogenous mixture was filtered to afford 6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinecarbonitrile and 4-methyl-2-oxo-6-(phenylmethyl)-1,2-dihydro-3-pyridinecarbonitrile (12.06 g, 52%). LCMS MH+=225.1 1H NMR (400 MHz, DMSO-d6) (mixture of compounds) δ 7.21-7.31 (m, 10H), 6.06 (s, 2H), 3.89 (s, 2H), 3.79 (s, 2H), 2.24 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride (5.00 g, 15.46 mmol) in THF (5 ml) was added to a solution of morpholine (1.62 ml, 18.55 mmol) and triethylamine (2.15 ml, 15.46 mmol) in tetrahydrofurane. The reaction mixture was stirred for 12 h at RT. Ethyl acetate (80 ml) was added, the organic phase was separated and washed with water (20 ml), hydrochloric acid (1 M, 20 ml) and brine (20 ml) and dried over sodium sulphate. After evaporation the product was obtained (5.708 g, 99%) and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]([CH:14]([CH3:28])[CH2:15][C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH:24][CH3:25])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[ClH:31]>O1CCCC1>[OH2:9].[ClH:1].[ClH:31].[CH3:25][NH:24][CH2:22][CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:14]([N:12]2[CH2:11][CH2:10][O:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13]2)[CH3:28])=[CH:27][CH:26]=1.[CH3:25][NH:24][CH2:22][CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:14]([N:12]2[CH2:11][CH2:10][O:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13]2)[CH3:28])=[CH:27][CH:26]=1.[ClH:1].[ClH:1]
Reactant: CNC(=O)COc1ccc(CC(C)N2CCOC(c3cccc(Cl)c3)C2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNCCOc1ccc(CC(C)N2CCOC(c3cccc(Cl)c3)C2)cc1
Product: O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4[2-(2-[3-chlorophenyl]morpholino)propyl]phenoxy-N-methylacetamide (3.6 g) in dry tetrahydrofuran (80 ml) was added borane-methyl sulphide complex (10 ml) in dry tetrahydrofuran (20 ml), under nitrogen. The solution was boiled under reflux for 4 hours, and, after cooling to room temperature, methanol (30 ml) was added carefully. This solution was allowed to stand overnight at room temperature, hydrogen chloride gas passed through for 10 mins, boiled under reflux for one hour, cooled and evaporated to dryness. Aqueous sodium carbonate was added to the residue and extracted with dichloromethane (×2). The combined organic extracts were washed with brine (×2), dried over magnesium sulphate, filtered and evaporated to dryness. Ethereal hydrogen chloride was added to the residue and the resultant solid recrystallised from methanol-ethyl acetate to give the title compound, m.p. 145°-55° C.