Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([NH2:6])(=[O:5])[CH2:3][SH:4].[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11]Br)[CH3:8]>C(O)C>[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][S:4][CH2:3][C:2]([NH2:6])=[O:5])[CH3:8]
Reactant: CCOC(CBr)OCC
Reactant: NC(=O)CS
Agent: [Na]
Solvent: CCO
Product: CCOC(CSCC(N)=O)OCC

Procedure:
Sodium (0.878 g) was dissolved in absolute ethanol (150 ml) under an inert atmosphere. Thioglycolamide (3.47 g) (prepared as described by Sokol and Ritter, J.A.C.S. 70 3517 (1948)) was added and, when practically all the amide had dissolved, bromoacetaldehyde diethyl acetal (11.5 ml) was added. The mixture was heated at 60°-65° C. for 7 hours, cooled and filtered, and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and brine (50 ml), the layers separated and the brine extracted with ethyl acetate (50 ml). The combined ethyl acetate extracts were dried over Na2SO4 and evaporated under reduced pressure to yield an oil. Chromatography on silica (50 g), eluting with ethyl acetate/petrol, provided the title compound (6 g) as an oil. νmax (CHCl3) 3500, 3400 and 1690 cm-1 ; δ(CDCl3) 1.20 (6H, t, J 7 Hz, --CH2CH3 ), 2.80 (2H, d, J 5 Hz, >CHCH2S--), 3.25 (2H, s, --SCH2CO--), 3.58 (4H, 2q J 7 Hz, --OCH2CH3), 4.62 (1H, t, J 5 Hz, --CHCH2S--), 7.00 (2H, s, --CONH2); Found 207.0951 (M+) C8H17NO3S requires 207.0929.
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:15][C:3]=12.[OH:20][CH2:21][CH2:22][C:23](=O)[CH3:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH:23]([CH3:24])[CH2:22][CH2:21][OH:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[O:15][C:3]=12
Reactant: CC(=O)CCO
Reactant: FC(F)(F)c1nc2cc3c(c(Br)c2o1)CCNCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(CCO)N1CCc2cc3nc(C(F)(F)F)oc3c(Br)c2CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
A mixture of 10-bromo-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (250 mg, 1 eq), 4-hydroxy-butan-2-one (0.077 ml, 1.2 eq), acetic acid (0.042 ml, 1 eq) and sodium triacetoxyborohydride (314 mg, 2 eq) in THF (2.5 ml) was stirred at room temperature for 20 hours. Additional 4-hydroxy-butan-2-one (0.24 eq) and sodium triacetoxyborohydride (0.4 eq) were added and the mixture was stirred for 5 hours. Then, the mixture was diluted with DCM and washed with 5% NaHCO3 and brine. The organic phase was dried (Na2SO4) and concentrated. The crude was purified on silica gel (DCM/MeOH/conc.NH4OH, 100/2.5/0.25) providing the title compound (218 mg, 72% yield).
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][C:5](=[O:13])[N:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:19][N:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]1=[O:35].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:16]1([CH2:15][O:14][C:3]2[C:2]([C:24]3[CH:23]=[CH:22][C:21](=[O:35])[N:20]([CH3:19])[CH:25]=3)=[CH:7][N:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](=[O:13])[CH:4]=2)[CH2:18][CH2:17]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CS(=O)(=O)Cn1cc(Br)c(OCC2CC2)cc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cn(CS(C)(=O)=O)c(=O)cc2OCC2CC2)ccc1=O
Temperature: 70 °C
Yield: 31.3 %

Procedure:
The title compound from step 4 (50 mg, 0.15 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (42 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg, 14.9 umol) and K3PO4 (63 mg, 0.3 mmol) in dioxane (5 mL) and water (5 drops) were degassed and then heated to 70° C. under N2 overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by column chromatography (PE:DCM:EA=3:0:1 to 0:1:4) followed by preparative HPLC to afford the title compound (17.09 mg, 31.5%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.50 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 5.96 (s, 1H), 5.16 (s, 2H), 3.86 (d, J=6.8 Hz, 1H), 3.63 (s, 3H), 2.99 (s, 3H), 1.26-1.21 (m, 1H), 0.70-0.66 (m, 2H), 0.36-0.32 (m, 2H). LCMS: 365.0 (M+1)+
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[NH3:32]>C(O)C>[NH2:32][C@H:25]1[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]2[CH:30]=[CH:31][C:18]([S:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)(=[O:17])=[O:16])=[CH:19][C:20]1=2
Reactant: N
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O[Si](C)(C)C(C)(C)C)c3)cc2[C@@H]2O[C@@]21C
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O)c3)cc2[C@@H](N)[C@]1(C)O
Temperature: 45 °C

