Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(Cl)OC(Cl)(Cl)Cl.[Cl:9][CH2:10][C:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH3:25])[C:20]([OH:22])=O)[N:18]=1)=[O:12].[NH2:26][C@H:27]1[C@H:30]([S:31][CH3:32])[NH:29][C:28]1=[O:33].C1OC1C>C(Cl)Cl.C(N(CC)CC)C.CN(C=O)C>[Cl:9][CH2:10][C:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH3:25])[C:20]([NH:26][C@H:27]2[C@H:30]([S:31][CH3:32])[NH:29][C:28]2=[O:33])=[O:22])[N:18]=1)=[O:12]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CS[C@@H]1NC(=O)[C@H]1N
Agent: CC1CO1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1SC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.228 g of DMF in 5 ml of methylene chloride is added at -10° C. 0.137 ml of diphosgene. The mixture is then stirred for 30 minutes at room temperature, to which is added at a temperature of -70° C. 15 ml of methylene chloride solution containing 0.80 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid and 0.316 g of triethylamine. The mixture is stirred for two hours at -25° C., then cooled to -70° C., followed by addition of 0.632 g of triethyl amine, 0.69 g of tosyl salt of (3R,4S)-3-amino-4-methylthio-2-oxoazetidine and 2 ml of propylene oxide. The temperature of the mixture is raised up to 0° C. in the course of one hour, while stirring. The mixture is stirred for further two hours at the same temperature, then concentrated, followed by addition of THF and removal of the resulting insolubles by filtration. The filtrate is concentrated and the residue is purified on a silica-gel column (AcOEt:CHCl3 :CH3OH=3:3:1) to yield 0.461 g of (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18][CH:17]([CH2:25][O:26][CH3:27])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:27][O:26][CH2:25][CH:17]1[CH2:16][NH:15][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18]1
Reactant: COCC1CN(C(=O)OC(C)(C)C)c2ccccc2S1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC1CNc2ccccc2S1
Reaction time: 3 h

Procedure:
3 ml of a 25% trifluoroacetic acid solution in methylene chloride are added to 435 mg of 4-tert-butoxycarbonyl-2(R,S)-methoxymethyl-3,4-dihydro-2H1,4-benzothiazine at 0° C. and the mixture is stirred for 3 h. The reaction mixture is concentrated and the residue is chromatographed over 30 g of silica gel with a 99:1 mixture of methylene chloride and methanol, This gives the title compound: Rf (99:1 mixture of methylene chloride/methanol)=0.67.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[O:36])[CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1.I[CH3:38]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]([CH3:38])[C:13](=[O:36])[CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COC(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
NaH 80% in oil (0.0069 mol) was added portionwise to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzoxazepin-2(3H)-one (see Example B1) (0.0069 mol) in N,N-dimethylformamide (35 ml). The mixture was stirred at room temperature for 30 min. Iodomethane (0.0069 mol) was added. The mixture was stirred at room temperature for 30 min, hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 0.47 g (13%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-1-methyl-4,1-benzoxazepin-2(3H)-one, mp. 160° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:23])([F:22])[S:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:18]1[CH:19]=[N:20][C:15]([S:14][C:13]([F:23])([F:22])[F:12])=[CH:16][CH:17]=1)=[O:9]
Reactant: Nc1ccc(SC(F)(F)F)nc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloronicotinic acid and 6-(trifluoromethylthio)pyridin-3-amine to afford an off-white powder. HPLC (Condition 4) tR=6.43 min, UPLC-MS (Condition 3) tR=1.15 min, m/z=411.9 [M−H]−.
