Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].[C:20](O)(=O)[CH:21]([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[N:9]=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:8][C:6]=2[CH:7]=1
Reactant: CC(C)C(=O)O
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Temperature: 120 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 5-bromo-3-nitrobenzene-1,2-diamine (prepared following the same procedure as for Example 1, 5.0 g) in isobutyric acid (20 mL) was stirred at 120° C. overnight. The mixture was cooled to room temperature and poured into water (100 mL). The pH was neutralized with aqueous Na2CO3 solution. It was then extracted with EtOAc and the organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:1 to afford the desired product as a yellow solid (4.7 g, 77%). 1H NMR (300 MHz, CDCl3) δ ppm 1.51 (m, 6H, J=6.9 Hz), 3.32 (m, 1H, J=6.9 Hz), 8.16 (d, 1H, J=1.5 Hz), 8.25 (d, 1H, J=1.5 Hz), 10.26 (br s, 1H); LC-MS: m/e=284 [M+1]+
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:34])[C:6]([CH2:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:25]=3[N:24]=2)=[C:7]2[C:11]=1[N:10](S(C1C=CC(C)=CC=1)(=O)=O)[CH:9]=[CH:8]2.[OH-].[K+].C(N)CC(C)C>CCO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:34])[C:6]([CH2:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:25]=3[N:24]=2)=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(C)cc(CO)c32)cc1
Agent: CC(C)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CO)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 2-((7-(hydroxymethyl)-5-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (13 mg, 0.028 mmol), KOH (15.5 mg, 0.276 mmol) and isoamylamine (64 μL, 0.553 mmol) in EtOH (0.8 mL) was stirred at 100° C. using microwave irradiation for 45 minutes. The mixture was directly purified using RP-HPLC (HC-A) to provide the title compound. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 10.84 (s, 1H) 7.96 (s, 1H) 7.59 (d, J=8.34 Hz, 1H) 7.45-7.55 (m, 1H) 7.22 (t, J=2.78 Hz, 1H) 6.95 (s, 1H) 6.44-6.51 (m, 1H) 4.74 (s, 2H) 4.47 (s, 2H) 2.39 (s, 3H). HRMS calcd. for C19H16N4O (M+H)+ 317.1402. found 317.1404.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24][CH3:25])=[O:23])=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccccc1S
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: COC(=O)c1ccccc1SC1=C/C(=C2/C(=O)NN=C2C)Nc2ccccc21

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and methyl 2-mercaptobenzoate using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 3.88 (s, 3H) 6.77 (s, 1H) 7.50-7.72 (m, 3H) 7.76-7.92 (m, 3H) 7.96 (d, J=8.12 Hz, 1H) 8.16 (d, J=8.18 Hz, 1H) 10.39 (s, 1H) 13.20 (bs, 1H); ESI-MS: m/z calc'd for C21H17N3O3S 391.10. found 392.3 (M+H)+.
Reaction SMILES: CS(O)(=O)=O.C([O:13][C:14]1[CH:39]=[CH:38][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][C:22]=2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:19])=[CH:16][CH:15]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[BrH:48].C(OCC)C>C(O)(=O)C>[BrH:48].[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][C:22]=2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:19])=[CH:38][CH:39]=1
Reactant: N=C(N)c1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)c(C(=O)c2ccccc2)c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: N=C(N)c1ccc(OC(=O)c2ccc(O)cc2)c(C(=O)c2ccccc2)c1
Reaction time: 5 h

Procedure:
To 25 ml of acetic acid, was added 2.7 g of 4-amidino-2-benzoylphenyl 4-benzyloxybenzoate methanesulfonate followed by 1 ml of anisole. To the mixture cooled in ice, was added 13.5 g of a 30% solution of hydrogen bromide in acetic acid. The mixture was stirred for 5 hours and mixed with ethyl ether. The precipitate was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 1.4 g of 4-amidino-2-benzoylphenyl 4-hydroxybenzoate hydrobromide.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(Cl)o2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccc(Cl)o3)cc2)no1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a mixture of (4-(5-chloro-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Manufacturing Example 62-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2-ylamine (8.0 mg, 0.068 mmol) described in Manufacturing Example 1-2-3 and triethylamine (19 μL, 0.14 mmol) at room temperature, which was stirred for 1 hour at 55° C. The mixture was cooled to room temperature and water was added at the same temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound as a crude product, and this was then purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (3.8 mg, 15%).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[C@H:10]([CH3:22])[CH2:9][C:8]1=[CH:7][C:6](=[O:23])[CH2:5][C@H:4]2[CH3:24].[OH:25][CH2:26][C@@:27]12[C@@H:44]3[C@H:35]([C@H:36]4[C@@:40]([CH2:42][CH2:43]3)([CH3:41])[C:39](=[O:45])[CH2:38][CH2:37]4)[CH2:34][C@H:33]([CH3:46])[C:32]1=[CH:31][C:30](=[O:47])[CH2:29][C@H:28]2[CH3:48].OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)C[C@H]2C>>[CH3:24][C@H:4]1[C@@:3]2([CH:2]=[O:1])[C:8]([CH2:9][C@@H:10]([CH3:22])[C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])=[CH:7][C:6](=[O:23])[CH2:5]1.[CH3:48][C@H:28]1[C@@:27]2([CH:26]=[O:25])[C:32]([C@@H:33]([CH3:46])[CH2:34][C@@H:35]3[C@@H:44]2[CH2:43][CH2:42][C@@:40]2([CH3:41])[C@H:36]3[CH2:37][CH2:38][C:39]2=[O:45])=[CH:31][C:30](=[O:47])[CH2:29]1
Reactant: C[C@@H]1CC(=O)C=C2[C@@H](C)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Reactant: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Product: C[C@@H]1CC(=O)C=C2[C@@H](C)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C=O
Product: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(C=O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
Substituting 19-hydroxy-1β,7α-dimethyl-4-androstene- 3,17-dione and 19-hydroxy-1β,6α-dimethyl-4-androstene- 3,17-dione for the 19-hydroxy-1β-methyl-4-androstene-3,17 -dione above results in the preparation of 1β,7α-dimethyl- 4-androstene-3,17,19-trione and 1β,6α-dimethyl-4 -androstene-3,17,19-trione.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-phenol to give (1H-pyrazol-3-yl)-(1-p-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[C:20]([C:21]#[N:22])=[C:16]3[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:40]>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][CH:28]=4)[C:20]([C:21]([NH2:22])=[O:40])=[C:16]3[NH:15][CH2:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC21CCN(Cc2ccccc2)CC1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC21CCN(Cc2ccccc2)CC1

Procedure:
The desired product was prepared from 1′-benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile according to the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J=8.4 Hz, 2H), 7.45-7.39 (m, 3H), 7.37-7.31 (m, 4H), 7.16 (t, J=7.6 Hz, 1H), 7.12-6.94 (m, 4H), 6.43 (s, 1H), 3.78 (s, 2H), 3.55 (br s, 2H), 2.89-2.82 (m, 2H), 2.15-2.11 (m, 2H), 1.84-1.72 (m, 2H). MS (ESI, m/e) [M+1]+ 479.9.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:9]1[CH2:10][C:11]1[C:23](OS(C(F)(F)F)(=O)=O)=[CH:22][CH:21]=[CH:20][C:12]=12)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:19][C@:13]12[C:16]([CH3:17])([CH3:18])[C@H:9]([NH:8][CH2:15][CH2:14]1)[CH2:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]2=1
Reactant: CC1(C)[C@H]2Cc3c(OS(=O)(=O)C(F)(F)F)cccc3[C@]1(C)CCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)[C@H]2Cc3ccccc3[C@]1(C)CCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Pd/C (0.20 g) is added to a solution of (2R,6S)-trifluoro-methanesulfonic acid 3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-yl ester (0.50 g) in ethanol (10 mL). The resulting mixture is shaken under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst is separated by filtration and Pd(OH)2 (0.2 g) is added to the filtrate (the benzyl group was not completely removed after the treatment in the presence of Pd/C). The mixture is shaken in hydrogen atmosphere (50 psi) at room temperature for another 16 h. The catalyst is separated and the filtrate is concentrated under reduced pressure to give the crude product that is used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH2:18])[C:14]([O:16]C)=[O:15])[C:3]([O:5]C)=[O:4].Cl>>[NH2:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH2:18])[C:14]([OH:16])=[O:15])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)[C@@H](N)CCCCCC[C@H](N)C(=O)OC
Agent: Cl
Product: N[C@@H](CCCCCC[C@H](N)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Dimethyl (S,S)-2,9-diaminodecanedioate (1.40g, 5.38 mmol) was dissolved in 6N HCl (40 ml, 240 mmol), and stirred under N2 at 60° C. for 12 hours. The solvent was evaporated, the residue dissolved in EtOH and crystallized by the addition of diethyl ester. The crystals were filtered off.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C:12]([O:14]C(=O)C3C=CC=CC=3)([CH3:13])[CH:11]([O:23]C(=O)C3C=CC=CC=3)[CH:10]([CH2:32][O:33]C(=O)C3C=CC=CC=3)[O:9]2)[C:4](=[O:42])[N:3]=1.C[O-].[Na+].CO>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C:12]([OH:14])([CH3:13])[CH:11]([OH:23])[CH:10]([CH2:32][OH:33])[O:9]2)[C:4](=[O:42])[N:3]=1
Reactant: CC1(OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)C(COC(=O)c2ccccc2)OC1n1ccc(N)nc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(O)C(O)C(CO)OC1n1ccc(N)nc1=O

Procedure:
In one synthesis method, depicted in FIG. 5, the synthesis comprises reacting cytosine, BSA and SnCl4/acetonitrile with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (FIG. 5, compound 1) to form 4-amino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (FIG. 5, compound 2); and reacting (FIG. 5, compound 2) with NaOMe/MeOH to provide 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (FIG. 5, compound 3), also known as 2-C-methyl-β-D-ribofuranose. The use of cytosine as a starting material rather than benzoyl-cytosine improves the “atom economy” of the process and simplifies purification at later steps.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@H:44]([C:54]([NH:56][C@H:57]([C:60]([NH:62][C@H:63]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH3:64])=[O:61])[CH2:58][OH:59])=[O:55])[CH2:45][CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:42])[CH2:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:30])[CH2:20][CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:17])[CH3:15])=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>[Pd].CO>[NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@H:44]([C:54]([NH:56][C@H:57]([C:60]([NH:62][C@H:63]([C:65]([O:67][C:68]([CH3:69])([CH3:70])[CH3:71])=[O:66])[CH3:64])=[O:61])[CH2:58][OH:59])=[O:55])[CH2:45][CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42])[CH2:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:30])[CH2:20][CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:17])[CH3:15])=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)CNC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Yield: 96 %

Procedure:
A solution of 4.0 g. (3.48 mmoles) of Z-25-32-OtBu in 140 ml. of methanol is hydrogenated in the presence of 0.5 g. of palladium-on-carbon. When the reaction terminates, the catalyst is filtered off; the filtrate is evaporated to dryness; the residue is triturated with ether and filtered off. 3.4 g. (96 %) of H-25-32-OtBu are obtained. M.p.: 188°-190°C; Rf4 = 0.5; [α]D = -6.6° (c = 0.89, in DMF).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([Cl:32])=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[CH:23]=2)[O:7][C@@H:6]1[CH2:33][O:34]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:32][C:21]1[S:20][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:33][OH:34])[O:7]2)=[CH:23][C:22]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C)cc3)c(Cl)s2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.4 %

Procedure:
To a suspension of acetate 40 (339 mg, 0.612 mmol) in MeOH (15 mL) was added NaOMe (25 wt % in MeOH, 0.2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 41 (55 mg, 23%).
Reaction SMILES: [Cl-].[CH:2]([O:5][C:6]1[CH:31]=[C:30]([CH3:32])[C:9](C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:8]([CH3:33])[C:7]=1[CH3:34])([CH3:4])[CH3:3].CC1C(C)=CC(C)=CC=1O>>[CH:2]([O:5][C:6]1[CH:31]=[C:30]([CH3:32])[CH:9]=[C:8]([CH3:33])[C:7]=1[CH3:34])([CH3:4])[CH3:3]
Reactant: Cc1cc(OC(C)C)c(C)c(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C)c(C)c(O)c1
Agent: [Cl-]
Product: Cc1cc(C)c(C)c(OC(C)C)c1

Procedure:
The 4-isopropoxy-2,3,6-trimethyl-benzyl-triphenyl-phosphonium chloride employed as the starting material is prepared by the procedure described in Example 18 by alkylation of 2,3,5-trimethylphenol to give 2,3,5-trimethylphenyl isopropyl ether (boiling point 115° C./11 mmHg), by haloformylation of the ether obtained to give 4-isopropoxy-2,3,6-trimethyl-benzyl chloride (nD20 =1.5433) and by reaction of the latter compound with triphenylphoshine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[Br:19])[CH:8]=[N:7][CH:6]=1.[Cl-].CC([O-])(C)C.[K+]>>[Br:19][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:11]=1[CH:10]1[N:9]2[CH:8]=[N:7][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2]1)[C:15]#[N:16]
Reactant: N#Cc1ccc(Cn2cncc2CCCO)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1

Procedure:
4-{5-[3-Hydroxypropyl]imidazol-1-ylmethyl}-3-bromobenzonitrile is converted to the corresponding chloride according to Example 14B. The resulting chloride is treated with a base, such as t-BuOK as in Example 14C above, to effect cyclization to the title compound. MS (ESI) m/z 302.1, 304.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.74-1.85 (m, 2H), 2.08-2.17 (m, 1H), 2.34-2.43 (m, 1H), 2.82-2.91 (m, 1H), 2.93-3.00 (m, 1H), 5.88 (t, J=5.6 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.82 (d, J=1.0 Hz, 1H), 7.34 (s, 1H), 7.69 (dd, J=8.1, 1.5 Hz, 1H), 8.09 (d, J=1.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([CH3:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.C(N(CC)CC)C.[CH:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>C(Cl)Cl>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[C:9]([O:14][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:10]=[C:11]([CH3:13])[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Cc1cc(O)cc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
To a solution of Intermediate 54a (430 mg, 1.75 mmol) in DCM (10 mL) and triethylamine (0.36 mL, 2.63 mmol) was added triisopropylsilyltrifluoromethanesulphonate (0.52 mL, 1.93 mmol). Mixture stirred for 1 h at RT, diluted with DCM, washed with sat. sodium hydrogen carbonate solution then brine, dried, and concentrated in vacuo. The residue was purified by FCC, using 0-25% EtOAc in cyclohexane, to give impure title compound (740 mg), contaminated with the ˜25% bis-silyl impurity. 1H NMR (300 MHz, CDCl3): inter alia 1.03-1.15 (18H, m), 1.18-1.35 (12H, m), 2.32 (3H, s), 3.74 (2H, br s), 5.49 (1H, s), 6.60-6.66 (1H, m), 6.85-6.89 (1H, m), 6.95-7.00 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:48][N:47]=[C:46]([CH3:49])[CH:45]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:43][C:44]2[S:48][N:47]=[C:46]([CH3:49])[CH:45]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1cc(N)sn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)ns4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.3 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (84 mg) was dissolved in chloroform (2.5 ml) and triethylamine (0.50 ml) to prepare a solution. A solution of triphosgene (38 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 5-amino-3-methylisothiazole (38 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated and was evaporated to dryness. Diethyl ether was added to the residue, and the solid was collected by filtration and was washed with methyl alcohol to give the title compound (32.2 mg, yield 27%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[Li+].[OH-].[OH-].[Na+].[C:23](OCC)(=O)C>C1COCC1.CO.O>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][C@H:7]1[CH:9]1[CH2:23][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature. To the mixture was added 1.0M NaOH (15 mL), water (20 mL) and ethyl acetate (20 mL). The mixture was shaken, the phases were separated, and the organic phase was again extracted with 20 mL 0.5M NaOH. The combined aqueous phases were acidified with 1.0M HCl until pH=4 and extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4), and filtered to provide the desired product as a white solid (2.62 g, 87%). 1H NMR: (DMSO-d6) δ1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); LC-MS MS m/z 228 (M++H).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[S:6]1[CH2:7][CH2:8][CH2:9][N:10]=[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C1=NCCCS1)[N+](=O)[O-]

Procedure:
8.0 G OF TETRAHYDRO-2-(NITROMETHYLENE)-2H-1,3-thiazine, prepared as described in Example 2 of Ser. No. 554,361, 5.95 g of N,N-dimethylformamide dimethyl acetal and 25 ml of chloroform were mixed and the mixture was refluxed for about 16 hours. The solvent then was evaporated under reduced pressure to leave a dark orange solid. Recrystallization from ethyl acetate and methanol gave (1), as a light orange solid, m.p.: 168.5°-170°.