Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C@@H:8]([CH3:12])[C:9]([OH:11])=O.[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH2:25])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH:25][C:9](=[O:11])[C@@H:8]([N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[CH3:12])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: C[C@@H](C(=O)O)n1ccccc1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)n1ccccc1=O
Temperature: 0 °C
Yield: 91.5 %

Procedure:
A stirred mixture of (S)-2-(2-Oxo-2H-pyridin-1-yl)-propionic acid (70 mg, 0.42 mmol), 3-Amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (91 mg, 0.44 mmol), HOAt (63 mg, 0.46 mmol) and DMAP (59 mg, 0.48 mmol) and anhydrous THF (5 ml) was cooled to 0° C. then EDC (88 mg, 0.46 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (3% methanol in ethyl acetate) to afford the title compound as a white foam (137 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.3-1.5 (9H, 2×s), 2.5-2.7 (2H, m), 3.4-3.7 (1H, m), 3.9-4.6 (4H, m), 5.4-5.6 (1H, m), 6.2-6.3 (1H, m), 6.5-6.6 (1H, m), 7.1-7.6 (3H, m); 19F NMR (376 MHz, CDCl3) δ −230.14, −230.14, −230.17, −230.95, −231.07.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:16][NH2:17])=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.O.[CH3:58][O:59][C:60]([CH2:62][N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[C:64]1[C:72](O)=[O:73])=[O:61]>CN(C)C=O>[CH3:58][O:59][C:60](=[O:61])[CH2:62][N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[C:64]1[C:72](=[O:73])[NH:17][CH2:16][C:14](=[O:15])[N:13]([C:5]1[C:6]([O:11][CH3:12])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[O:3][CH3:2])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: COc1cc(C)cc(OC)c1N(CCC(C)C)C(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(C(=O)NCC(=O)N(CCC(C)C)c2c(OC)cc(C)cc2OC)cc2ccccc21
Reaction time: 20 h
Yield: 91 %

Procedure:
0.8 9 of [(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl]methylamine hydrochloride (compound 100) is dissolved in 10 ml of dimethylformamide and 0.58 g of 1-(methoxycarbonylmethyl)-2-indolecarboxylic acid, 1.12 g of BOP and then, dropwise, 0.75 g of triethylamine are successively added to the reaction mixture at room temperature. The reaction mixture is left at room temperature for 20 hours, is then poured into cold water and the aqueous phase is extracted with ethyl acetate. The organic extracts are washed with water and then dried over anhydrous sodium sulphate. Evaporation of the solvent leaves a yellow oil which is purified by flash chromatography on a column of silica gel, eluent: dichloromethane/methanol 98/2 (v/v) in order to obtain white crystals of methyl{2-[[(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl]methylcarbamoyl]-1-indolyl}acetate; M.p.=141° C.; Yield: 91%.
Reaction SMILES: [CH:1]12[BH:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[ClH:10]>CCOCC.CCCCCC>[Cl:10][B:9]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:1]1[CH2:2][CH2:3][CH2:4]2
Reactant: Cl
Reactant: B1C2CCCC1CCC2
Solvent: CCCCCC
Solvent: CCOCC
Product: ClB1C2CCCC1CCC2
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield following the method of Example 1 by treating 9-borabicyclo[3.3.1]nonane (9-BBN, Aldrich Chemical Company, Inc., Milwaukee, Wis.) with anhydrous HCl in ether. 11B NMR δ 79 ppm in hexane, bp 65° C. (0.3 mm).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:27])[C:5]2[O:9][CH:8]([C:10]3([OH:25])[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:4]1[C:5]2[O:9][CH:8]([C:10]3([OH:25])[CH2:11][CH2:12][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:14][CH2:15]3)[CH2:7][C:6]=2[CH:26]=[C:2]([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)[CH:3]=1
Reactant: CCCc1cnc(N2CCC(O)(C3Cc4cc(Br)cc(F)c4O3)CC2)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc(F)c4O3)CC2)nc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 103.4 %

Procedure:
To a degassed solution of 4-(5-bromo-7-fluoro-2,3-dihydrobenzofuran-2-yl)-1-(5-propylpyrimidin-2-yl)piperidin-4-ol (0.122 g, 0.280 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.112 g, 0.363 mmol), and K2CO3 (97 mg, 0.699 mmol) in dioxane (2.9 mL) and H2O (1 mL) was added Pd(Ph3P)4 (16 mg, 0.014 mmol). Upon completion of addition, the reaction mixture was stirred at 100° C. for 15 hour under argon. At the conclusion of this period, the reaction mixture was cooled to room temperature and then diluted with EtOAc/Et2O (5 mL, 1:1 v/v). The organic layer was washed with aqueous NaHCO3 (saturated, 6 mL) and aqueous NaCl (saturated, 6 mL), dried (Na2SO4), filtered, and then concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc) to afford Compound 1I as a light yellow solid (0.156 g, 97% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 2 H), 6.96 (s, 1 H), 6.91 (d, J=12.1 Hz, 1 H), 5.90 (br. s., 1 H), 4.67 (t, J=9.1 Hz, 1 H), 4.50-4.63 (m, 2 H), 4.03 (d, J=2.8 Hz, 2 H), 3.60 (t, J=5.6 Hz, 2 H), 3.26-3.40 (m, 3 H), 3.11 (dd, J=15.7, 9.1 Hz, 1 H), 2.33-2.48 (m, 4H), 1.92-2.00 (m, 2 H), 1.68-1.81 (m, 1 H), 1.52-1.67 (m, 4 H), 1.44-1.52 (m, 9H), 0.90-0.97 (t, J=7.3 Hz, 3 H). LC/MS (m/z)=539 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH:13]([C:14]([NH:16][C:17]2([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)=[O:15])[CH2:12][CH:11]2[CH:9]([CH2:10]2)[CH2:8]1.O[Li].O>>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH:13]([C:14]([NH:16][C:17]2([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)=[O:15])[CH2:12][CH:11]2[CH:9]([CH2:10]2)[CH2:8]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 62.2 %

Procedure:
The title compound (E24) (32 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from (methyl 4-(1-(3-(3-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (D141) (53 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH:31][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:9]=2)[CH3:30])[O:26][N:25]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ncco3)c2)nc1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3nc(C)no3)cc(-c3ncco3)c2)nc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 109.9 %

Procedure:
To a solution of hydrochloride salt of 3-(5-methylpyridin-2-yl)-5-(1,3-oxazol-2-yl)benzoic acid (103 mg, 0.292 mmol) in N,N-dimethylformamide (4 mL) were added (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride salt (72 mg, 0.437 mmol), EDC (168 mg, 0.875 mmol), HOBT (134 mg, 0.875 mmol) and N,N-diisopropylethylamine (204 μL, 1.17 mmol). The reaction mixture was stirred at 20° C. for 16 h. The mixture was purified by reverse-phase HPLC gave the hydrochloride salt of the title compound (125 mg). HRMS 390.1560 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.82-8.78 (m, 2H); 8.74 (t, J=1.7 Hz, 1H); 8.61 (d, J=8.2 Hz, 1H); 8.52 (s, 1H); 8.42 (d, J=8.3 Hz, 1H); 8.13 (d, J=0.9 Hz, 1H); 7.43 (d, J=0.8 Hz, 1H); 5.50 (q, J=7.2 Hz, 1H); 2.65 (s, 3H); 2.39-2.35 (m, 3H); 1.75 (d, J=7.2 Hz, 3 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Si:17]([O:1][CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc2cnccc2[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1nc2cnccc2[nH]1

Procedure:
A procedure similar to that described in Preparation 49 was repeated, except that 5.00 g of 2-hydroxymethyl-1H-imidazo[4,5-c]pyridine, 6.85 g of imidazole, 7.58 g of t-butyldimethylsilyl chloride and 100 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.40 g of the title compound, melting at 53°-55° C.
Reaction SMILES: [CH:1]1(O)[C:9]2[CH:8]=[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]3=[CH:5][C:4]=2[CH2:3][CH2:2]1>OS(O)(=O)=O>[CH:1]1[C:9]2[CH:8]=[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]3=[CH:5][C:4]=2[CH2:3][CH:2]=1
Reactant: OC1CCc2cc3ccccc3cc21
Agent: O=S(=O)(O)O
Product: C1=Cc2cc3ccccc3cc2C1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 8.6 g of benz[f]indan-1-ol in 250 mL of 10% H2SO4 was refluxed for 24 h. After cooling to room temperature the reaction mixture was extracted with three 150-mL portions of a mixture of benzene and hexane (1:2). The extracts were washed three times with 100-mL portions of water, dried (MgSO4), and evaporated to give 7.6 g (98%) of a colorless solid, mp 160°-163° C. Recrystallization from 340 mL of 95% ethanol gave 6.6 g (85%) of the hydrocarbon as colorless crystals: mp 163°-164° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH:35]=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:43][O:42][C:38]1[CH:37]=[C:34](/[CH:35]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:29][CH:28]=2)[CH:33]=[C:32]([O:31][CH3:30])[C:39]=1[O:40][CH3:41]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 4-methoxybenzyltriphenylphosphonium chloride (6.4 g, 15.3 mmol) and 3,4,5-trimethoxybenzaldehyde (3 g, 15.3 mmol) in CH2Cl2 was added a cooled aqueous solution of NaOH (62.5 eq) in H2O. The mixture was stirred at room temperature for 48 hours. The organic phase was separated and the aqueous phase was washed with CH2Cl2. The organic phase was concentrated and the residue was recrystallised from ethanol to yield the title E-trans isomer. 1H NMR (CDCl3) δ 8.7 (1H, d:), 8.2 (4H, m), 8.0 (2H, s), 5.2 (6H, s), 5.0 (6H, s). Mass Spectrum (FAB) 301 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Br)cn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a cooled, stirred solution of 5-bromopyridine-2-carbaldehyde (3.72 g, CAS 31181-90-5) and (trifluoromethyl)trimethylsilane (3.56 ml) in THF (30 ml) at 0° C. was added dropwise tetrabutylammonium fluoride solution (1.0 ml, 1 M solution in THF). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 hours. The mixture was then diluted with 1 N aq. HCl (20 ml) and stirring was continued for a further 2 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanol as a light yellow solid (3.35 g, 65%). MS (ISP): 258.0 ([{81Br}M+H]+), 256.1 ([{79Br}M+H]+).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[NH2:14][C:15]1[N:20]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=[C:17]([NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[CH:16]=1>CN(C=O)C>[CH2:22]([S:21][C:19]1[N:18]=[C:17]([NH:29][C@H:30]([CH3:33])[CH2:31][O:32][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:16]=[C:15]([NH2:14])[N:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(N)nc(SCc2ccccc2)n1
Reaction time: 24 h

Procedure:
Imidazole (0.29 g) was added to a solution of tert-butyldimethylsilyl chloride (0.34 g) and the subtitle product of step i) (0.6 g) in DMF (10 ml). The reaction was stirred for 24 h before addition of a further equivalent of tert-butyldimethylsilyl chloride and imidazole. After stirring for an additional 24 h the reaction mixture was partitioned between EtOAc (100 ml) and H2O (200 ml). The aqueous was extracted further with EtOAc (3×100 ml), the organics combined, washed with H2O (100 ml), brine (100 ml), dried (MgSO4) and concentrated to a crude solid. This material was purified by column chromatography (1:1 Et2O/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 0.50 g.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: N#CCCCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCC#N)ccc(C(C)=O)c1O
Yield: 83 %

Procedure:
A mixture of 5.8 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 ml of 7-bromoheptanenitrile and 8.3 g of anhydrous potassium carbonate in 50 ml of dimethyl formamide was stirred and heated at 75° for 20 hours. The reaction mixture was filtered and the filtrate was concentrated on the oil pump. The residual oil was chromatographed on 200 g of silica gel using 5% ethyl acetate-toluene to give 7.5 g (83% yield) of 7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptane nitrile. This was dissolved in 200 ml of ether-methanol (1:1) and cooled in an ice bath while a stream of hydrochloric acid gas was introduced for 10 minutes. The reaction mixture was kept at 3° for 1 hour and at room temperature for 16 hours. Water (40 ml) was added and most of the solvent was removed in vacuo. The residue was treated with sodium bicarbonate solution to basify and the product was extracted with ether. The crude product was dissolved in 140 ml of methanol, treated with 120 ml of 1N sodium hydroxide and the solution was heated on the steam bath for 10 minutes and left at room temperature for 66 hours. The methanol was removed in vacuo and the aqueous solution was extracted with ether. The basic aqueous layer was acidified and extracted with ether. The dried (over magnesium sulfate) extract was concentrated and chromatographed on 50 g of silica gel. Elution with acetic acid (5): ethyl acetate (25): toluene (70) and crystallization of the combined pure fractions from ether-hexane gave 2.20 g, mp 64°-66°, of 7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:8]=1[CH2:9][OH:10].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:8]=1[CH2:9][OH:10])=[O:3]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(N)c1CO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C)c1CO
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A solution of methyl chloroformate (0.416 g) in methylene chloride (1 ml) was added dropwise to a solution of 2-amino-6-methylbenzyl alcohol (0.549 g) and pyridine (0.364 g) in methylene chloride (10 ml) with ice cooling. After being stirred for 1 hour, the mixture was poured into 1N hydrochloric acid and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with n-hexane and dried to give 2-methoxycarbonylamino-6-methylbenzyl alcohol (0.64 g).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[S:15]1[C:19]2[C:20](C(Cl)=O)=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.Cl>C(#N)C.C(N(CC)CC)C>[S:15]1[C:19]2[C:20]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)c1cccc2nnsc12
Temperature: 0 °C
Yield: 83.2 %

Procedure:
4.8 g of magnesium chloride in 50 ml of acetonitrile are treated with 7.6 ml of diethyl malonate and 14 ml of triethylamine, with ice-cooling and stirring. The mixture is stirred for 20 minutes and then treated at 0°-5° C. with portions of a suspension of 9.6 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in 50 ml of acetonitrile, the temperature being maintained at between 5° C. and 15° C. The resulting beige suspension is stirred for a further hour in an ice-bath at 0° C. and subsequently overnight at room temperature. On the next day, it is cooled again to 0° C., brought to pH 4.5 using 15% hydrochloric acid, and extracted with ethyl acetate. The extracts are dried over sodium sulfate, filtered over silica gel and evaporated. This results in the title compound in a yield of 83.2% of theory and with a melting point of 72°-74° C.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([F:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccc(F)cc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Pyridine (500 uL, 6.19 mmol) was added to a solution of 4-fluoro-3-nitro-phenylamine (1 g, 6.41 mmol) and 4-fluoro-benzenesulfonyl chloride (1.2 g, 6.19 mmol) in dichloromethane (DCM) (20 mL) and the reaction was stirred at room temperature overnight. The reaction was then partitioned between water and DCM. The organic layer was washed several times with water and concentrated. Recrystalization from ethanol/water gave 1.57 g of the sub-title compound as tan crystals.
Reaction SMILES: C(N(CC)CC)C.Cl.ClC1C=C(C[C@H](N)CN(C)C)C=CC=1.[CH2:23]([O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[N:29]1CC1C=CC=C(C=O)C=1)=[O:27])[CH3:24].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:23]([O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:33])(=[O:34])[NH:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(C=O)c1
Agent: CN(C)C[C@@H](N)Cc1cccc(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCS(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 231.8 %

Procedure:
Triethylamine (338 μL, 2.4 mmol) was added to a solution of (S)-3-(3-chloro-phenyl)-N1,N1-dimethyl-propane-1,2-diamine hydrochloride salt (264 mg, 1.06 mmol) in methanol (2 mL) under argon at room temperature. The mixture was stirred for 10 min and then a solution of 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (Intermediate 8 Step 3; 250 mg, 0.96 mmol) in methanol (4 mL) was added under argon. The mixture was stirred at room temperature for 15 min and then cooled in an ice-bath. Solid sodium cyanoborohydride (90.9 mg, 1.45 mmol) and glacial acetic acid (750 μL) were added. The reaction mixture was allowed to warm to room temperature and stir. The progress of the reaction was monitored by LCMS. When the reaction was substantially complete, the solvents were evaporated and ethyl acetate (50 mL) was added. The solution was washed with washed with water (2×10 mL) and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give crude 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (430 mg) as a yellow foam which was used directly in the next step without further purification.
Reaction SMILES: C[O:2][P:3]([CH2:7][N:8]([S:10]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)(=[O:12])=[O:11])[CH3:9])(=[O:6])[O:4]C.Br[Si](C)(C)C>ClCCl>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[S:10]([N:8]([CH2:7][P:3](=[O:2])([OH:4])[OH:6])[CH3:9])(=[O:11])=[O:12]
Reactant: COP(=O)(CN(C)S(=O)(=O)c1cccs1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(CP(=O)(O)O)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonic acid dimethyl ester (obtained as described in Example 46, step 2) (180 mg, 0.6 mmol) in dichloromethane (3 mL) at 0° C. was slowly added bromotrimethylsilane (190 μL, 1.4 mmol). The reaction was gradually warmed to room temperature and allowed to stir overnight. The reaction mixture was concentrated, the residue was redissolved in dichloromethane, and the solution was again concentrated. Methanol (10 mL) was added to the residue, and the solution was stirred at room temperature for 30 min. The solution was then filtered and concentrated. The oily residue was triturated with 1:1 ether-hexanes, and an orange solid was collected by filtration. The orange solid was boiled in dichloromethane (3 mL), cooled, and filtered to yield the title compound (120 mg, 74%) as a colorless solid: 1H NMR (400 MHz, CD3OD) δH 7.87 (dd, J=1.5, 4 Hz, 1 H, Ar—H, 7.66 (dd, J=1.5, 3.5 Hz, 1 H, Ar—H), 7.25 (dd, J−4, 5 Hz, 1 H, Ar—H), 3.31 (d, J=12.5 Hz, 2 H, CH2P), 2.92 (s, 3 H, NCH3).
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[CH3:11][NH:12][NH2:13]>O>[NH2:8][C:7]1[C:6]([C:9]#[N:10])=[C:3]([S:4][CH3:5])[N:12]([CH3:11])[N:13]=1
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CNN
Solvent: O
Product: CSc1c(C#N)c(N)nn1C

Procedure:
9.63 g (56.6 mmol) of bis(methylmercapto)methylenemalononitrile are suspended in 50 ml of water and admixed with 3.7 ml (67.9 mmol) of methylhydrazine. The mixture is heated at the boil for 1 hour, the reaction solution is cooled and the precipitate is filtered off with suction and recrystallized from ethanol.