Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH2:34][CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([CH:18]([OH:33])[C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[OH:33][CH:18]([C:9]1[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=[C:7]([CH2:6][C:5]([CH3:36])([CH3:4])[CH2:34][CH3:35])[N:8]=1)[C:19]([OH:32])([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(=O)c2ccc(-c3ccccn3)cc2)n1
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(C)(O)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (28 μL, 0.09 mmol) was added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-[1-hydroxy-2-oxo-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (20 mg, 0.04 mmol) in tetrahydrofuran (2 mL). After stirring at 0° C. until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 2-[1,2-dihydroxy-2-(4-pyridin-2-ylphenyl)propyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:8]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:26][NH2:27]>C1COCC1>[CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:8][NH:27][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Reactant: CN
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S,3S)-3-cyclopentyl-3-hydroxy-2-(1,3-dioxoisoindolin-2-yl)propanal (1.339 g, 4.7 mmol) in dry THF (20 mL) was cooled to 0° C. Acetic acid (2.5 mL, 44 mmol), methylamine (33% in EtOH, 2.5 mL, 20 mmol), and NaHB(OAc)3 (4.4937 g, 21.3 mmol) were added sequentially in single portions. The ice bath was removed and the mixture was stirred for 2 h at rt. The solvent was stripped and the crude 2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione was used directly in the next step. LC-MS (3 min) tR=1.07, m/z=303 (M+1).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([NH:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=1.[N+](=[CH:46][Si](C)(C)C)=[N-]>C1COCC1.CO>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:31]([NH:30][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:16])([F:17])[F:18])[CH:9]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=2)[CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:46])[N:1]=2)=[O:43])=[CH:33][C:34]=1[C:39]([F:40])([F:41])[F:42]
Reactant: O=C(NC(Cc1nn[nH]n1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of N-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (18 mg, 0.029 mmol) in THF (0.4 mL) and MeOH (0.1 mL) at rt was added (diazomethyl)trimethylsilane (0.02 mL, 2.0 M solution). The resulting solution was stirred at rt for 20 min. The solvents were evaporated and resulting residue was purified by ISCO flash chromatography (silica gel, hexane/EtOAc) to give 4-fluoro-N-(2-(2-methyl-2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 281, 11 mg, yield: 60%). LCMS: RT=4.06 min [M+H] 638.23, [M+Na] 661.26 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH2:4].[C:5]([C:8]1[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=O)[CH3:6]>O>[OH2:3].[CH3:6][C:5]1[C:8]2[C:9](=[CH:13][C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)[C:10](=[O:11])[O:12][C:2]=1[C:1]([OH:4])=[O:3]
Reactant: CC(=O)c1cc(C)c(C)cc1C(=O)O
Reactant: CCO
Solvent: O
Product: Cc1cc2c(C)c(C(=O)O)oc(=O)c2cc1C

Procedure:
4,6,7- Trimethylisocoumarin -3- carboxylic acid monohydrate, mp. (EtOH-H2O) 241°, (Found: C, 62.27; H, 5.74. C13H12O4. H2O requires C, 62.39; H, 5.64) was prepared from 2- acetyl -4, 5- dimethyl benzoic acid by an analogous procedure to that described in Example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CNC(=O)COC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)COC(=O)N1CCCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cn2)CC1
Temperature: 150 °C
Yield: 57.5 %

Procedure:
0.12 g (0.3 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate, prepared in step 11.3., 0.25 g (1.2 mmol) of 4-(trifluoromethoxy)-phenylboronic acid and 0.9 ml (1.8 mmol) of aqueous sodium carbonate solution (2M), suspended in 3.5 ml of toluene and 0.8 ml of ethanol are introduced into a Pyrex reactor. 0.07 g (0.06 mmol) of tetrakis-(triphenylphosphine)palladium is then added and, after sealing the reactor, it is maintained at 150° C. for 15 minutes under microwave irradiation. The organic phase is recovered after separation of the phases by settling, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 30/70/5 mixture of ethyl acetate, cyclohexane and methanol. After crystallization from diisopropyl ether, 0.078 g of product is obtained in the form of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:13][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1)c1ccncc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Compound 186 (209 mg, 0.770 mmol) was dissolved in DMF (4 mL), and isonicotinic acid (190 mg, 1.54 mmol), EDC hydrochloride (296 mg, 1.54 mmol) and 1-hydroxybenzotriazole monohydrate (236 mg, 1.54 mmol) were added thereto, followed by stirring at 50° C. for 3 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, followed by reslurrying with ethanol to afford the entitled Compound 187 (211 mg, 72%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: O
Solvent: CCO
Product: CNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
1,4-Difluoro-2-nitrobenzene (2.63 g, 16.53 mmol) was dissolved in EtOH (9 mL) and Methylamine 40% in Water (9 mL) was added dropwise at 0° C. and the mixture was warming up to RT overnight. 75 mL of water was added to the reaction mixture and the orange solid was filtered and washed with water (2*10 ml) to afford 2.78 g of 4-fluoro-N-methyl-2-nitrobenzenamine (Yield: 99%) as an orange crystalline solid.
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10]([OH:17])[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21](F)=[CH:20][C:19]=2[F:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:40]=[CH:39][C:32]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=1.[H-].[Na+]>CS(C)=O>[CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10]([OH:17])[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21]([O:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:40][CH:39]=3)=[CH:20][C:19]=2[F:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Oc1nc2ncnn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Reactant: COc1ccc(COCCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COCCCOc2cc(F)c(-c3c(O)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152.3 %

Procedure:
To a solution of 7-cycloheptyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (362 mg, 1.0 mmol) and 3-[(4-methoxybenzyl)oxy]-1-propanol (490 mg, 2.5 mmol) in 4.0 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol). The mixture is stirred at room temperature for 3 h, and partitioned between ethyl acetate and 1.0 N hydrochloric acid. The organic solution is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 66% ethyl acetate in hexanes to 5% methyl alcohol in ethyl acetate. Concentration provides 7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol as a yellow oil (820 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCCN1CCCCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCCN1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 3-(piperidine-1-yl)propylamine (46 mg, 0.32 mmol). The title compound was obtained as a solid (50 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.37 (1H, m), 9.03 (2H, s), 8.46 (1H, s), 7.32 (2H, dd), 7.20 (2H, dd), 4.43 (2H, m). MS m/z: 475.09, 477.08 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][NH2:50])[CH:44]=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:50][CH2:49][C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCc3cccnc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3-pyridylmethylamine (12.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-3-pyridylmethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (36.2 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[OH:16])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25]Br>CC#N>[Br:23][CH2:24][CH2:25][O:16][C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: BrCCBr
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCBr)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a stirred mixture of 2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenol (3 g, 13.63 mmol) and K2CO3 (2.4 g, 17.79 mmol) in MeCN (30 mL) was added 1,2-dibromoethane (3.3 g, 17.71 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL) and washed with brine (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to give 1-(2-(2-bromoethoxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (2.2 g, 49.5%) as a light orange solid. LC-MS (M+H)+=327.13. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (1H, s), 8.09-8.04 (3H, m), 4.70-4.69 (2H, m), 3.99-3.97 (2H, m), 2.40 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:20]([C:18]2[N:17]([CH3:23])[N:16]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:19]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NC2CC2)n(C)n1
Yield: 76 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (92 mg, 0.28 mol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (78 mg, 76%) which was obtained as a white solid. MS: m/e=371.3 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].B(F)(F)F.CCOCC>C(Cl)Cl>[C:2]1([CH:1]2[S:13][CH2:9][CH2:10][CH2:11][S:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: SCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(C2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of benzaldehyde (10.6 g, 100 mmol) and 1,3-propane dithiol in CH2Cl2 (150 mL) at room temperature was dropwise added BF3.Et2O (6.3 mL, 50 mmol) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with CH2Cl2, filtered and the filtrate washed with brine, saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford a white solid, which was recrystallized from a 1:1 mixture of ether and hexane to afford 17.0 g (87%) of the title compound (65) as white crystalline needles. 1H NMR (CDCl3, 400 MHz): δ 1.91 (m, 1H), 2.14 (m, 1H), 2.89 (m, 2H), 3.04 (m, 2H), 5.16 (s, 1H), 7.35-7.28 (m, 3H), 7.46 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].Cl[C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>C(Cl)Cl>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:4]([O:3][CH3:2])=[O:5]
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1c1nc2ccccc2o1
Temperature: 120 °C
Yield: 93 %

Procedure:
A mixture of 1.66 G (S)-pyrrolidine-2-carboxylic acid methyl ester, hydrochloride salt and 1.15 mL of 2-chlorobenzoxazole in 6 mL CH2Cl2 was subjected to microwave heating at 120° C. for 0.5 h. Solvent was evaporated. Purification by chromatography (SiO2, EtOAc/heptane) provided 2.283 g (93% yield) of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester as a waxy white solid, m/z 247.16 (MH+). A mixture of 2.0 g of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester and 1.02 G LiOH H2O in 15 mL MeOH and 15 mL water was stirred overnight at room temperature. The reaction was acidified with 1N HCl, was extracted three times with MeOH/CH2Cl2, was dried over Na2SO4 and was evaporated to provide the title compound. m/z 233.17 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][BH:12][O:11]1>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([CH:2]=[CH:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[O:11]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#Cc1cccnc1
Solvent: Cc1ccccc1
Product: CC1(C)OB(C=Cc2cccnc2)OC1(C)C
Temperature: 50 °C

Procedure:
Commercially available 3-ethynyl-pyridine 3b (1.03 g, 10 mmol) and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7.26 mL, 50 mmole) in toluene (40 mL) were combined with carbonylchlorohydridotris(triphenylphosphine) ruthenium (II), RuHCl(CO)(PPh3) (476 mg, 0.50 mmol) at ambient temperature and the reaction mixture was heated at 50° C. in an oil-bath for 16 h. The toluene was evaporated and the crude compound was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and water. The organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was eluted with a gradient of 10:1 to 2:1 hexane/ethyl acetate by flash chromatography to yield 3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-vinyl]-pyridine Compound 3c (2.2 g, 95% yield) as a yellow syrup. 1H NMR (300 MHz, CDCl3) δ 8.75 (d, 1H), 8.54 (dd, 1H), 7.83 (dt, 1H), 7.39 (d, 1H), 7.31 (dd, 1H), 6.27 (d, 1H), 1.34 (s, 12H); MS (ESI) m/z: 232.14 (M+H+).
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37]([N:41]=[C:42]=O)[CH:38]=[CH:39][CH:40]=1>>[F:33][C:34]([F:44])([F:45])[C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[N:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)/C=C/c1cnccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)/C=C/c1cnccc1N=C=Nc1cccc(C(F)(F)F)c1

Procedure:
300 mg (0.34 mmol) of iminophosphorane from Example 12A are reacted by general procedure [B] with 70 mg (0.38 mmol) of 3-trifluoromethylphenyl isocyanate, and the crude product is reacted further without purification.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 19.3 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)6, R is C2H5, R' is CH3CO] was prepared from 0.47 g of lithium hydride, 11.6 g of diethyl acetonylphosphonate and 22 g of 6-(2-chloro-4-methoxyphenoxy)hexyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil and further purified by preparative TLC on silica gel to give 5.0 g of diethyl [1-acetyl-7-(2-chloro-4-methoxyphenoxy)heptyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13]>O>[C:15]1([C:11](=[N:2][OH:3])[CH2:12][CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NO
Reactant: CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Hydroxylamine hydrochloride (17.1 g, 246 mmol) and sodium acetate (20.2 g, 246 mmol) were added to 110 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. Propiophenone (30 g, 224 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (100 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 32.4 g of the title compound. 1H NMR (CDCl3, 200 MHz): δ=9.21 (s, 1H), 7.60-7.72 (m, 2H), 7.38-7.50 (m, 3H), 2.91 (q, 2H, J=7.8 Hz), 1.23 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[O:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccc(C(=O)c2ccnc(Cl)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc(C(O)c2ccnc(Cl)n2)c1
Reaction time: 1.67 h
Yield: 95.9 %

Procedure:
3-[(2-chloropyrimidin-4-yl)carbonyl]benzonitrile (3 g, 12.31 mmol) was dissolved in 90 mL dry methanol and cooled to 0 C. Sodium borohydride (Acros, 0.512 g, 13.54 mmol) was dissolved in 30 mL dry methanol and added slowly via syringe, and the reaction mixture stirred at 0 C for 100 min. Additional sodium borohydride (0.256 g, 6.77 mmol) was dissolved in 15 mL dry methanol and added via syringe. After 20 minutes the reaction mixture was diluted with methylene chloride and quenched with saturated sodium bicarbonate. The resulting mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The aqueous portion was extracted with methylene chloride (3×), and the combined organic portion dried over sodium sulfate and concentrated in vacuo to give 3-[(2-chloropyrimidin-4-yl)(hydroxy)methyl]benzonitrile (2.9 g, 96%). LRMS m/z (M+H) Calcd: 246.7, found: 246.0.
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14](O)(=O)[C:15]1C=CC=CC=1>>[CH3:13][O:12][C:3]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:10][CH:11]2[CH:1]([CH2:14][CH2:15]2)[O:2]1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: O=C(O)c1ccccc1
Product: COC1(c2ccccc2)OC2CCC2O1
Yield: 4737.1 %

Procedure:
21.5 g (0.25 mol) of cyclobutane-cis-1,2-diol, 47.8 g (0.26 mol) of orthobenzoic acid trimethyl ester and 0.5 g of benzoic acid are heated to 100° to 150° C. in the course of 3 hours. The methanol which forms is distilled off continuously. The residue is subjected to fractional distillation and gives 40.0 g (78%) of 3-methoxy-3-phenyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) of boiling point0.7 92°.