Reaction SMILES: CN1CCOCC1.[F:8][C:9]1[C:10]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)[CH2:37][CH2:36]3)=[CH:29][CH:28]=2)=[CH:11][C:12](=[O:26])[N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[CH:14]=1.ClC1N=C(OC)N=C(OC)N=1.[O:59]1[CH2:64][CH2:63][CH2:62][CH2:61][CH:60]1[O:65][NH2:66]>CC1CCCO1.O>[F:8][C:9]1[C:10]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)[CH2:37][CH2:36]3)=[CH:31][CH:32]=2)=[CH:11][C:12](=[O:26])[N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([NH:66][O:65][CH:60]2[CH2:61][CH2:62][CH2:63][CH2:64][O:59]2)=[O:19])[CH:14]=1
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)O)S(C)(=O)=O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methyl morpholine (340 uL, 3.09 mmol) was added to a suspension of (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (1.28 g, 2.21 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (510 mg, 2.87 mmol) in 2-methyltetrahydrofuran (30 mL) and the reaction was stirred for 1 h at rt. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (61 mg, 0.52 mmol) was added, and the reaction was stirred overnight at rt. Water (50 mL) was added, and the mixture was extracted with EtOAc (3×150 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (75-100%) to afford the title compound as a light brown residue (700 mg, 46%). MS (LCMS) m/z 677.4 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15](Cl)=[O:16].[N+](=[CH2:20])=[N-].[BrH:21]>CCOCC>[Br:21][CH2:20][C:15]([C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][O:8][C:4]=1[CH2:3][O:2][CH3:1])=[O:16]
Reactant: C=[N+]=[N-]
Reactant: COCc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: Br
Solvent: CCOCC
Product: COCc1onc(-c2ccccc2)c1C(=O)CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 5-methoxymethyl-3-phenyl-isoxazole-4-carboxylic acid chloride (11.16 g, 44 mmol) in dry ether (350 mL) was added diazomethane solution in ether (0.1 N, 100 mL) at iced-bath cooling temperature. The reaction was stirred for 2 h at 0° C. Aqueous solution of hydrobromic acid (>40 wt %, 100 mL) was then added dropwise to the reaction solution at iced-bath cooling temperature. After complete addition, the organic layer was separated, and the aqueous phase was extracted with ether. The combined ether solution was washed with water and brine, dried over magnesium sulphate and evaporated to afford the title compound (12.83 g, 94%) which was obtained as a light yellow liquid. MS: m/e=310.0/311.9 [M+H]+.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[CH3:9][NH:10][O:11][CH3:12].CN1CCOCC1.CN(C)CCCN=C=NCC.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH3:12][O:11][N:10]([CH3:9])[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCC(=O)N(C)OC
Yield: 84.8 %

Procedure:
Part A: To a magnetically stirred solution of valeric acid (10.9 ml, 0.1 mol) in dichloromethane (200 ml) was successively added: N-methyl-N-methoxy-amine.hydrochloride (10.14 gram, 0.104 mol), N-methylmorpholine (22.9 ml, 0.208 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDCI) (19.92 gram, 0.104 mol) and HOBt (14.04 gram, 0.104 mol) and the resulting mixture was reacted for 20 hours at room temperature. The obtained suspension was successively washed with water, aqueous citric acid (a solution of 24 gram citric acid in 250 ml H2O) and 5% aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to give pentanoic acid methoxy-methyl-amide (12.31 gram, 85% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 0.93 (t, J=7, 3H), 1.31-1.43 (m, 2H), 1.57-1.66 (m, 2H), 2.42 (br t, J=7, 2H), 3.18 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:10]=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:21]=[CH:20]3)[CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C)c1-c1cccc(COc2ccc3[nH]ccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ccc2cc(OCc3cccc(-c4c(C)cccc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
5-[(2′,6′-Dimethylbiphenyl-3-yl)methoxy]-1H-indole (0.95 g, 2.90 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and N,N-dimethylformamide (4 mL). The solution was ice-cooled, and sodium hydride (60% in oil, 0.12 g, 3.0 mmol) was added, and the mixture was stirred at the same temperature for 20 min. Then, ethyl bromoacetate (0.36 mL, 3.25 mmol) was added to the solution, and the mixture was allowed to warm to room temperature and stirred for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.0 g, yield 83%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:13][NH:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:13])[CH2:15][CH:16]=[O:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNCCO
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC=O)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
4-Cyanobenzenesulfonyl chloride (6 g, 0.0297 mol) in 50 ml of dry DCM was added at 0° C. to a solution of N-methylethanolamine (2.67 g, 0.0356 mol) and triethylamine (7.49 g, 0.0742 mol) in dry dichloromethane (75 ml) under nitrogen atmosphere and stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with dichloromethane. Organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded crude product as solid. This solid was then washed with petroleum ether (three times) and dried under vacuum to give the sub-title compound (5.18 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[C:34]([Cl:40])=[N:35][C:36](Cl)=[CH:37][CH:38]=1)=[O:32].C1N2CCN(CC2)C1>>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][C:34]=1[Cl:40]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: C1CN2CCN1CC2
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1Cl

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl-2,6-dichloro-pyridine-3-carboxylate and DABCO (21 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.2 [M+H+].
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br[CH2:12][CH2:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:12][CH2:13][O:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(OCCBr)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
A heterogeneous mixture of 2-mercapto-5-nitropyridine (4) (46 mg, 0.29 mmol), 2-bromoethyl-3-chlorobenzoate (3) (77 mg, 0.29 mmol), and K2CO3 (0.160 g, 1.1 mmol) in acetone (1 mL) was stirred at 55° C. for 5 h. The cooled reaction mixture was filtered through Celite®, concentrated, and then purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)thio]ethyl-3-chlorobenzoate (5) as a white solid. 1H NMR (CDCl3): δ 9.22 (d, J=1.8 Hz, 1H), 8.24 (dd, J=2.4 and 9.0 Hz, 1H), 7.95-7.91 (m, 1H), 7.90 (t, J=0.9 Hz, 1H), 7.56-7.51 (m, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 4.61 (t, J=6.6 Hz, 2H), 3.68 (t, J=6.6 Hz, 2H)
Reaction SMILES: [F:1][C:2]1([CH2:9][OH:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[OH-].[NH4+:12].[NH4+:13].[Cl-].[C-:15]#N.[Na+]>CO>[NH2:12][C:5]1([C:15]#[N:13])[CH2:6][CH2:7][C:2]([F:1])([CH2:9][OH:10])[CH2:3][CH2:4]1
Reactant: [NH4+]
Reactant: O=C1CCC(F)(CO)CC1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(N)CCC(F)(CO)CC1
Reaction time: 8 h
Yield: 86 %

Procedure:
A flask was charged with 4-fluoro-4-(hydroxymethyl)cyclohexanone, derived from Intermediate 31, (12.1 g, 83 mmol), methanol (200 mL), aqueous ammonium hydroxide (32.2 mL, 828 mmol) and then NH4Cl (8.86 g, 166 mmol). After the ammonium chloride had dissolved, NaCN (8.11 g, 166 mmol) was added. The reaction was stirred under nitrogen overnight. The mixture was then concentrated. Brine (100 mL) was added to the resulting residue. The slurry was extracted with chloroform/isopropanol (200 mL, 10%, 7 times) and the combined organic fractions dried (MgSO4) and evaporated giving the title compound (12.2 g, 70.8 mmol, 86% yield)] as a creamy white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:14][C:13]([CH3:28])([CH3:27])[C:12]=3[N:11]=[C:10]([CH:29]([CH3:31])[CH3:30])[C:9]=2[CH:32]=[O:33])=[CH:4][CH:3]=1.C[Si]([C:38]#[N:39])(C)C.CO.Cl>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:38]([CH:32]([OH:33])[C:9]1[C:10]([CH:29]([CH3:30])[CH3:31])=[N:11][C:12]2[C:13]([CH3:28])([CH3:27])[CH2:14][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])[CH2:16][C:17]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:39]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(O)C#N)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl 4-(4-fluorophenyl)-3-formyl-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 1) (4.28 g, 9.09 mmol), trimethylsilyl cyanide (1.46 ml, 10.91 mmol) and zinc iodide (0.145 g, 0.455 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 2.5 h. MeOH (100 mL) was added and the reaction stirred 22 h at room temperature. Additional trimethylsilyl cyanide (2 mL) was added and stirring continued at room temperature for 24 h. 1M HCl (10 mL) was added and stirring continued for 24 h. The reaction mixture was concentrated and the residue taken up in Et2O (200 mL), washed with satd NaHCO3 (50 mL), water (25 mL), brine (25 mL), dried (Na2SO4), filtered and solvent removed to give 2-(trimethylsilyl)ethyl 3-(cyano(hydroxy)methyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (4.16 g) as a tan powder contaminated with about 20% of starting material. This was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:13]=2[CH:25]=1.C(Cl)Cl.CC[N:31]([CH:35](C)C)C(C)C.CN=C=[S:41]>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:31][CH3:35])=[S:41])[C:13]=2[CH:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCCOc1cc(=O)oc2ccc(Cl)cc12
Reactant: CN=C=S
