Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.C([Si](C(C)C)(C(C)C)O/[N:15]=[C:16]1/[CH2:17][CH2:18][C:19]2[C:24]/1=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)(C)C.S(C)C.O>CCOCC>[Br:25][C:22]1[CH:23]=[C:24]2[C:19]([CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:20][CH:21]=1
Reactant: CC(C)[Si](O/N=C1/CCc2ccc(Br)cc21)(C(C)C)C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: CSC
Product: Brc1ccc2c(c1)NCCC2
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 30.5 %

Procedure:
BF3.Et2O (49.2 g, 56.7 mL, 346.2 mmol) was added to a solution of (Z)-6-bromo-2,3-dihydro-1H-inden-1-one O-triisopropylsilyl oxime (10) (66 g, 173.1 mmol) in 400 mL of dry Et2O. Me2S.BH3 (31.5 g, 39.48 mL 415.5 mmol) was then added dropwise. The reaction mixture was heated to reflux for 48 hours (followed by TLC 100% petroleum ether until complete disappearance of starting material). The mixture was cooled to 0° C. and dropped to ice/water cautiously, followed by 60 mL of 1:1 solution of water/concentrated HCl. This reaction mixture was heated to 70° C. for 80 minutes and then allowed to cool to rt and stirred for 3.5 hours, washed with Et2O. The pH of the remaining aqueous phase was adjusted to pH>10 with 5M NaOH and extracted three times with Et2O. The combined organic phases were washed with brine and dried over K2CO3. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc (100:1) to provide 11.2 g (31%) of the desired product 7-bromo-1,2,3,4-tetrahydroquinoline (1E): 1H-NMR (DMSO-d6, 400 MHz): δ1.7 (m, 2H), 2.6 (m, 2H), 3.15 (m, 2H), 5.9 (s, 1H), 6.45 (m, 1H), 6.55 (m, 1H), 6.75 (m, 1H). LC/MS (APCI): m/z 211.7 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:20]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:11](=[O:13])[C:10]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=3)[CH:9]=2)[CH2:29][CH2:30]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Product: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.4 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 0.9 g (3.52 mmol) and piperazine-1-carboxylic acid ethyl ester (0.556 g, 3.52 mmol) were used to afford 0.52 g of the required product. Percentage purity (LCMS): 90.2%, (M+1)=395.1+1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1)=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][CH:37]=[C:32]([CH:33]=4)[C:30]([O:29][CH3:28])=[O:31])=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: COC(=O)c1cncc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Temperature: 100 °C
Yield: 74.4 %

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (250 mg, 0.6 mmol), 5-(methoxycarbonyl)pyridin-3-ylboronic acid (163 mg, 0.9 mmol), PdCl2(PPh3)2 (50 mg, 20%) and aqueous Cs2CO3 solution (2 M, 2 mL) in 1,4-dioxane (6 mL) was heated to reflux at 100° C. overnight under N2. The mixture was filtered, and the filtrate was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to the crude product, which was purified by preparative HPLC to give methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (220 mg, crude).
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:4])[CH:2]=[CH2:3].Cl.[NH2:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CC(O)C>[CH:15]1([CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH2:14][N:5]2[C:1](=[O:4])[CH2:2][CH2:3][NH:22][CH2:23][C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=CC(=O)N1CCc2ccccc2C1C1CCCCC1
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(CCNCC1(O)CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Yield: 28 %

Procedure:
2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (516 mg) was dissolved in iPrOH (15 mL). To the reaction mixture were added 1-(aminomethyl)cyclohexanol hydrochloride (635 mg) and triethylamine (0.59 mL), followed by stirring under heating at reflux for 16 hours. Thereafter, the solvent was evaporated and water was added to the mixture, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) and then further purified by alkaline silica gel column chromatography (chloroform) to obtain 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]amino}methyl)cyclohexanol (214 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+:8]([O-])[CH:9]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[n+]([O-])c1C(=O)OCC
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(N)cnc1C(=O)OCC
Reaction time: 0.33 h

