Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccc(OC2CCNCC2)cc1

Procedure:
A solution of 46.0 g of 1-benzyl-4-(p-trifluoromethylphenoxy)piperidine, the free base of Part (a), in 250 ml. of 95% ethanol is treated with 6.0 g of 10% palladium-on-charcoal catalyst and is shaken with hydrogen gas at 50° C. until the theoretical amount of hydrogen is absorbed. The suspension is cooled, filtered, and the solvent is removed. The residual oil is fractionally distilled under reduced pressure and the fraction which boils at 74°-76° C/0.05 mm is collected. The collected oil crystallizes on standing to give a solid of 4-(p-trifluoromethylphenoxy)piperidine.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.S(Cl)([Cl:16])=O>>[CH:1]1([C:11]([Cl:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1C=CCc2ccccc21
Product: O=C(Cl)C1C=CCc2ccccc21

Procedure:
In an example of this reaction 1,4-dihydro-alpha-naphthoic acid is reacted with thionyl chloride at room temperature for 1-6 hours to obtain 1,4-dihydro-alpha-naphthoic chloride. This compound is then reacted with an amine of the formula (3) and triethylamine in ether solvent under reflux for 0.1-3 hours to obtain a compound of the formula (1a). Compounds of the formulae (1b) and (1c) may also be produced in the same manner as just described using 3,4-dihydro-alpha-naphthoic acid and 1,2,3,4-tetrahydro-alpha-naphthoic acid, respectively as starting materials.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:19]([O:23][C:24]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:35]Cl)=[O:25])([CH3:22])([CH3:21])[CH3:20].[I-].[K+].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:19]([O:23][C:24]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:35][N:8]([CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: c1cnc2c(c1)CCCC2NCCn1ccnc1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1c(CN(CCn2ccnc2)C2CCCc3cccnc32)nc2ccccc21
Temperature: 60 °C
Yield: 12 %

Procedure:
A mixture of (2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (92 mg, 0.37 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (101 mg, 0.379 mmol), potassium iodide (3 mg, 0.02 mmol), and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in acetonitrile (4 mL) was heated at 60° C. for 15 h. Saturated NaHCO3(aq) (15 mL) was added, and the mixture was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (250:5:1 CH2Cl2/MeOH/NH4OH) gave a yellow oil (21 mg, 12%). 1H NMR (CDCl3) δ 1.45 (m, 1H), 1.66 (m, 10H), 1.91 (m, 2H), 2.69 (m, 2H), 2.92 (m, 1H), 3.18 (m, 1H), 3.67 (m, 2H), 4.20 (dd, 1H, J=10, 5.6 Hz), 4.67 (d, 1H, J=15 Hz), 4.80 (d, 1H, J=15 Hz), 6.74 (s, 1H), 6.90 (s, 1H), 7.01 (dd, 1H, J=7.7, 4.7 Hz), 7.33 (m, 4H), 7.73 (m, 1H), 7.86 (m, 1H), 8.38 (d, 1H, J=3.3 Hz).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)CC)C>C(OCC)(=O)C.CS(Cl)(=O)=O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:11][C:16]#[N:18])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: N#CCc1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 3-phenoxybenzylalcohol (25.0 g) and triethylamine (26.3 ml) in ethyl acetate (300 ml), methanesulfonyl chloride (14.6 ml) was added dropwise at 0° C. After stirring for 1 hour, the reaction mixture was washed with saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in acetone (300 ml), admixed with sodium iodide (37.5 g) and then stirred for 1 hour. The reaction mixture was concentrated, and the residue was diluted with water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was dissolved in dimethyl sulfoxide (100 ml) and stirred with sodium cyanide (7.35 g) for 15 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel to obtain 3-phenoxyphenylacetonitrile (8.36 g, yield 32%) as an oil from a fraction eluted with ethyl acetate-hexane (1:7. v/v).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([Br:13])[CH:11]=2)[C:6](=[O:15])[CH:5]1[CH3:16])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:20]>C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([Br:13])[CH:11]=2)[C:6](=[O:15])[C:5]1([CH3:20])[CH3:16])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)N1c2cc(Br)c(F)cc2C(=O)C1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1c2cc(Br)c(F)cc2C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
To a stirred mixture of 1-acetyl-6-bromo-5-fluoro-2-methylindolin-3-one (D88) (800 mg, 2.80 mmol) in THF (20 mL) at 0° C. was added sodium hydride (224 mg, 5.59 mmol). After stirring for 10 min, iodomethane (0.210 mL, 3.36 mmol) was added to the mixture. The mixture was allowed to warm to RT. The mixture was stirred for 1 hour at RT. The reaction was quenched with addition with saturated NH4Cl aq. and the mixture was poured into water (100 mL). The mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give title compound (300 mg). LCMS (A): m/z (M+H)+ 300/302, C12H11BrFNO2 requires 299/301 (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([C:16]([O:18]C)=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1.[NH3:20]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([C:16]([NH2:20])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1
Reactant: COC(=O)C1CCCCc2c1[nH]c1ccc(Cl)cc21
Reactant: N
Solvent: CO
Product: NC(=O)C1CCCCc2c1[nH]c1ccc(Cl)cc21
Temperature: 90 °C
Yield: 21 %

