Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7]C(=O)OC(C)(C)C)=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2cccnc2)nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Nc1cn(-c2cccnc2)nc1Cl
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To tert-butyl (3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (2 g, 6.79 mmol) in dichloromethane (6.79 ml) was added trifluoroacetic acid (6.79 ml) and the mixture was left stiffing at room temperature for 2 hours. Toluene (12 mL) was added and the reaction was concentrated to near dryness. The mixture was poured into a separatory funnel containing saturated aqueous sodium bicarbonated and was extracted with dichloromethane. The combined organic layers were concentrated to give 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.954 g, 4.90 mmol, 72.2%) as a white solid: mp 137.9-139.9° C.; 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=2.4 Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.52 (s, 1H), 7.37 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 3.18 (s, 2H); ESIMS m/z 196 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16]C(=O)C.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:36][N+:37]#[C-:38])(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:38]=[N:37][CH:36]=2)[C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][C:5]=1[NH2:16]
Reactant: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(-c2cnco2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 28.5 %

Procedure:
2-Acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (880 mg, 3.043 mmol) in MeOH (10 mL) was treated with potassium carbonate (463 mg, 3.35 mmol) and toluene-4-sulfonyl methylisocyanide (594 mg, 3.04 mmol) and the mixture was refluxed for 5 h. The reaction mixture was cooled to r.t., concentrated in vacuo and the residue was purified by flash chromatography (100 g silica gel, DCM) to give the title product (248 mg, 28%) as a yellow powder. API-ES: m/z 287.1 [M+H]+, rt 4.40 min.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (3-hydroxy)-2-(S)-(t-butoxycarbonylamino)propionate (58 g, 196 mmol), dry methylene chloride (150 ml), p-toluenesulfonyl chloride (43.35 g, 227.4 mmol), 4-(dimethylamino)pyridine (2.4 g, 19.6 mmol) and pyridine (30 ml, 371 mmol) were combined and stirred at room temperature overnight. The reaction solution was concentrated in vacuo to a pale yellow oil. The oil was stored in vacuo overnight, then the white solid that formed was isolated to give 75.33 g of crude product. The product was triturated in petroleum ether (approximately 200 ml) to yield methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate: n.m.r.: (CDCl3, 90 MHz): δ7.72, 7.31 (2x dd, 4, aromatic protons), 5.26 (m, 1, nitrogen proton), 4.48 (m, 1, C-2 proton), 4.32 (m, 2, C-3 protons), 3.68 (s, 3, methyl protons of methyl ester), 2.44 (s, 3, methyl protons of toluene moiety), 1.40 (s, 9, protons of t-butyl moiety); i.r. (CHCl3): 3435, 3019, 1753, 1711, 1502, 1369, 1351, 1250, 1215, 1190, 1177 cm-1 ; m.s.: 279, 210, 172, 91, 41;
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH3:19])=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].C=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([N:14]([CH:17]([CH3:19])[CH3:16])[CH3:20])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)N(C)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
Example 1 h, Step 1: A sample of (4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (available from Albany Molecular Research; 2.00 g, 10.7 mmol, 1 eq.), acetone (1.18 mL, 16.1 mmol, 1.5 eq.), sodium triacetoxyborohydride (3.41 g, 16.1 mmol, 1.5 eq.) and 50 mL of methylene chloride were stirred at RT for 20 hours. Added 20 mL of 1 N NaOH and stirred 10 minutes then extracted 3× with methylene chloride. The organic layers were combined, dried and stripped in vacuo to obtain an oil. Added sodium triacetoxyborohydride (3.41 g, 16.1 mmol, 1.5 eq.) and 37% formaldehyde (aqueous) (2.62 mL, 32.2 mmol, 3 eq). Stirred 4 hours. Added 20 mL of 1 N NaOH and stirred 10 minutes then extracted the aqueous 3× with methylene chloride. The organic layers were combined, dried and stripped in vacuo to give cis-[4-(Isopropyl-methyl-amino)-cyclohexyl]-carbamic acid tert-butyl ester (3.20 g) as a colorless oil. MS found: (M+H)+=271.
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:46]2[C:47]([CH:53]=O)=[N:48][CH:49]=[C:50]([Cl:52])[CH:51]=2)[CH2:43][O:44][CH3:45])(=[O:41])=[O:40])=[CH:35][C:34]=1[C:55]([F:58])([F:57])[F:56]>C1COCC1.CCOCC>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:46]2[C:47]([CH:53]3[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][C:23]=4[Cl:22])[C:26](=[O:28])[O:27]3)=[N:48][CH:49]=[C:50]([Cl:52])[CH:51]=2)[CH2:43][O:44][CH3:45])(=[O:41])=[O:40])=[CH:35][C:34]=1[C:55]([F:56])([F:58])[F:57]
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCN(c1cc(Cl)cnc1C1OC(=O)c2cccc(Cl)c21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -50 °C
Reaction time: 4 h
Yield: 26.5 %

Procedure:
To a solution of n-BuLi in hexane (0.69 mL, 1.1 mmol, 1.6 M solution in hexane) under N2 atm at −20° C. was added a solution of 2,2,6,6-tetramethyl piperidine (TMP, 187 μL) in THF (1 mL). The mixture cooled to −50° C. and a solution of 3-chlorobenzoic acid (78.3 mg, 0.5 mmol) in THF (0.5 mL) was added. The resulting reaction mixture was stirred at −50° C. for 4 h and treated slowly with 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (884 mg, 2.0 mmol) in THF (1 mL), warmed to room temperature and stirred for 2 h. The reaction mixture was slowly poured in ice cold water (10 mL), and ether was added. The bilayer was separated and the aqueous portion was washed with diethyl ether (2×25 mL) and separated. The aqueous layer was acidified with 4 N HCl solutions to pH 2 and extracted with diethyl ether (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residual solid was dissolved in CH2Cl2 (5 mL), treated with p-toluenesulfonic acid monohydrate (100 mg), and stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by flash chromatography (25% EtOAc in hexanes) to obtain 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (77 mg) in 26.6% yield. MS m/z: 581 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[NH2:36])O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:36][C:35]1[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccccc1-c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 125 °C
Yield: 90.4 %

