Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]Br.[OH-].[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10%) to pH ˜8.0-9.0 under cooling and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (80 mL×2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90%). 1H-NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]12[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=12)[CH3:2].C1C(=O)N([Br:30])C(=O)C1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[Br:30][C:11]1[C:12]([NH2:14])=[CH:13][C:8]2[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:15][C:16]4([CH2:21][CH2:22][C:3]3([CH2:1][CH3:2])[C:9]=2[CH:10]=1)[O:17][CH2:18][CH2:19][O:20]4
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC12CCC3(CC1CCCc1cc(N)ccc12)OCCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC12CCC3(CC1CCCc1cc(N)c(Br)cc12)OCCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
rac-(4aR,11bS)-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (22, R2=Ethyl) (0.345 g, 1.145 mmol) in THF (8 mL) was cooled to about 0° C. then NBS (0.204 g, 1.145 mmol) was added. After about 10 min, sat. aq. NaHCO3 (20 mL) and EtOAc (25 mL) were added. The mixture was warmed to rt and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,11bS)-10-bromo-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (23, R2=Ethyl) (0.255 g, 59%); LC/MS, method 3, Rt=2.85 min, MS m/z 380, 382 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.03 (s, 1H), 6.55 (s, 1H), 5.04 (s, 2H), 3.89-3.73 (m, 4H), 2.80-2.73 (m, 1H), 2.58-2.46 (m, 1H), 2.26-2.19 (m, 1H), 2.14-2.05 (m, 1H), 2.02-1.88 (m, 2H), 1.72-1.45 (m, 4H), 1.43-1.18 (m, 5H), 0.60 (t, J=7.4 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>O1CCCC1>[S:1]1[CH:5]=[C:4]([C:6]([CH:8]=[CH:9][C:10]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:12])=[O:7])[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: O=C(O)C=CC(=O)c1csc2ccccc12
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1csc2ccccc12

Procedure:
As for Example 1, 3-(benzo[b]thien-3-ylcarbonyl)acrylic acid (0.01 mole) is coupled to L-proline (0.01 mole) with N,N'-carbonyldiimidazole in tetrahydrofuran to give 1-[3-(benzo[b]thien-3-ylcarbonyl)acryloyl]-L-proline.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[C:17]([N+:6]([O-:9])=[O:7])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Yield: 92 %

Procedure:
A 3 liter three neck round bottom flask is charged with 125 mL H2SO4. Fuming nitric acid is added (8.4 mL, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 minutes at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice water mixture and extracted with diethyl ether (3×600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 minutes after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (−) m/z 220 (M−1) detected.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][N:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[N:34]=[C:33]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[O:32][N:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3noc(-c4ccccc4)n3)C2=O)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole, to give the desired product as a brown oil (67%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH:20]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[CH:20]1([CH2:25][CH2:26][NH:27][CH2:18][C:16]2[CH:15]=[CH:14][C:3]([O:4][C:5]3[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=3)=[C:2]([F:1])[CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)cc2F)cn1
Reaction time: 8 h
Yield: 9.5 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-cyclopentylethylamine (0.792 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.0850 g, 10%): TOF MS ES+ 358.2 (M+H)+, HRMS calcd for C20H25N3O2F 358.1931 (M+H)+, found 358.1925, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 ml, 20-95% over 18], tR=11.8 min, 94.2% purity.
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:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 75. Step 1. LC-MS Method 3 tR=1.111 min, m/z=478.23; 1H NMR (CDCl3) 1.15 (d, 6H), 1.55 (d, 3H), 2.17-2.29 (m, 4H), 2.42 (m, 1H), 2.91 (m, 1H), 3.95 (s, 3H), 5.70 (m, 1H) 6.80 (d, 1H), 7.03 (m, 4H), 7.30 (m, 4H), 7.71 (m, 1H), 8.30 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[C:10]1=[O:24].C(NC1C=CC=[C:31]([O:35]C)C=1)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([O:35][CH3:31])[CH:21]=2)[C:10]1=[O:24]
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Reactant: C=CCNc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(N2CCCC[C@H](N)C2=O)c1

Procedure:
(S)-3-Amino-1-(3-methoxyphenyl)azepan-2-one trifluoroacetate (143 mg, 0.411 mmol) was synthesized as described for the preparation of Intermediate 62 using N-allyl-3-methoxyaniline in step A.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](N1C=CN=C1)=[S:12].Cl.[CH3:19][O:20][C:21](=[O:31])[CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23]>CN(C)C=O>[CH3:19][O:20][C:21](=[O:31])[CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:23][C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 1-[(2-benzothiazolyl) thiocarbamoyl] imidazole (1.30 g, 5.0 mmol) and DL-phenylalanine methyl ester hydrochloride (1.08 g, 5.0 mmol) in N,N-dimethylformamide (50 mL) was heated at 90° C. for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystallized from ethyl ether-hexanes to provide 1.31 g (70%) of the titled product: mp 168°-169° C.; IR (KBr, cm-1) 3168, 3030, 1732, 1548, 1525, 1206, 1193; 1H NMR (300 MHz, DMSO-d6) δ 10.30 (br s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 7.32 (t, 1H), 7.20-7.29 (m, 6H), 5.18 (q, 1H), 3.70 (s, 3H), 3.22 (m, 2H); MS (FD) m/e 371 (M+); UV (EtOH) 303 nm (ε=25329), 247 nm (ε=12095), 203 nm (ε=28990). Anal. Calcd for C18H17N3O2S2 : C, 58.20; H, 4.61; N, 11.31. Found: C, 58.19; H, 4.70; N, 11.30.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14](O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([Cl:23])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCC2O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCC2Cl
Temperature: 25 °C

Procedure:
7-Benzenesulfonyl-chroman-4-ol (483 mg, 1.66 mmol) was dissoved in 10 mL toluene, and 182 uL (02.49 mmol) of thionyl chloride was added. The reaction was refluxed for two hours, and then cooled to room temperature. Solvent was removed under reduced pressure to yield 7-benzenesulfonyl-4-chloro-chroman (512 mg) as a crude oil. MS: 308 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[C:14](=N)(OCC)[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:14]1[NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[N:1]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(=N)OCC
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Product: CCCCc1nc2c(C(=O)OC)cccc2[nH]1
Yield: 87.3 %

Procedure:
Using the procedure of Step A of Example 1, 2.5 g of methyl 2,3-diaminobenzoate [J. Chem. Soc., Vol. 117 (1920) p 775 and CAN. J. Chem., Vol.55 (1977), p. 1653 to 1657] and 2.73 g of ethyl pentanimidoate hydrochloride [J.A.C.S., Vol. 64, p. 1827 (1942)] were reacted to obtain 3.05 g of the desired product which after crystallization from essence G melted at approximately 85° C. The analytical sample was obtained by two successive crystallizations of 280 mg of product from isopropyl ether to obtain 100 mg of the product melting at 97° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH2:23])[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CC1C=CC=CC=1C>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:23][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CNc2ncc(Br)cn2)C[C@@H]2C[C@@H]21
Temperature: 138 °C

Procedure:
5-Bromo-2-chloro-pyrimidine (18.4 mmol) is added to a solution of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (14.1 mmol) in o-xylene (28 mL). K2CO3 (42.4 mmol) and DIPEA (42.4 mmol) are added and the mixture is heated to 138° C. for 16 h. The mixture is cooled to RT and filtered. The residue is washed with DCM and the combined filtrates are concentrated in vacuo to give a crude product which is purified by flash chromatography (gradient: heptane/EtOAc 90/10 to 85/15). LC-MS: tR=1.05 min; [M+H]+=369.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]([NH:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:25]2[CH:37]=[CH:38][CH:39]=[CH:40][C:24]=2[S:23][CH2:22]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:41]>>[ClH:41].[CH2:1]([O:8][C:9]([C@@H:11]([NH:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25]2[CH:37]=[CH:38][CH:39]=[CH:40][C:24]=2[S:23][CH2:22]1)[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)CSc2ccccc21
Agent: Cl
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)CSc2ccccc21

Procedure:
In a manner similar to that described in Example 5, 0.35 g of tert-butyl 3(R)-[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 44 is treated with hydrogen chloride to give 0.25 g of 3(R)-[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as colorless powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:23])C.[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:20])[O:23][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CCCCOCc2ccccc2)CCCCC1=O
Reactant: CC(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CCCCOCc2ccccc2)CCCCC(=O)O1
Yield: 90.6 %

Procedure:
A solution of 2-(4'-benzyloxybutyl)-2-methylcyclohexanone (25.2 g, 0.092 mol), sodium acetate (8.2 g, 0.1 mol), m-chloroperoxybenzoic acid 85% (24.2 g, 0.12 mol) and distilled methylene chloride (1200 ml) is heated at reflux under a nitrogen atmosphere for 7 hours. The solution is cooled and filtered and the filtrate is washed with satd. NaHCO3, satd. NaCl, and dried (MgSO4). The solvent is removed under reduced pressure and the crude product (30.6 g) is chromatographed on SilicAR CC-7 (600 g) in hexane. Elution with 20% ethyl acetate/hexane gives 7-(4'-benzyloxybutyl)-7-methyl-1-oxa-cycloheptan-2-one (6) as a clear light yellow oil (24.2 g, 91%): ir (neat) 1720 cm-1 (lactone); nmr (CDCl3) δ1.42 (s, 3H, CH3), 2.64 (m, 2H, OC--CH2 --CH2), 3.50 (m, 2H, O--CH2 --CH2), 4.50 (s, 2H, O--CH2 --Ph), 7.32 (s, 5H, aromatic).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO>[OH:17]/[N:16]=[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)\[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCC(=O)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC/C(=N\O)c1ccccc1
Yield: 90.9 %

Procedure:
A mixture of methyl 3-benzoylpropionate (15.0 g), hydroxylamine hydrochloride (6.50 g), sodium acetate (9.60 g) and methanol (150 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and methyl E-4-hydroxyimino-4-phenylbutyrate (14.7 g, yield 91%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[N:26]1[NH:27][N:28]=[N:29][C:30]=1[NH2:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[N:26]1[NH:27][N:28]=[N:29][C:30]=1[NH:31][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:25])[NH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18]1
Reactant: Nc1nn[nH]n1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1)Nc1nn[nH]n1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol). 2H-tetrazol-5-amine (8.00 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.26 (m, 2 H), 1.43-1.57 (m, 2 H), 1.76-1.92 (m, 5 H), 2.36-2.41 (m, 2 H), 6.96-7.23 (m, 1 H), 7.23-7.46 (m, 2 H), 7.57-7.80 (m, 2 H), 11.99 (s, 1 H), 13.98 (s, 1 H), 15.83 (s, 1 H); MS (ESI) m/z 420 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
A solution of triphenylphosphine (236 mg, 0.9 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (160 mg, 0.9 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (151 mg, 0.45 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (135 mg, 1.35 mmol), and the resulting suspension was stirred for 20 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide (80 mg, 42%) as a white solid: mp 190-193° C.; EI-HRMS m/e calcd for C19H21ClN6OS (M+) 416.1186, found 416.1183.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:16])[C:9]2[C:14]([CH3:15])=[N:13][S:12][C:10]=2[N:11]=1)[CH:3]([CH3:5])[CH3:4].Br[CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1>CN(C=O)C.O>[CH2:17]([N:7]1[C:8](=[O:16])[C:9]2[C:14]([CH3:15])=[N:13][S:12][C:10]=2[N:11]=[C:6]1[CH:2]([NH:1][CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1)[CH:3]([CH3:5])[CH3:4])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nsc2nc(C(N)C(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: BrCCC1OCCO1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nsc2nc(C(NCCC3OCCO3)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 70 °C
Yield: 95.6 %

Procedure:
To a solution of 6-(1-amino-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 30) (1.6 g, 4.88 mmol) in anhydrous DMF (20 mL), 2-(2-bromo-ethyl)-[1,3]dioxolane (0.88 g, 4.88 mmol) was added and the resulting solution was heated at 70° C. for 2 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×60 mL). The combined organic extracts were dried (Na2SO4) and concentrated to provide the crude product (2 g), which was used as such in the next reaction. m/z 429 (MH+); 1H-NMR (300 MHz) δ 0.88 (d, 3H), 0.96 (d, 3H), 1.54-1.62 (m, 2H), 1.86-2.05 (m, 2H), 2.18 (bs, 1H), 2.38-2.46 (m, 1H), 2.84 (s, 3H), 3.57 (d, 1H), 3.74-3.94 (m, 4H), 4.78 (t, 1H), 4.99 (d, 1H), 5.85 (d, 1H), 7.15-7.38 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[C:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([CH:22]2[CH2:23][CH2:24]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C=C(c2ccccc2)C2CC2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Yield: 102.4 %

Procedure:
[4-(2-Cyclopropyl-2-phenyl-vinyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (94 mg, 0.28 mmol) is dissolved in methanol (1.5 mL) and DCM (1.5 mL). Then 5% palladium on carbon (59 mg, 0.028 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give 97 mg of the crude product which is used in the next step without purification.