Procedure:
Methyl 2-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-6-carboxylate (10 g, 36 mmol) was dissolved in 7 N ammonia in methanol (350 mL) and transferred to Parr pressure reactor. The reaction vessel was purged briefly to displace any air with Nitrogen. The reaction was then heated to 90° C. for 48 h. The reaction was cooled to r.t. and the solvent removed in vacuo, the crude residue was applied to a Biotage and eluted with grading (1/1 heptane/ethyl acetate to 0/1 heptane/ethyl acetate) to afford product as an off white foam, which was triturated with DCM to afford pure product 2 g (21%) as an off white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37]OS(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])([CH3:14])[C:4]([OH:3])=[O:24])=[CH:8][CH:9]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxyphenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 7.18 (d, 2H, J=8.21 Hz), 7.06 (t, 1H, J=7.82 Hz), 6.88 (d, 1H, J=8.21 Hz), 6.83-6.79 (m, 3H), 6.62 (d, 1H, J=7.82 Hz), 4.12 (t, 2H, J=6.65 Hz), 3.82 (s, 3H), 3.29 (d, 1H, J=14.08 Hz), 3.09 (d, 1H, J=14.08 Hz), 2.85 (t, 2H, J=6.65 Hz), 2.70-2.63 (m, 1H), 2.21 (s, 3H), 1.99 (d, 2H, J=12.51 Hz), 1.77 (d, 2H, J=12.90 Hz), 1.67 (d, 1H, J=11.73 Hz), 1.50 (q, 2H, J=12.51 Hz), 1.37-1.21 (m, 5H). MS [ES+] m/z exact mass calcd for C29H36NO6 494.2543, found 494.2562.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:43][C:44]([F:74])([F:73])[C:45]1[CH:46]=[C:47]([C:55]([CH3:72])([CH3:71])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][NH:61][CH2:60]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>C1COCC1>[F:53][C:51]([F:52])([F:54])[C:49]1[CH:48]=[C:47]([C:55]([CH3:71])([CH3:72])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][N:61]([C:6]([C@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:60]2)=[O:57])[CH:46]=[C:45]([C:44]([F:43])([F:73])[F:74])[CH:50]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)[C@H]2CCCO2)C[C@H]1c1ccccc1
Reaction time: 48 h
Yield: 24.2 %