Procedure:
17 g (0.060 mol) of diethyl 5-nitropyridine-2,3-dicarboxylate-N-oxide in 200 ml of glacial acetic acid were added to a mixture of 10.7 g (0.19 mol) of iron powder in 50 ml of glacial acetic acid at 70° C. with stirring in the course of 20 minutes. After stirring at 70° C. for 1 hour, the reaction mixture was cooled, and the precipitate was filtered off with suction and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride, washed with water and with saturated sodium chloride solution, dried over magnesium sulfate and filtered off with suction through silica gel. After concentrating under reduced pressure, 11 g (77% of theory) of the title compound were obtained as a semisolid mass.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([NH2:18])=[N:15][O:16][N:17]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl.CN(C1C=CN=CC=1)C>[F:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:18][C:14]1[C:13]([CH3:12])=[N:17][O:16][N:15]=1)=[O:6]
Reactant: O=C(O)c1c(F)cncc1F
Reactant: Cc1nonc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nonc1NC(=O)c1c(F)cncc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg (1.26 mmol) of 3,5-difluoroisonicotinic acid and 125 mg (1.26 mmol) of 4-methyl-1,2,5-oxadiazol-3-amine are dissolved at RT in 6 ml of dichloromethane, and 0.88 ml (6.29 mmol) of triethylamine, 31 mg (0.25 mmol) of DMAP and 1.20 g (1.89 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 5 ml each time of water. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield: 100 mg (31%).
Reaction SMILES: [CH:1]1([N:7]([O:14][CH3:15])[C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:20]([CH3:23])[CH:21]=O)(=O)C.C(O)C(C)C>[Fe].O>[CH3:15][O:14][N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([C:9]1[CH:21]=[C:20]([CH3:23])[O:11][C:10]=1[CH3:12])=[O:13]
Reactant: CC(=O)OC(C)C=O
Reactant: CON(C(=O)CC(C)=O)C1CCCCC1
Agent: [Fe]
Solvent: O
Solvent: CC(C)CO
Product: CON(C(=O)c1cc(C)oc1C)C1CCCCC1
Reaction time: 7.5 h

Procedure:
A mixture of 85.2 parts of N-cyclohexyl-N-methoxyacetoacetamide and 58.2 parts of 95.7% pure α-acetoxypropionaldehyde is added dropwise to a suspension of 19.4 parts of iron-III chloride in 100 parts of isobutanol at 40°-45° C. The mixture is then kept at 45° C. for 7.5 hours. Water is added to the reaction mixture, the batch is extracted with methylene chloride and the extract is evaporated. 104 parts of crude product are obtained; this can be distilled at 138°-145° C./0.3 mm Hg, to give 88.5 parts of pure O-methyl-N-cyclohexyl-2,5-dimethylfuran-3-hydroxamic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:8].O=CCCCNC(=O)C1C=CC=CC=1>>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:8]
Reactant: O=C(NCCCCO)C1Cc2ccccc2C1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCCCNC(=O)C1Cc2ccccc2C1
Yield: 99 %

Procedure:
Indane-2-carboxylic acid-(4-oxobutyl)amide (26C) is prepared from 26B as described for 1E.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:24][C:20]2[CH:21]=[N:22][CH:23]=[C:18]([C:16]3[CH:15]=[CH:14][C:10]4[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:9]=4[N:17]=3)[CH:19]=2)(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 4-chloro-2-fluorobenzene-1-sulfonyl chloride (0.043 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 4-chloro-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.034 g, 43%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.24 (1H, d, J=8.4 Hz), 7.86-7.90 (1H, m), 8.24 (1H, d, J=8.8 Hz), 8.39 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=7.6 Hz), 8.85 (1H, s), 9.19 (1H, s). m/z=516.1 [M+1]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:17]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 0 °C

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.0 g, 19.15 mmol) in tetrahydrofuran (100 mL) was treated with tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (5.38 g, 28.73 mmol) and triphenylphosphine (7.53 g, 28.73 mmol). The reaction mixture was cooled to 0° C. on an ice bath. Diethylazodicarboxyate (5.0 g, 28.73 mmol) was slowly added to the reaction mixture. The solvent was removed under reduced pressure after 6 days. The crude oil was used directly in the subsequent reaction without further analysis.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:34][C:35]([F:65])([F:64])[C:36]1[CH:37]=[C:38]([CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1)[C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][C@H:42]1[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)=[O:40].C(=O)(O)[O-].[Na+]>ClCCl>[F:63][C:60]([F:61])([F:62])[C:58]1[CH:57]=[C:38]([CH:37]=[C:36]([C:35]([F:34])([F:64])[F:65])[CH:59]=1)[C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:7](=[O:8])[CH2:6][CH2:5][CH2:4][N:3]([CH3:10])[CH3:2])[CH2:43][C@H:42]1[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)=[O:40]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CN(C)CCCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
To a stirred mixture of 4-(dimethylamino)butyric acid hydrochloride (70 mg) and 1-hydroxybenzotriazole hydrate (160 mg) in dichloromethane (10 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg) under ice cooling. After stirring for 30 minutes, a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (200 mg) in dichloromethane (5 ml) was added at the same temperature. The resulting mixture was stirred for 2.5 hours at room temperature. Dichloromethane and aqueous sodium bicarbonate solution were added to the reaction mixture and then the organic layer was separated and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(dimethylamino)butyryl]-2-(1H-indol-3-yl-methyl)piperazine (0.25 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][CH3:16]>C(O)C>[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1cccc([N+](=O)[O-])c1CBr
Agent: [Na+]
Solvent: CCO
Product: COc1cccc([N+](=O)[O-])c1CC#N
Yield: 61 %

Procedure:
Sodium cyanide (165 mg, 3.36 mmol) was added to a solution of 2-bromomethyl-1-methoxy-3-nitro-benzene (680 mg, 2.56 mmol) in ethanol (5 mL) and the mixture was heated at reflux overnight. The solvent was removed in vacuo, water (30 mL) was added and the mixture was extracted with dichloromethane (25 mL). The organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether to afford (2-methoxy-6-nitro-phenyl)-acetonitrile (300 mg, 61%).
Reaction SMILES: CN(C1C=CC=CN=1)C.[CH:10]1([N:16]=[C:17]=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CN(C)C=[O:28]>>[CH:19]1([NH:18][C:17](=[O:28])[NH:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C)C=O
Agent: CN(C)c1ccccn1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An equimolecular mixture (10-2M) of L-N-Boc-NG -nitroarginine and N-B-hydroxyethyl morpholine is dissolved in 30 ml of anhydrous dimethyl formamide (DMF), then 3×10-3M of dimethylaminopyridine (DMAP) is added. The solution is cooled to 0 degrees C. and 10-2M of dicyclohexyl carbodiimide (DDC) is added. It is stirred at 0 degrees C. for 10 minutes, then the stirring is continued at room temperature for 24 hours. The precipitate of dicyclohexyl urea formed is filtered and the solvent eliminated. The residue is recovered by ethyl acetate, then washed once with water and once with saturated NaCl. The elimination of the solvent leaves a viscous product which is chromatographed on a silica column (eluant CHCl3/MeOH9595 then 90:10); the compound (4) is obtained in the form of an oil which crystalizes.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].NC1C=CC(C#N)=C([F:40])C=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:23]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:40])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)cc2)c1
Reactant: N#Cc1ccc(N)cc1F
Product: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)c(F)c2)c1

Procedure:
According to the procedure for the preparation of Intermediate 370.4, 4-amino-2-fluorobenzonitrile (46 mg, 0.34 mmol) gave 75 mg of Intermediate 373.1 as a white solid. LCMS 412.30 (M+H)+.
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[N:7]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]2)=[O:10])[N:6]=[C:5]([C:19]([F:22])([F:21])[F:20])[CH:4]=1.N(CCO)CCO>CN(C)C=O>[CH3:2][C:3]1[N:7]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[S:1])[NH2:18])[CH2:13][CH2:12]2)=[O:10])[N:6]=[C:5]([C:19]([F:22])([F:20])[F:21])[CH:4]=1
Reactant: S
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C#N)CC1
Solvent: CN(C)C=O
Solvent: OCCNCCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Hydrogen sulfide gas was passed into a solution of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile (i.e. the product of Example 1, Step B) (9.0 g, 30 mmol) and diethanolamine (3.15 g, 30 mmol) in N,N-dimethylformamide (15 mL) at 50° C. in a flask equipped with dry-ice condenser. The hydrogen sulfide feed was stopped when the reaction mixture became saturated with hydrogen sulfide, as indicated by condensation on the cold-finger. The reaction mixture was stirred for an additional 30 minutes at 50° C. Then excess hydrogen sulfide gas was sparged into the scrubber by a subsurface nitrogen flow, and water (70 mL) was gradually added. The reaction mixture was cooled to 5° C., filtered, and washed with water (2×30 mL). The filter cake was dried at 50° C. in a vacuum-oven to give 8.0 g of the title compound as a solid, melting at 185-186° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Zn]>[CH3:2][C:3]1[C:4]([CH2:2][C:3]2[S:18][C:6]3[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=3[C:4]=2[C:19]([O:21][CH3:22])=[O:20])=[C:5]([CH3:6])[N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: NNc1ccccc1
Agent: CC(=O)/C=C(/C)O
Agent: [Zn]
Product: COC(=O)c1c(Cc2c(C)nn(-c3ccccc3)c2C)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
Prepared from methyl 6-(bromomethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate (500 mg), zinc acetylacetonate hydrate and phenyl hydrazine following the procedure of example 26, part a). Crude product was purified by column chromatography over silica, eluting with ethyl acetate/iso-hexane (2:3) to give the sub-title compound (555 mg) as a solid. MS(ESI) 481 [M+H]+. δ 1HDMSO 0.95 (6H, d), 2.24 (3H, s), 2.27 (3H, s), 2.20-2.30 (1H, m), 3.39 (3H, s), 3.71 (2H, d), 3.95 (3H, s), 3.96 (2H, s), 7.36-7.50 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)=[O:19].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)[OH:19]
Reactant: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)c1cccc(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
To a solution of 7-{(R)-2-[(E)-3-(3-bromo-phenyl)-3-oxo-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester (0.78 g, 1.79 mmol) in 15 mL of methanol stirred at 0° C. under nitrogen was added sodium borohydride (0.074 g). The reaction mixture was stirred at room temperature for 6 hours. After addition of 1 N HCl solution the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by chromatography eluting with 50% EtOAc and Hexane followed by 100% EtOAc to yield 670 mg of 7-{(R)-2-[(E)-3-(3-bromo-phenyl)-3-hydroxy-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester. Step 3
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][OH:14])=O)C1C=CC=CC=1>[Pd].CO.O1CCOCC1>[NH2:11][C@@H:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][OH:14]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H](N)CO
Temperature: 25 °C
Yield: 105.8 %

Procedure:
10% Palladium on activated carbon (10 mg) was added to a solution of (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanol (920 mg) in methanol (10 mL) and dioxane (1 mL). The mixture was stirred under hydrogen atmosphere (3.5 atm) for one and a half days at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo to give (S)-2-amino-3-(tert-butoxycarbonylamino)propanol (571 mg) as a white solid substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([S:9][C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=1.[Cl:19]N1C(=O)CCC1=O>CO>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([S:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Sc2cc3ccccc3[nH]2)nn1
Solvent: CO
Product: COc1ccc(Sc2[nH]c3ccccc3c2Cl)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 3-methoxy-6-(indole-2-sulfenyl)-pyridazine) (2.92 mmol, 750 mg), N-chloro-succinimide (2.92 mmol, 390 mg) and methanol (15 mL) was stirred overnight at room temperature. Excess methanol was removed and the residue was extracted with EtOAc (3×10 mL). The EtOAc extract was collected, dried, filtered and evaporated to dryness to obtain a residue, which was purified by silica gel chromatography (eluent:hexanes:EtOAc::19:5) to yield 3-methoxy-6-(3-chloro-indole-2-sulfenyl)-pyridazine (40%, 338 mg).