Procedure:
(3S,4S)-6-(3-tert-butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (2.2 g) (see Preparation 15) was dissolved in ethanol (25 ml) and 35% aqueous ammonia solution (25 ml) was added. The mixture was heated at 40-50° C. for 24 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using 7.5:92.5 methanol:dichloromethane as the eluent to yield (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1.42 g) as a foam. Found: C,54.39; H,5.22; N,3.19. C18H21NO5S, 0.50 CH2Cl2 requires C,54.75; H,5.46; N,3.45%.
Reaction SMILES: [NH:1]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34]CC)=O)[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][C:21](=[O:23])[NH2:22])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[NH2:44][NH2:45].O>CO>[NH:1]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:44][NH2:45])=[O:34])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][C:21](=[O:23])[NH2:22])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: NN
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 48 h
Yield: 79 %

Procedure:
2.80 Grams of Boc-Gly-Ser(Bzl)-Asn-Leu-OEt was dissolved in 30 ml of methanol. Thereto was added 2.25 ml of NH2NH2.H2O. The mixture was allowed to stand for 2 days at room temperature. The resulting precipitate was collected by filtration and washed with methanol to obtain 2.16 g (yield: 79.0%) of the above objective compound. Melting point: 221°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCC(C#N)c1ccc(Cl)cc1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1ccc(Cl)cc1

Procedure:
rac-2-[1-(4-Chloro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(4-chloro-phenyl)butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 223.0 ((M+H)+.).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.CO>C1COCC1>[OH:5][CH2:4][C:3]1[C:2]([OH:1])=[N:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccnc1O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cccnc1O
Temperature: 80 °C
Yield: 28.6 %

Procedure:
To a suspension of 2-Hydroxynicotinic acid (1.01 g, 7.26 mmol) in THF (2 mL) was added BH3.THF (1.0 m in THF, 18 mL, 18 mmol) and the mixture was heated to 80° C. for 18 hours. MeOH (2 mL) was added and the mixture was heated to 80° C. for an additional 2 hours before being cooled to room temperature and concentrated under reduced pressure. The resultant crude syrup was repeatedly dissolved in MeOH (5 mL) and concentrated (3×). Purification by column chromatography on silica gel (20:1—CH2Cl2:MeOH) afforded the desired alcohol (260 mg, 29%) as a white solid. 1H NMR (CD3OD) δ 4.50 (s, 2H), 6.43 (t, 1H, J=6.6 Hz), 7.34 (d, 1H, J=4.5 Hz), 7.65 (d, 1H, J=6.3 Hz).
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=O)(C)(C)C>Cl.C(O)C>[NH2:8][CH:9]([CH:17]([OH:24])[CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)CC(O)C(O)C(N)CC1CCCCC1

Procedure:
(2S,3R, 4S)-2-[(tert-Butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (5.05 g, 14.7 mmol, Luly et al., J. Org. Chem. 1988, 53, 6109) was stirred for 90 min in 4M hydrochloric acid in ethanol and then evaporated. Ether was added and evaporated 3 times and the residue was dried under high vacuum. The title compound was used without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: CC(C)Nc1ccccc1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(C(=O)CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 54.8 %

Procedure:
To a solution of N-isopropylaniline (21.58 g, 180 mmol) in CH2Cl2 (350 mL) was added triethylamine (26.7 mL, 190 mmol). The solution was cooled to 0° C. and bromoacetyl bromide (14.0 mL, 160 mmol) was added slowly over 1 hour. The reaction was warmed to room temperature and was stirred for 24 hours. The reaction was diluted with 5% aqueous HCl. The organic solution was washed with 5% aqueous HCl (2×), aqueous NaHCO3 (1×), and brine (1×). The organic solution was filtered through a silica gel pad, eluting with CH2Cl2. Recrystallization from hexanes (60 mL) provided 22.47 g of 2-bromo-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 7.45 (m, 3H), 7.21 (m, 2H), 4.89 (m, 1H), 3.52 (s, 2H), 1.05 (d, 6H); MS 256.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](I)=[CH:6][CH:7]=1.[C:10](#[N:12])C.[Cu](C#N)C#N.[C-]#N.[Na+]>[OH-].[NH4+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]#[N:12])=[N:4][C:3]=1[CH3:9]
Reactant: CC#N
Reactant: Cc1nc(I)ccc1Br
Agent: N#C[Cu]C#N
Agent: [C-]#N
Agent: [NH4+]
Product: Cc1nc(C#N)ccc1Br
Temperature: 80 °C
Reaction time: 0.38 h

Procedure:
3-Bromo-6-iodo-2-methylpyridine (1 equiv) and acetonitrile were combined and copper cyanide (0.5 equiv), sodium cyanide (0.8 equiv) were added. The reaction slurry was heated to 80° C. for 24 h. The reaction solution was cooled to room temperature and diluted with ammonium hydroxide (0.5 M aqueous solution). The mixture was stirred 15-30 min, filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The filtrate and wash were combined and diluted with ethyl acetate. The aqueous and organic phases were separated and the organic layer was washed with ammonium hydroxide (0.5 M aqueous solution) and saturated aqueous sodium chloride, dried, filtered, and concentrated under reduced pressure to provide 5-bromo-6-methylpicolinonitrile as a. MS (ESI) m/z 196.9 [M]+, 198.9 [M+2]+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Product: O=c1c(NCCc2ccc(Oc3ccccc3)cc2)c(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared according to an analogous procedure to that described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 2-(4-phenoxyphenyl)-ethylamine. The reaction mixture was heated to reflux for 2 h instead of stirring 18 h at r.t.
Reaction SMILES: [H-].[Na+].[O:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH2:4][CH3:5].[Br:13][C:14]1[C:15](Cl)=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1.CCOC(C)=O>CN(C=O)C.CC#N>[Br:13][C:14]1[C:15]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:3][CH2:4][CH3:5])=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: CCOc1ccccc1O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOc1ccccc1Oc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of NaH (0.42 g 60% in mineral oil, 10.5 mmol) in DMF (8.0 mL) was slowly added 2-ethoxylphenol (1.34 g, 9.7 mmol) in MeCN (4.0 mL) at 0° C. under N2. After the addition, the reaction mixture was allowed to warm up to room temperature for 0.5 hour. 5-bromo-2,4-dichloropyrimidine (2.0 g, 8.8 mmol) in MeCN (16.0 mL) was slowly added and then the resulting reaction mixture was stirred at room temperature for 24 hour. EtOAc (120 mL) was added and washed with NaOH (30 mL, 0.5N) and brine (25×2 mL). The organic layer was dried with MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% to 30% EtOAc in Hexanes, gradient elution) to provide the 5-bromo-2-chloro-4-(2-ethoxyphenoxy)pyrimidine. MS m/z=330 [M+1]+. Calc'd for: C12H10BrClN2O2: 329
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([CH3:31])[S:26][C:27]=1[C:28](O)=[O:29].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:28]([C:27]3[S:26][C:25]([CH3:31])=[N:24][C:23]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])=[O:29])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: Cc1nc(-c2ccccc2F)c(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2F)c(C(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (92 mg, 0.44 mmol), 4-(2-fluoro-phenyl)-2-methyl-thiazole-5-carboxylic acid (104 mg, 0.44 mmol), di-isopropylethylamine (0.25 mL, 1.30 mmol) and HATU (247 mg, 0.65 mmol) were dissolved into DMF (5 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 1N NaOH (10 mL) and water (2×100 mL). The organic layers were combined, dried, filtered and concentrated to yield the title compound (125 mg, 67%). MS (ESI) mass calcd. for C12H18FN3OS, 431.41; m/z found, 432.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[O:38])[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])C.[CH3:39]NC([C@@H]1CCCN1)=O>>[CH3:14][C:11]([CH3:12])([CH3:13])[C@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:9]([N:8]1[CH2:7][CH2:5][CH2:4][C@H:3]1[C:2](=[O:38])[NH:1][CH3:39])=[O:37]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Reactant: CNC(=O)[C@@H]1CCCN1
Product: CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C

Procedure:
Compound 76 was prepared according to the procedure for the synthesis of compound 72 by replacing leucine amide with (S)-N-methylpyrrolidine-2-carboxamide. LCMS (+ESI) m/z=535.2 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[N:12]=[CH:11][C:10]=1[C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1(NC(C2C=NN(C3C=CC(C(OC)=O)=CC=3)C=2SC2CCCC2)=O)CCCCC1>>[CH:26]1([NH:25][C:24]([C:10]2[CH:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[C:9]=2[S:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Reactant: SC1CCCCC1
Agent: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCC2)cc1
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCCC2)cc1