Procedure:
To a stirred solution of (R)-tetrahydro-furan-2-carboxylic acid (described in Tetrahedron Asymmetry, 2003, 14(10, 1385) (5.0 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 5.8 mg (28%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.[NH2:41][C:42]1[NH:46][N:45]=[N:44][N:43]=1.N1C=CC=CC=1>ClCCl>[NH:43]1[C:42]([NH:41][C:1]([C:4]2[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:14][CH2:13]3)=[CH:6][CH:5]=2)=[O:2])=[N:46][N:45]=[N:44]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(OCCCN2CCC(OC(c3ccc(Cl)cc3)c3ccccn3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nnn[nH]1)c1ccc(OCCCN2CCC(OC(c3ccc(Cl)cc3)c3ccccn3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To 0.84 g (1.75 mmol) of 1-[3-(4-carboxyphenoxy)propyl]-4[(4-chlorophenyl)-2-pyridylmethoxy]piperidine dissolved in 8 ml of dichloromethane was added dropwise 1.5 ml of oxalyl chloride under cooling in an ice bath. The mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 0.5 hour, and concentrated under reduced pressure. The residue was added dropwise to a mixed solution of 0.15 g (1.76 mmol) of 5-amino-1,2,3,4-tetrazole dissolved in 10 ml of dichloromethane and 5 ml of pyridine under cooling in an ice bath. After completion of the dropwise addition, the mixture was stirred at 0° C. for 2 hours and then at room temperature for 2 hours, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography using a mixed solvent of chloroform and methanol in a volume ratio of 20:1 and then using a mixed solvent of chloroform, methanol and 28% aqueous ammonia in a volume ratio of 100:10:1 as eluents to obtain 0.54 g (yield: 57%) of 1-{3-{4-[N-(1,2,3,4-tetrazol-5-yl)carbamoyl]phenoxy}propyl}-4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine as an orange foamy product.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].Cl>[Cl-].[Zn+2].[Cl-].O.CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 13 ml of sulfolane were added 2.72 g of 7-ACA, 3.5 g of methanol, 8.0 g of zinc chloride and 2.9 g of antimony pentachloride. The mixture was heated at 50° C. for 80 min while stirring to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 150 ml of water. Then, the mixture was adjusted to pH 7.5 with sodium bicarbonate at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings The resulting mixture was concentrated by evaporation under reduced pressure, and adjusted to pH 7 with 1N HCl. Then, the mixture was applied to a column packed with XAD-II (packing material for reversed phase adsorption chromatography manufactured and sold by Rohm and Haas Co., U.S.A.). Then, the elution was conducted using water as an eluent to obtain an eluate The eluate was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.73 g. The yield of the desired product was 71 %.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH:34]([S:35]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:37])=[O:36])=[CH2:33]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (260 mg, 0.8 mmol) in CH2Cl2 at 0° C., triethylamine (0.44 mL, 3.2 mmol) and 2-chloroethylsulfonyl chloride (0.168 mL, 1.6 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between CH2Cl2 (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic phase washed with brine (50 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified via filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the title compound (245 mg, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:26][CH2:27][O:28][CH3:29])[CH2:21]3)[C:8]=2[N:7]=1)=[O:5])[CH3:2].C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:25][CH2:24][N:23]([CH3:32])[C@@H:22]([CH2:26][CH2:27][O:28][CH3:29])[CH2:21]3)[C:8]=2[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCOC)C1
Agent: C=O
Agent: [Na+]
Product: CCOC(=O)c1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCOC)C1
Yield: 90.5 %

Procedure:
Using the method of Example 322, using (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-4H-3-thia-1,4,9-triaza-benzo[f]azulene-2-carboxylic acid ethyl ester (300 mg, 0.72 mmol), formaldehyde (37%, w/w, aq) (72.9 mg, 0.90 mmol) and sodium triacetoxyborohydride (228.9 mg, 1.08 mmol) gives 280 mg (yield 90%) of (5)-10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-4H-3-thia-1,4,9-triaza-benzo[f]azulene-2-carboxylic acid ethyl ester: mass spectrum (electrospray) (m/e): 430.0 (M+1), 428.1 (M−1); 1H NMR (400 MHz, DMSO-d6): 8.50 (s, 1H), 6.91-6.80 (m, 3H), 6.69-6.67 (m, 1H), 4.30 (q, 2H, J=6.8 Hz), 3.83-3.81 (m, 2H), 3.32-3.30 (m, 2H), 3.13 (s, 3H), 3.12-3.06 (m, 1H), 2.81-2.70 (m, 2H), 2.22-2.13 (m, 5H), 1.83-1.75 (m, 1H), 1.53-1.46 (m,1H), 1.27 (t, 3H, J=7.2 Hz). The dihydrochloride is form by adding 5 eq of acetyl chloride (256.2 mg, 3.26 mmol) to the free base (280 mg, 0.65 mmol) in ethanol. Collect the precipitates via vacuum filtration to afford 300 mg of yellow solid of the title compound: mass spectrum (electrospray) (m/e): C21H27N5O3S.2HCl, Calc. Mass (M+1): 430.1913,
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH3:6][O:7][C:8]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:42])[C@@H:17]([NH:25][C:26](=[O:41])[C@H:27]([NH2:40])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C@H:36]([OH:39])[CH2:37][OH:38])=[CH:30][CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:13][CH:14]=1)=[O:9].C(N(CC)CC)C>O1CCCC1.O>[CH3:6][O:7][C:8]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:42])[C@@H:17]([NH:25][C:26](=[O:41])[C@H:27]([NH2:40])[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C@H:36]([O:39][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:37][O:38][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH:32][CH:33]=2)[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:13][CH:14]=1)=[O:9]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccc(OC[C@H](O)CO)cc2)n1
Reactant: C[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccc(OC[C@@H](CO[Si](C)(C)C)O[Si](C)(C)C)cc2)n1
Reaction time: 3 h
Yield: 64.6 %