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=S)NCCCOc1cc(=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt (0.272 mmol, 100 mg) is suspended in 5 mL of 1:1 DMF:DCM. DIEA is added dropwise until pH=9 by pH paper. Methyl isothiocyanate (0.299 mmol, 0.022 g) is added and the reaction is stirred at ambient temperature for 3 hrs. The reaction mixture is concentrated in vacuo and the crude material is purified by reversed-phase HPLC to afford the title compound (66.1 mg, 78.7%). 1H NMR (DMSO-d6, 300 MHz) δ 7.85 (1H, d, J=2.5 Hz), 7.71 (1H, dd, J=2.75, 9 Hz), 7.55 (1H, br m), 7.46 (1H, d, J=9 Hz), 5.95 (1H, s), 4.24 (2H, t, J=5.75 Hz), 3.59 (2H, br s), 2.79 (3H, br s), 2.07 (2H, m); MS (ESI, Pos.) calcd for C14H15ClN2O3S m/z [M+H]=327.0, found 327.0.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]2[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]2)=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl.ClC(Cl)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:19]2[CH2:20][C@H:21]([OH:23])[CH2:22][C@@H:18]2[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][C:3]3=[O:2])=[CH:14][CH:13]=2)=[O:17])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
7.1 16 g (12.86 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 15 g (64.86 mmol) of cis-N′-BOC-4-hydroxy-D-proline and 12.47 g (64.86 mmol of 1-(4-amino-phenyl)-1H-pyridin-2-one in 250 ml of toluene, and the mixture is stirred at room temperature for 18 hours. The precipitated product is subsequently filtered off, washed successively with 50 ml of toluene and 50 ml of diethyl ether and dried in a desiccator, giving 24.5 g (93.2%) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a grey-white powder. ESI 406. 7.2 300 ml of 4N hydrochloric acid in dioxane are added to a solution of 15 g (37 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate in 200 ml of dioxane, and the mixture is stirred at room temperature for 12 hours. The precipitate is subsequently filtered off, washed with 50 ml of dioxane and 50 ml of diethyl ether and dried in a desiccator, giving 12.64 g (100%) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride as a white powder. ESI 306. 7.3 12.64 g (36.98 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride are suspended in 1200 ml of dichloromethane, and 5.4 ml of triethylamine are added with cooling in an ice bath. The solution of 5.96 g (38.83 mmol) of 4-chloro-phenyl isocyanate in 100 ml of dichloroethane is subsequently added dropwise to the mixture at 2° C. over the course of 1.5 hours, and the reaction solution is then left to stir for a further 30 minutes with ice cooling. The dichloromethane solution, is then washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the methylene chloride solution has been evaporated to ⅓ of the original volume in a rotary evaporator, the precipitated product is filtered off, washed with 50 ml of petroleum ether and dried in a desiccator, giving 14.6 g (86%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxamide (“A8”) as a white powder, ESI 459; m.p. 216°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=O.COC(OC)[N:19]([CH3:21])C.O.[NH2:25]N>CO>[NH:19]1[CH:21]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:6][CH:5]=2)=[N:25]1
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CO
Product: c1cc(-c2ccc(N3CCOCC3)cc2)n[nH]1

Procedure:
A mixture of 2.05 g of 4-morpholinoacetophenone (10 mmol) and N,N-dimethylformamide dimethyl acetal was heated under reflux for 7 hours. The mixture was then mixed with 30 ml of methanol and, after addition of 0.57 ml of hydrazine hydrate, again heated under reflux for about 6 hours. The solid formed on cooling the mixture was filtered off with suction and thoroughly washed with methanol, resulting in 3.8 g of the title compound.