Procedure:
Methyl 4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanylpyrazol-1-yl]benzoate was prepared from cyclohexylthiol and methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate #15) by the same process used for Intermediate #96.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([Si](C)(C)C)[N:16]=[N:15]2)=[CH:10][CH:9]=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[N:14]1([C:11]2[CH:10]=[CH:9][C:8]([C:3]3[N:4]=[C:5]([NH2:7])[S:6][C:2]=3[Cl:1])=[CH:13][CH:12]=2)[CH:18]=[CH:17][N:16]=[N:15]1
Reactant: C[Si](C)(C)c1cn(-c2ccc(-c3nc(N)sc3Cl)cc2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(-c2ccc(-n3ccnn3)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)thiazol-2-amine (0.70 g, 2.0 mmol), prepared in the previous step, in THF (10 mL) at 0° C. was added acetic acid (0.125 mL, 2.2 mmol) and tetrabutylammonium fluoride (2.2 mL, 1 M in THF, 2.2 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h, heated to 40° C. for 2 h, and additional AcOH (0.035 mL, 0.61 mmol) and TBAF (0.60 mL, 1 M in THF, 0.60 mmol) were added. Stirring was continued at 40° C. After 3 h, the reaction mixture was poured into water (300 mL). The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes gave 4-(4-(1H-1,2,3-triazol-1-yl)phenyl)-5-chlorothiazol-2-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C@@H:10]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:25])=[O:24])=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=1>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C@@H:10]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:36])=[O:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:24])=[O:25])=[C:14]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:13]=1
Reactant: Nc1ccccc1NC(=O)[C@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)c3nc4ccccc4[nH]3)cc2OCc2ccccc2)S(=O)(=O)N1

Procedure:
A solution of (S)—N-(2-aminophenyl)-2-benzenesulfonylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide in acetic acid is stirred at 60° C. for 4 h. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: C([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]3[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(#N)C>[F:24][C:22]([F:23])([F:25])[C:20]1[CH:21]=[C:12]2[CH2:11][CH2:10][CH:9]([P:4]([OH:8])(=[O:3])[OH:5])[N:14]3[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]([CH:19]=1)=[C:13]23
Reactant: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=c1[nH]c2cc(C(F)(F)F)cc3c2n(c1=O)C(P(=O)(O)O)CC3
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.7 %

Procedure:
1.63 g of 9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester is introduced into 40 ml of acetonitrile under nitrogen at room temperature. 3.63 ml of trimethylsilylbromide is rapidly instilled. The solution is stirred for 20 hours at room temperature and concentrated by evaporation. The residue is suspended in 50 ml of water, suctioned off and washed with water. The residue is dried at 105° C. and 0.7 torr. 1.12 g of 9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid of melting point 262° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.C([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([OH:27])[CH:26]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1(SC)C=CC=CC=1>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:27][C:25]1[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][C:24]=1[CH3:28]
Reactant: Cc1ccc(OCc2ccccc2)cc1O
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CSc1ccccc1
Product: Cc1ccc(O)cc1Oc1ccnc2ccc(Br)cc12
Temperature: 150 °C
Yield: 47 %

Procedure:
141 mg (0.58 mmol) of 6-bromo-4-chloroquinoline and 150 mg (0.7 mmol) 5-(benzyloxy)-2-methylphenol in 5 ml acetonitrile are mixed with 97 mg (0.7 mmol) of potassium carbonate and heated in the microwave oven to 150° C. for 3 h. The mixture is diluted with water and then extracted with ethyl acetate. The organic layers are washed with brine and dried over sodium sulfate. The solvent is evaporated and the resulting residue is dissolved in 5 ml TFA. 54 mg (0.44 mmol) thioanisole is added and the mixture is stirred over night. The solvent is evaporated, the resulting residue is dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layers are dried over sodium sulfate, the solvent is evaporated and the resulting residue is purified by preparative HPLC. 90 mg (46%) of the desired product are obtained
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[C:27]([CH:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=1)#[N:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1([CH3:26])[C@@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][CH:29]([C:27]#[N:28])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:31]=1)=[O:24]
Reactant: C=C=C[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@H]1[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
2.06 g of dicyclohexylcarbodiimide were added at 0° C. to a solution of 1.52 g (1R,cis) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylic acid in 30 ml of methylene chloride followed by the addition of a few crystals of 4-dimethylamino-pyridine after which the mixture was stirred at 0° C. for 15 minutes. A solution of 2.47 g of (RS)α-cyano-3-phenoxy-benzyl alcohol in 10 ml of methylene chloride was added to the mixture which was stirred at 20° C. for 4 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 3-7 benzene-petroleum ether (b.p.=35° to 70° C.) mixture and then with a 7-3 benzene-petroleum ether (b.p.=35° to 70° C.) mixture yielded 2.89 g of (RS)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate.