Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH2:4][C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)[NH2:2].[CH:22](OCC)(OCC)OCC.S(=O)(=O)(O)O>>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]3[CH:22]=[N:2][N:1]=[C:3]3[CH2:4][C:5](=[O:21])[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:13]=1
Reactant: NNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: O=C1Cc2nncn2-c2ccc(Cl)cc2N1c1ccccc1
Reaction time: 0.5 h

Procedure:
2-Hydrazino-7-chloro-4,5-dihydro-5-phenyl-3H-1,5-benzodiazepin-4-one is heated with triethyl orthoformate and concentrated sulfuric acid. The mixture is stirred for 30 minutes to give 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepine-5(6H)-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2.CCN(C(C)C)C(C)C.[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:27]([S:34][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1Cc2ccc(SCc3ccccc3)cc2C1
Temperature: 90 °C
Yield: 92.1 %

Procedure:
To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (2 g, 6.71 mmol) in 1,4-dioxane (17.1 mL) in a round bottom flask was added Pd2(dba)3 (0.154 g, 0.168 mmol), xantphos (0.194 g, 0.335 mmol), DIPEA (2.343 mL, 13.41 mmol) and benzyl mercaptan (0.873 mL, 7.38 mmol) and the resulting mixture was stirred and heated at 90° C. under nitrogen for overnight. The reaction mixture was filtered through celite, rinsed with ethyl acetate and the filtrate concentrated in vacuo. The residue was purified on silica gel, eluting with ethyl acetate in cyclohexane (0-20%) to afford the title compound (2.11 g). LCMS (A): m/z [(M-tBu)+H]+ 286, C20H23NO2S requires 341 (acidic).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:11]([O:10][CH2:9][CH2:8][NH2:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCOCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Dissolve (2-benzyloxyethyl)-carbamic acid tert-butyl ester (15 g) in DCM (50 mL), add trifluoroacetic acid (20 mL) and stir at 0° C. for 3 h. Concentrate and dissolve the residue in a minimal amount of DCM. Purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc and 2M ammonia in methanol to give the title compound (8.3 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:34](=[O:35])[CH2:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)Cc5ccccc5)c4)CC3)cccc2n1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and phenylacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]#[N:11])=[C:4]([CH3:12])[CH:3]=1.[Na].Cl.[CH3:15][CH2:16][O:17]C(C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH:9]([C:16](=[O:17])[CH3:15])[C:10]#[N:11])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(C)c1CC#N
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na]
Product: CC(=O)C(C#N)c1c(C)cc(Cl)cc1C
Temperature: 90 °C

Procedure:
Dissolve 4-chloro-2,6-dimethyl phenyl acetonitrile (2.3 g, 179.2 g/mol) in 15 mL EtOAc and add sodium metal (0.35 g, pea-sized fragments). Heat to reflux (90° C. bath temperature) under N2 overnight. Evaporate down to solid and slurry up in Et2O (100 mL); stir vigorously to break up fragments. Filter and wash solid with copious amounts of Et2O. Dissolve solid in H2O to form a clear yellow solution, and add 1.0 N HCl (100 mL) to pH 1. Extract the resulting cloudy solution with CH2Cl2 (3×100 mL) until aqueous layer is clear. Pool and dry the organic layers over Na2SO4, filter and evaporate to yellow oil (1.8 g). TLC: Rf=0.2 using 20% EtOAc/80% hexanes as eluent. LCMS=222.3 (MH+); 220.2 (M−)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]([OH:38])/[CH:11]=[CH:12]/[C@H:13]1[C@@H:17]([F:18])[CH2:16][C@H:15]([O:19]C2CCCCO2)[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]([OH:38])/[CH:11]=[CH:12]/[C@H:13]1[C@@H:17]([F:18])[CH2:16][C@H:15]([OH:19])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1O
Temperature: 50 °C
Yield: 17.2 %

Procedure:
To a stirring mixture consisting of (Z)-isopropyl 7-((1R,2R,3S,5S)-2-((S,E)-3-(2,3-dihydro-1H-inden-2-yl)-3-hydroxyprop-1-enyl)-3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step I, 15.2 g) in a 10:1 isopropanol-water solution (300 mL) was added p-toluenesulfonic acid (1 g) and the reaction mixture was heated to 50° C. The reaction progress was monitored by TLC. Upon completion of reaction, the reaction mixture was evaporated to dryness and redissolved in ethyl acetate. The organic solution was washed twice with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel. Elution with hexanes-ethyl acetate (9:1) afforded the title intermediate (2.2 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.[CH3:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[CH:22][C:21]=1[F:28]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:26]([C:25]2[CH:24]=[N:23][CH:22]=[C:21]([F:28])[C:20]=2[CH3:19])=[NH:27])[CH:13]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Cc1c(F)cncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(F)cncc1C(=N)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium bis(trimethylsilyl)amide (1.0 M, 4.1 mL, 0.0041 mol) was added slowly for a period of 5 min to a solution of 4-chloro pyridin-2-amine (0.35 g, 0.00273 mol) in anhydrous tetrahydrofuran (30 mL) at 0° C. and stirred for 15 min at same temperature. Then 4-methyl-5-fluoronicotinonitrile (0.37 g, 0.00273 mol) in tetrahydrofuran (5 mL) was added. The reaction temperature was raised to RT and the reaction mixture was stirred it for 18 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compounds. 1H NMR (400 MHz, CDCl3) δ 10.60 (bs, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.25-8.24 (d, J=4 Hz, 1H), 7.25-7.24 (d, J=4 Hz, 1H), 7.02-7.00 (d, J=4 Hz, 1H), 2.48 (s, 3H), MS (M+1): 265.1.
Reaction SMILES: O[C:2]1([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CCC(O)(c2cccs2)CC1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(CNS(=O)(=O)C(C)C)C1CCC(c2cccs2)CC1
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 80 mg (0.23 mmol) of the material prepared in Example 1 in 2 ml of dichloromethane and 32 mg (0.28 mmol) of triethylsilane at −78° C., was added 49 mg (0.35 mmol) of boron trifluoride diethyl etherate. The mixture was stirred for 1 h., the bath was removed and stirred at ambient temperature for 30 min. A saturated solution of sodium bicarbonate (2 ml) was added and extracted with dichloromethane, dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (75 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded 38 mg (50%) of the title compound. Analysis calculated for C16H27NO2S2: %C, 58.32; %H, 8.26; %N, 4.25. Found: %C, 59.06; %H, 8.48; %N, 4.31. Field Desorption Mass Spectrum: M=329.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([F:9])[CH3:8])([O:5][CH3:6])=[O:4].C(OC(=O)[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][C:27]=1[NH2:37])(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:6][O:5][P:3]([C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:37][C:27]2[CH:28]=[C:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH:30]=[CH:31][C:26]=2[NH2:25])=[CH:17][CH:18]=1)([F:9])[CH3:8])(=[O:4])[O:2][CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COP(=O)(OC)C(C)(F)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(C)(F)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[1-(Dimethoxy-phosphoryl)-1-fluoro-ethyl]-benzoic acid (50 mg, 0.18 mmol), (2-Amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (63 mg, 0.22 mmol), BOP (96 mg, 0.22 mmol), and DIPEA (70 mg, 0.54 mmol) were combined and diluted with DMF (0.72 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, and concentrated in vacuo. The residue was diluted with 5:1 CH2Cl2:TFA. The resulting solution was stirred at ambient temperature for 1 h then concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) 10.15 (s, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.56-7.62 (m, 3H), 7.43-7.48 (m, 2H), 7.37 (d, J=3.5 Hz, 1H), 7.06-7.09 (m, 2H), 3.72 (d, J=10.8 Hz, 3H), 3.57 (d, J=10.8 Hz, 3H), 1.86-1.96 (m, 3H). MS: cal'd 449 (MH+), exp 449 (MH+)
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@H:13]([OH:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:9]1[C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:11]2[CH2:12][NH:8]1
Reactant: O[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: [H][H]
Solvent: CCO
Product: O[C@@H]1CC[C@@H]2CNC[C@@H]21

Procedure:
(3aR,4R,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (2.88 g, 13.25 mmol) from Example 28 and ethanol (40 mL) were added to 20% Pd(OH)2—C, wet (0.576 g, 4.10 mmol) in a 250 mL stainless steel pressure bottle and stirred for 2 hours at 30 psi hydrogen gas at 50° C. The mixture was filtered through a nylon membrane, and the solvent was removed in vacuo to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 4.82 (s, 4H), 4.37 (dd, J=10.5, 4.8, 1H), 3.52 (dd, J=10.8, 1.7, 1H), 2.96-2.86 (m, 1H), 2.76 (dd, J=10.8, 6.9, 1H), 2.71 (dd, J=10.8, 1.8, 1H), 2.56-2.45 (m, 2H), 1.89 (td, J=11.7, 5.3, 1H), 1.80 (ddd, J=12.5, 10.3, 6.8, 1H), 1.66-1.58 (m, 1H), 1.50-1.42 (m, 1H); MS (ESI+) m/z 128 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:24])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 99.1 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid (300 mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol) and EDC-HCl (320 mg, 1.70 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum and the residue was subjected to flash silica gel column chromatography eluting with methanol/CH2Cl2 (1:99, v/v) to give the desired amide 18 as a white solid (360 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.88 (d, 2H), 7.15 (m, 3H), 7.35 (m, 7H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (ESI): 433 [C26H28N2O4+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1.[CH3:12]COCC.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:12])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1
Reactant: CCOCC
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cl)c(Cl)nc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 3 ml of tetrahydrofuran there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (144 mg; 0.75 mM) prepared as in Example 1, Step B above, and then 2 ml of ether was added. The reaction mixture was cooled in a dry ice/acetone bath, and methyl magnesium bromide (0.75 ml of 11% solution in ether; 0.75 mM) was then added dropwise over 10 minutes. The reaction mixture was stirred for 0.25 hour at the cooled temperature, allowed to gradually warm to room temperature, and then stirred an additional 0.5 hour. Ammonium chloride solution was then added with stirring for 0.25 hour, followed by addition of more ether. Layers separated; the organic layer was washed with water; the aqueous layer extracted three times with ether, washed with water. The solvent was evaporated and the residue dried, then passed through a silica gel column, eluting first with dichloromethane, then 5% ethyl acetate in dichloromethane. Product yield was 98 mg.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[NH2:9][C:10]([NH2:12])=[S:11].C(O)C>C(OCC)(=O)C>[ClH:2].[ClH:1].[CH3:7][N:6]([CH3:8])[CH2:5][CH2:4][CH2:3][S:11][C:10](=[NH:9])[NH2:12]
Reactant: CN(C)CCCCl
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)CCCSC(=N)N
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
A stirred mixture of 1-chloro-3-(dimethylamino) propane hydrochloride (305.7 g), thiourea (150 g) and ethanol (1530 ml) was heated under reflux for 24 hours then cooled to ambient temperature. Ethyl acetate was added until a faint opalescence was observed, then the mixture was stored at 4° C. for 72 hours. The resulting solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at 40° C. to give S-[3-(dimethylamino)propyl]isothiourea dihydrochloride as a white solid (403 g), m.p. 155°-157° C.
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[C:3]([O:5][CH3:6])=[O:4].S(Cl)([Cl:14])=O>ClCCl.CN(C)C=O>[Cl:14][C:2]1([C:3]([O:5][CH3:6])=[O:4])[CH2:7][CH2:8][C:9](=[O:10])[O:11]1
Reactant: COC(=O)C(=O)CCC(=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1(Cl)CCC(=O)O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In 10 ml of dichloromethane was dissolved 1.0 g of Compound (10). To the solution were added 911 μl of thionyl chloride and one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated. The concentrate was subjected to a flash chromatography using silica gel, followed by elution with hexane-ethyl acetate (1:2) to give 985 mg of the subject Compound (13).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:25]=1[C:26]([F:29])([F:28])[F:27])=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].C1(C2C=CC=CC=2)C=CC(CC(NC(C2C=NN(C3C=CC(F)=CC=3)C=2[C:59]([F:62])([F:61])[F:60])=O)C(O)=O)=CC=1>C1COCC1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([N:24]2[C:25]([C:26]([F:27])([F:29])[F:28])=[C:21]([C:19]([NH:18][C@@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:13]=[CH:14][C:15]([C:59]([F:62])([F:61])[F:60])=[CH:16][CH:17]=4)=[CH:10][CH:11]=3)[C:3]([OH:2])=[O:37])=[O:20])[CH:22]=[N:23]2)=[CH:31][CH:32]=1
Reactant: O=C(NC(Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 85 %

Procedure:
A solution of 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.200 g, 0.731 mmol, prepared in example 635) in DMF (4.0 mL) was reacted with 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride (0.213 g, 0.731 mmol), HBTU (0.277 g, 0.731 mmol), and DIEA (0.450 mL, 2.566 mmol) as described in general procedure A. The crude compound was purified by flash column chromatography on silica gel using CHCl3 (+10% hexane) to give 0.150 g (41%) of 3-biphenyl-4-yl-2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid methyl ester. A solution of this ester (0.085 g, 0.166 mmol) in THF (3.0 mL) was treated with LiOH (0.025 g) by general procedure I to afford (0.070 g, 85%) of the title compound 3-Biphenyl-4-yl-2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid as a white solid. LCMS: 498 (M+1)+. 1H NMR (DMSO-d6) 8.94 [d, 1H], 8.08 [s, 1H], 7.58 [m, 6H], 7.42 [m, 7H], 4.63 [m, 1H], 3.22 [m, 1H], 3.04 [m, 1H].
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCCCCC.C(Cl)Cl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccccc1O
Reactant: OCCCCCCCCCCCCCCCCBr
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Yield: 83.4 %

Procedure:
12.8 g (66 mmol) of 2-hexyloxyphenol, 23.3 g (73 mmol) of 16-bromohexadecan-1-ol and 20.0 g (99 mmol) of tri-n-butylphosphine were added to 350 mL of dehydrated methylene chloride followed by cooling with ice in the presence of argon. After adding 25.0 g (99 mmol) of 1,1′-(azodicarbonyl) dipiperidine a little at a time while stirring, 150 mL of methylene chloride were added. After stirring for 30 minutes at room temperature in the presence of argon, the reaction solution was refluxed for 6 hours. After cooling, the reaction solution was dropped into 100 mL of hexane and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 26.5 g of a clear liquid.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O.O>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(Br)C(=O)O
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)OCc1ccccc1
Yield: 86 %

Procedure:
2-Bromopropionic acid (750 g, 4.90 moles) and benzyl alcohol (600 g, 3.55 moles) were dissolved in methylene chloride (1500 ml). To the resulting solution was added concentrated sulfuric acid (10 ml). The resulting solution was heated to a gentle reflux for two days, water separating during this time. Water (500 ml) was added and the layers were separated. The methylene chloride was washed with saturated sodium bicarbonate and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated to give a colorless oil which was vacuum distilled to give the pure product as a colorless oil (742 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)(C)C>[N:11]([CH2:4][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(F)c1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: [N-]=[N+]=NCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 2,6-diflourobenzyl bromide (100 gms), tetrabutylammonium bromide (10 gms), t-butanol (200 ml) and sodium azide (62.8 gm) were stirred at room temperature for 22-24 hours. After the completion, reaction mass was filtered and washed with t-butanol (2.5 ml ) to give 2-(azidomethyl)-1,3-difluorobenzene.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[CH:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:35]1([CH2:41][CH2:42][NH:43][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][CH:32]=[N:33][C:25]=2[S:24][CH2:23][CH2:22][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:20])=[O:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Reactant: NCCC1CCCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCC1CCCCC1)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
158 mg (0.93 mmol) of CDI were added to a solution of 300 mg (0.93 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (8 ml), and the mixture was stirred for 1 h at RT. A solution of 151 mg (0.93 mmol) of 2-cyclohexylethylamine hydrochloride and 157 μL (0.93 mmol) of diisopropylethyl-amine in DCM (8 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 390 mg (0.90 mmol, 97%) of N-(2-cyclohexylethyl)-2-(2-(phenylsulfonyl)-ethyl-thio)nicotinamide were obtained as residue. MS: m/z 433.2 [M+H]+.