Procedure:
Chloro-trimethyl-silane (0.086 ml, 0.68 mmol) was added to 2-((S)-2-{(R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (120 mg, 0.23 mmol) in tetrahydrofuran (5 mL) containing triethylamine (0.10 ml, 0.73 mmol) at room temperature and stirred for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, brine and dried over magnesium sulfate. Removal of solvents gave 2-((S)-2-{(R)-2-amino-2-[4-((S)-2,3-bis-trimethylsilanyloxy-propoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as an oil (100 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([OH:22])=[O:21])=O)=[C:5]([N+:31]([O-:33])=[O:32])[CH:4]=1.N>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]=[C:12]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:13][N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([OH:22])=[O:21])=[C:5]([N+:31]([O-:33])=[O:32])[CH:4]=1
Reactant: COc1ccc(C(=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])C(=O)N2CCCC2C(=O)O)cc1
Agent: N
Product: COc1ccc(C(=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])CN2CCCC2C(=O)O)cc1

Procedure:
General procedure d from 39 (90%); brown syrup; 1H NMR (400.13 MHz) δ 7.61 (s, 1H), 7.24 (d, J=4 Hz, 2H), 7.01 (s, 1H), 6.77 (d, J=4 Hz, 2H), 6.64 (s, 1H), 4.36 (d, J=7 Hz, 2H), 3.89 (s, 3H), 3.72 (t, J=7 Hz, 1H), 3.69 (s, 3H), 3.42 (s, 3H), 3.24 (m, 2H), 2.18 (m, 2H), 1.84 (m, 2H); MS (DCI/NH3) m/e: 429 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#N.Cl.[OH-].[Na+]>>[NH:14]([C:12]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1)[C:15]([NH2:17])=[NH:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: N#CNC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)Nc1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 17.7 %

Procedure:
A mixture of 4-nitro-o-phenylenediamine (15.3g 0.1 mol), cyanoguanidine (9.25g 0.11 mol) and dilute hydrochloric acid (40 ml, 0.2 mol) was heated under reflux for 11/2 hours. The reaction mixture was cooled, basified with dilute sodium hydroxide, and filtered. The resulting solid was washed well with water (ca 500 ml), dried in vacuo and boiled with ethanol to yield 2-guanidino-5-nitrobenzimidazole (3.90g; 20%) as pale yellow microcrystals m.p. 305°-307°C.
Reaction SMILES: Br[C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>CO>[F:35][C:36]([F:44])([F:45])[C:37]1[CH:38]=[CH:39][C:40]([NH:41][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[CH:42][CH:43]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)[C@@H](Br)C(=O)O
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 1 h

Procedure:
A solution of 10.01 g (55.3 mmol) of (R)-2-bromo-3-methylbutanoic acid in methanol is titrated with 1 M potassium hydroxide (~53 ml) in methanol to the phenolphthalein endpoint. The methanol is then removed under high vacuum at 35°, and the solid is kept at 35° under high vacuum for one hour. 4-Trifluoromethylaniline (23.89 g, 148.3 mmol) is added to the salt, and the mixture is heated in a pre-heated oil bath (90°) under nitrogen for 30 minutes. The mixture is then cooled and worked up immediately by partitioning between pentane/5% sodium hydroxide. The layers are separated and the pentane phase is extracted with 5% sodium hydroxide (2×). The combined aqueous phases are extracted with pentane (2×) and acidified with cold conc. hydrochloric acid. The aqueous phase is then extracted with ether (3×), and the combined ether phases are washed with brine and dried over magnesium sulfate. Filtration and evaporation yield (R)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid.