Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH3:8])[N:3]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].C(N(CC)CC)C.[NH2:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32].Cl.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1>ClCCl.CN(C=O)C>[CH3:8][O:7][C:4]1[N:3]=[C:2]([NH:1][C:9]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:10])[S:6][N:5]=1.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1
Reactant: COc1nsc(N)n1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nsc(NC(=O)N[C@@H](CC(C)C)C(=O)O)n1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
To 5-amino-3-methoxy-[1,2,4]thiadiazole (1.31 g, 10 mmol) in dichloromethane (15 mL) at room temperature was added 1,1'-carbonyldiimidazole, CDl, (1.78 g,11 mmol) followed by triethylamine (2.1 mL, 15 mmol). The resulting suspension was stirred under nitrogen for 2.5 h. Volatile materials were removed in vacuo and the residue was dissolved in DMF (20 mL). The latter was then added to a solution of L-leucine-L-proline methyl ester hydrochloride (4.18 g,15 mmol) and triethyl amine (2.1 mL, 15.1 mmol) in DMF (25 mL). The resulting mixture was heated at 120° C. for 2 h and then allowed to cool to room temperature. Volatile materials were removed in vacuo and the residue was diluted with ethyl acetate (250 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent mixture of hexane and ethyl acetate (1/1 and 2/3) afforded {3-methoxy-[1,2,4]-thiadiazol-5-yl}carbamoyl-L-leucine-L-proline methyl ester as a light yellow foam (3.2 g, 76.6%). M.p. 88-90° C.; 1H-NMR (CDCl3) δ12.75 (s, 1H, NH), 6.70 (d, J=12.0 Hz, 1H, NH), 4.79-4.87 (m, 1H, NCHpro), 4.54-4.59 (dd, J=11.8, 6.0 Hz, 1H, NCH), 4.12 (s, 3H, OMe), 3.64-3.90 (m, 2H, NCH2 pro), 1.56-2.26 (m, 6H, 3CH2), 0.94-1.12 (two d, J=9.7 Hz, 7H, 2CH3 +CH); 13C-NMR (CDCl3) δ178.3 (C3), 172.3, 171.1 (CO2), 165.9 (C5), 153.7 (NHC=ONH), 58.8, 56.6, 52.2, 49.8, 47.0 (CH2), 42.0 (CH2), 29.0 (CH2), 24.8 (CH2), 24.5, 23.2, 22.0; MS (m/z) 400 (M+ +1),326, 271, 243, 209,158, 130, 87.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[OH:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2cccc(O)c2)cc1

Procedure:
Compound (112) was prepared from compound (26) and (3-hydroxy-phenyl)-boronic acid by adapting the procedure of Example 27A. LC/MS System B; Rt=1.23 mins, m/z (ES−)=323 (M−H for C19H16O5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=2[F:32])[C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.[CH3:62][N:63]([CH3:65])[NH2:64]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:63]([CH3:65])[CH3:62])=[O:29])=[CH:25][C:24]=2[F:32])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)N
Reactant: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(C(=O)O)cc2F)S(=O)(=O)c2ccc(Cl)cc2)C1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)NC(=O)c1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid (0.15 g, 0.30 mmol) was dissolved in DMF (20 ml) and treated with 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) (0.1 g, 0.33 mmol), Hünig's base (0.15 ml, 0.90 mmol) and N,N-dimethyl hydrazine (0.07 ml, 0.90 mmol). After 1 h the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with NaHCO3, KHSO4/K2SO4, brine, dried (Na2SO4) filtered anconcentrated under reduced pressure. Crystallisation from isopropyl acetate yielded 4-chloro-N-[4-(N′,N′-dimethyl-hydrazinocarbonyl)-2-fluoro-benzyl]-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide as a crystalline solid: δ 0.12 g; MS: m/e=525.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[Na].Cl.[C:15](#[N:17])[CH3:16]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:16][C:15]#[N:17])=[O:9])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC#N
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxybenzoate (7.2 kg) in dimethyl sulfoxide (21.6 L) were added sodium methoide (3.046 kg) and acetonitrile (2.135 kg) and the mixture was stirred at 110° C. for 2 hours. Then, water (10.83 L) was added dropwise thereto at 15° C. or lower and further acetonitrile (14.4L) was added to the mixture. Then, 6 N HCl was added thereto to adjust to pH 7.9 and the mixture was extracted with ethyl acetate (72L). The aqueous layer was further extracted with ethyl acetate (36.32 L). The organic layers were combined and concentrated until the content became 17.39 kg. Methanol (17.84 L) was added thereto and water (17.84 L) was added dropwise. Then, the mixture was stirred at 5° C. for 1 hours and crystals deposited were filtered off and washed with methanol-water (1:1) to obtain the titled compound '6.40 kg, 82.7 g). 1H-NMR (CDCl3) δ:3.90 (3H, s), 4.03 (2H, s), 6.98 (2H, d, J=11.25 Hz), 7.50 (2H, d, J=11.25 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(#N)C.C1CCN2C(=NCCC2)CC1.Cl[C:27]1[C:28]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N+:47]([O-:49])=[O:48])[CH:42]=2)(=[O:40])=[O:39])=[N:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>CO>[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH:5][C:27]1[C:28]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N+:47]([O-:49])=[O:48])[CH:42]=2)(=[O:39])=[O:40])=[N:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2
Reactant: COc1ccc(Cl)c(N)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 20 °C

Procedure:
Prepare a solution with 0.585 kg of 2-chloro-5-methoxyaniline-HCl, 3.5 volumes of acetonitrile and 0.46 kg of DBU. (solution A) Mix 1 kg of N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide and 5.5 volumes of acetonitrile. Heat to reflux. Add solution A and 1 volume of acetonitrile onto the reaction mixture. After completion of the reaction at reflux, cool down at 20° C., dilute with 10 volumes of methanol and filter. Wash the cake 3 times with 5 volumes of methanol and dry it under vacuum.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)(C)C.[Cl:31]N1C(=O)CCC1=O>C(#N)C.O1CCCC1>[Cl:31][C:20]1[N:21]=[C:17]([C@@H:8]([NH2:7])[C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[NH:18][C:19]=1[C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2F)[nH]1
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H](c1ccccc1)[C@H](N)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Reaction time: 1 h

Procedure:
To a solution of {(1S,2S)-1-[5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (1.10 g, 2.11 mmol) in 10:1 v/v acetonitrile/tetrahydrofuran (20 mL) under an atmosphere of nitrogen was added N-chlorosuccinimide (352 mg, 2.64 mmol) and the mixture was refluxed for 24 hours. The reaction was concentrated in vacuo, diluted with ethyl acetate (60 mL) and washed with saturated sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. To a solution of the crude product in dichloromethane (20 mL) under an atmosphere of nitrogen was added trifluoroacetic acid (6 mL) and the mixture was stirred for one hour. The reaction mixture was concentrated in vacuo then basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propylamine which was used in the subsequent step without further purification (860 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([Mg]Cl)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[OH:7])=[CH:4][CH:3]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzaldehyde (4.5 g, 24.32 mmol) in THF (40 ml) was immersed in an ice/methanol bath, followed by the dropwise addition of cyclohexylmagnesium chloride (2M) in diethylether (18.24 ml, 36.5 mmol) at −1° C. to +2° C. The reaction was allowed to warm up to room temperature and the reaction was stopped after 1 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by flash chromatography (normal phase, n-heptane (isom. mixture)/ethyl acetate 4:1) to obtain the title compound as yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)[CH:7]=[C:6]([O:17][C:18]2[CH:23]=[CH:22][C:21]([P:24]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:20][CH:19]=2)[CH:5]=1.O1CCOCC1.[OH-].[Na+]>O>[CH:27]([O:26][P:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([S:10][C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[CH:7]=2)[C:3]([OH:34])=[O:2])=[CH:19][CH:20]=1)([O:30][CH:31]([CH3:33])[CH3:32])=[O:25])([CH3:28])[CH3:29]
Reactant: COC(=O)c1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(Sc2nccn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)OP(=O)(OC(C)C)c1ccc(Oc2cc(Sc3nccn3C)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A mixture of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid methyl ester (292 mg, 0.58 mmol), 3 mL of dioxane, 3 mL of water and 1.2 mL of 1 M aqueous NaOH was stirred for 2 h at rt, diluted with water, washed with EtOAc, the aqueous layer pH lowered to 4 with 1 M NaHSO4, the aqueous layer extracted with 4:1 CH2Cl2/MeOH. The organic extract dried (MgSO4) and evaporated to provide 234 mg (82%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 1.18 (d, 6H, J=6 Hz), 1.28 (d, 6H, J=6 Hz), 3.64 (s, 3H), 4.55 (m, 2H), 7.03 (t, 1H, J=2 Hz), 7.13 (s, 1H). 7.15 (dd, 2H, J=8, 3 Hz), 7.31 (dd, 1H, J=2, 1 Hz), 7.35 (t, 1H, J=1 Hz), 7.50 (s, 1H), 7.72 (dd, 2H, J=12, 8 Hz); LCMS (m/z): 491.9 [C23H27N2O6PS+H]+.
Reaction SMILES: [C:1]([S:26]([OH:29])(=[O:28])=[O:27])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[P].FF>>[O:27]([S:26]([C:1]([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:23])([F:24])[F:25])([F:20])[F:21])([F:17])[F:18])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2])(=[O:28])=[O:27])[S:26]([C:1]([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:24])([F:25])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2])(=[O:29])=[O:28]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FF
Agent: [P]
Product: O=S(=O)(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 37 %

Procedure:
Then, the first distillation of Example 14 was repeated, thereby to obtain 79.9 kg of (C8F17SO2)2O which is colorless and transparent. By chemical analysis, this first distillate was found to have a purity of 91 wt % and contain 5 wt % of C8F17 SO2.OC8F17, 2 wt % of C7F15SO2.OC7 F15, up to 0.5 wt % of C6F13SO2.OC6F13, 2 wt % of C8F17SO3H, up to 0.5 wt % of C7F15 SO3H, 620 wt ppm of phosphorus, and 4,100 wt ppm of free fluorine. The amount of (C8F17SO2)2O produced by the reaction was 72.7 kg, and the yield was 37%, based on the amount of C8 F17SO3H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[C:28](=[N:29][N:30]([CH3:33])[N:31]=4)[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[C:28](=[N:29][N:30]([CH3:33])[N:31]=4)[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3nn(C)nc23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((2-methyl-6-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (22 mg, 0.042 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.3 mg, 0.084 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to 13 mg (71%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.32 (m, 2H), 7.30 (s, 1H), 6.99 (m, 2H), 4.80 (s, 2H), 4.51 (s, 3H), 3.53 (s, 2H), 2.57 (m, 2H), 2.21 (m, 7H), 2.00 (m, 2H). Mass spec.: 437.08 (MH)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:12])[CH3:11])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-Trifluoromethoxyphenyl)ethanone (1.00 g, 4.90 mmol) in THF (5 mL) at 0° C. was added IM LiAlH4 in THF (5.9 mL, 5.9 mmol), and the solution was allowed to warm to rt. A few drops of water were added to quench. The mixture was concentrated in vacuo, transferred to a separatory funnel, and extracted using DCM and sat. aq. Rochelle salt. The organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10](OC(=O)NC)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][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][CH3:32])(=[O:7])=[O:6].[CH3:39][N:40]=[C:41]=[O:42].O.C[N:45](C)C=O>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:45][C:41]([NH:40][CH3:39])=[O:42])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][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][CH3:32])(=[O:6])=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC
Reactant: CN=C=O
Reactant: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 480 mg of the amine III e1' in 5 ml of N,N-dimethylformamide is added 0.2 ml of methylisocyanate. The mixture is stirred at room temperature for 1 h, poured to water and extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is subjected to flash chromatography on silica gel in chloroform:methanol (9:1) and recrystallized from ethyl acetate to give 469 mg (88.0% yield) of the titled compound. mp. 87°-90° C.
Reaction SMILES: Cl[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1)=O.[C:13]([NH2:19])([NH2:18])=[N:14][C:15]([NH2:17])=[S:16]>C(O)C>[NH:14]([C:15]1[S:16][C:2]([CH3:12])=[C:3]([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=2)[N:17]=1)[C:13]([NH2:19])=[NH:18]
Reactant: NC(=S)N=C(N)N
Reactant: Cc1ccnc(C(=O)C(C)Cl)c1
Solvent: CCO
Product: Cc1ccnc(-c2nc(NC(=N)N)sc2C)c1
Yield: 74.7 %

Procedure:
To a solution of 2-chloro-1-(4-methylpyridin-2-yl)propan-1-one (0.4 g) in ethanol (5 ml) was added 2-imino-4-thiobiuret (257 mg). The mixture was refluxed for 2 hours, and the solvent was evaporated under reduced pressure. To the residue were added ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution. The ethyl acetate layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, dichloromethane:methanol:triethylamine=80:10:1) to give 2-guanidino-5-methyl-4-(4-methylpyridin-2-yl)thiazole (402 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[NH2:10])[CH:2]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:9]=2[NH:10][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1Oc1cccnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A yellow solution of 2-(pyridin-3-yloxy)-5-(trifluoromethyl)aniline (263 mg, 1.035 mmol) and pyridine (108 μL, 1.341 mmol) in dry THF (8 mL) was treated dropwise with phenyl chloroformate (156 μL, 1.242 mmol) during 5 min at 0° C. The resulting suspension yellow suspension was stirred at 0° C. for an additional 5 min and then allowed to warm up to room temperature and stirred for 3 h. The yellow suspension was filtered over cotton, washed with Et2O and diluted with EtOAc. The yellow solution was washed with sat. aqueous NaHCO3 (30 mL) and H2O (30 mL), dried and concentrated to dryness to give a yellow oil. Purification by column gave a tan solid. Yield: 300 mg (77%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.Cl.[N+:37]([C:40]1[CH:48]=[CH:47][C:43]([CH2:44][CH2:45][NH2:46])=[CH:42][CH:41]=1)([O-:39])=[O:38]>ClCCl.O>[N+:37]([C:40]1[CH:41]=[CH:42][C:43]([CH2:44][CH2:45][NH:46][C:5]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:16]3[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=3)=[CH:21][CH:22]=2)=[O:11])=[CH:47][CH:48]=1)([O-:39])=[O:38]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1ccc([N+](=O)[O-])cc1)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 2 h
Yield: 40 %

Procedure:
0.5 g (1.7 mmol) of triphosgene is dissolved in 8 ml of dichloromethane in a 100 ml flask, under argon. Using a motorized syringe, a solution of 0.92 g (5 mmol) of 4-aminodiphenylamine and 1.44 ml (8.2 mmol) of diisopropylethylamine in 15 ml of dichloromethane is added over one hour. Five minutes after the addition is finished, 1.01 g (5 mmol) of 4-nitrophenethylamine hydrochloride followed by a solution of 1.44 ml (8.2 mmol) of diisopropylethylamine in 10 ml of dichloromethane are added in a single portion. After agitation for two hours at 20° C., the reaction mixture is diluted with 50 ml of dichloromethane and 20 ml of water. The organic phase is decanted and rewashed with 20 ml of water. After drying over MgSO4 and filtration, the organic solution is partially concentrated under vacuum. The precipitate formed is collected by filtration and rinsed with dichloromethane. A yellow solid is obtained with a yield of 40%. Melting point: 204-205° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]([O:10][C:11](=[O:24])[NH:12][CH:13]([CH:21]1[CH2:23][O:22]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11](=[O:24])[NH:12][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:21]([OH:22])[CH2:23][NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C1CO1
Reactant: CC(C)CN
Product: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
To 154.4 Kg isobutylamine, (1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (53.3 Kg) was added, and then the solution was heated under reflux. Under reduced pressure, isobutylamine was removed from the reaction mixture, and then replaced by toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C.[Ni]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1cc(N)c(F)cc1Cl
Yield: 95.2 %

Procedure:
A solution of ethyl 2-(2-chloro-4-fluoro-5-nitrophenyl)acetate (22.5 g, 86.2 mmol) in ethanol (200 mL) was stirred with Raney Ni (20% slurry in water, ˜5.0 g, 17 mmol) under a hydrogen atmosphere (30 psi) for 5 h. The catalyst was removed by filtration and the filtrate was concentrated to give ethyl 2-(5-amino-2-chloro-4-fluorophenyl)acetate (19 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.10 (d, J=11.2 Hz, 1 H), 6.71 (d, J=9.2 Hz, 1 H), 5.27 (s, 2H), 4.05 (q, J=6.8 Hz, 2 H), 3.57 (s, 2 H), 1.14 (t, J=6.8 Hz, 3 H); MS (ESI) m/z: 232.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1F

Procedure:
A mixture of 14.0 g (0.1 mole) of 2-fluorobenzoic acid and 30 ml of thionyl chloride (SOCl2) is refluxed in 70 ml of benzene for four hours. The mixture is cooled and concentrated under vacuum to give 2-fluorobenzoyl chloride as a liquid.