Procedure:
To a mixture of 1-(3-(7-chloroimidazo[1,2-a]pyridin-3-yl)phenyl)-3-(2,2,2-trifluoroethyl)urea (20 mg, 0.052 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15 mg, 0.066 mmol) and cesium carbonate (51 mg, 0.156 mmol) in THF/H2O mixture (2/1, 0.75 ml) was added Pd(PtBu3)2 (3 mg, 0.005 mmol). The vial was degassed for 5 minutes then capped and heated to 125° C. for 20 minutes in a microwave. After cooling to ambient temperature, the reaction mixture was filtered through a celite pad and purified via flash chromatography (0-10% MeOH/DCM gradient containing 10% NH4OH) to yield the title compound (20 mg, 90% yield). MS (ES+) C22H18F3N5O requires: 425. found: 426 [M+H]+.
Reaction SMILES: O[C:2]1(C)[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]1[CH2:12][C:13](=[O:15])[CH3:14].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=O)=[CH:20][CH:19]=1.[CH3:28]C1C=CC(S(O)(=O)=O)=CC=1.N12CCCN=C1CCCCC2>CN(C)C1C=CN=CC=1.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:27])[O:15][C:13]([CH3:14])([CH3:28])[C:12]=2[C:3]2[CH:2]=[CH:7][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)CC1C=CC(S(C)(=O)=O)=CC1(C)O
Agent: CN(C)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC1(C)OC(=O)C(c2ccc(Br)cc2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
A mixture of [2-hydroxy-2-methyl-4-(methylsulfonyl)phenyl]propanone (1.5 g, 6.2 mmol, B. Cameron et al., WO 9619469), 4-bromophenylacetic acid (1.8 g, 8.1 mmol), 1-cyclohexyl-3-(2-morphorynoethyl)carbodiimide metho-p-toluenesulfonate (3.4 g, 8.1 mmol) and 4-(dimethylamino)pyridine (30 mg, 0.25 mmol) was stirred for 18 h at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 12.7 mmol) was added and the mixture was refluxed for 3 h. After cooled to room temperature, H2O (50 mL) was added and extracted with CH2Cl2 (50 mL×2), washed with 2N aqueous HCl (50 mL), dried over MgSO4, and concentrated in vacuo. The reaction mixture was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to give title compound (1.7 g, 65%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CN(C=O)C.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[O:3]=[C:2]([CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:1]=[O:5]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Phenylpyruvic acid (25.0 g, 152.0 mmol) was coevaporated twice with dry pyridine and then redissolved in dry pyridine (250 mL). To this solution was added acetic anhydride (170 mL, 1.8 moles) and the solution was stirred at ambient temperature for 15 h. The reaction progress was monitored by TLC. When the reaction was complete, the solution was evaporated to a viscous syrup. The syrup was dissolved in dichloromethane (700 mL) and then washed three times with 0.1 M aqueous HCl solution (3×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an amber-colored syrup. This product was purified by flash chromatography on silica gel (250 g) using dichloromethane as mobile phase. Appropriate fractions were pooled and evaporated to afford 24 g of a dry solid. This material was dissolved in THF (150 mL) and the solution was cooled in an ice-water bath. To the solution was added dropwise oxalyl chloride (51 mL, 580 mmol). After 10 min DMF (7.5 mL) was added to the reaction mixture and the reaction was stirred for 4 h at 0° C. Toluene (100 mL) was added and the reaction mixture was evaporated to give a thick oil. This material was coevaporated twice with toluene and the crude product was dried under vacuum for 5 h. The dried product was dissolved in a 1:1 mixture of THF-dichloromethane (200 mL) and the solution was cooled to −78° C. (dry ice-isopropanol bath) under argon. Then, lithium tri-tert-butoxyaluminohydride (152 mL of a 1.0 M solution in THF, 152 mmol) was added at a rate such that the internal temperature of the reaction was below 60° C. After addition was complete, the reaction was stirred below −60° C. for 10 h. The reaction was quenched by the slow addition of 2 M aqueous HCl solution (100 mL) and the mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with dichloromethane (500 mL) and then washed twice with 0.1 M aqueous HCl solution (2×100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give an amber-colored syrup. This material was purified by flash chromatography on silica gel (250 g) starting with 95:5 heptane-ethyl acetate, then with 9:1 heptane-ethyl acetate as mobile phase. Appropriate fractions were pooled and evaporated to afford 13.5 g (80%) of the desired compound.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CBr
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OCC(C)C)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 367 and isobutyl bromide, white powdery N-[2-(3-difluoromethoxy-4-isobutoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 98.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Br:21]>S1(CCCC1)(=O)=O.CC(O)C>[Cl-:11].[NH2:1][C:2]1[N:6]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Br:21])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:3]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Br:21]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: ClCOc1ccc(Cl)cc1Br
Solvent: O=S1(=O)CCCC1
Solvent: CC(C)O
Product: Nc1n(COc2ccc(Cl)cc2Br)c2ccccc2[n+]1COc1ccc(Cl)cc1Br
Product: [Cl-]
Reaction time: 22 h

Procedure:
A mixture of 1.00 g (0.00745 mol) of 2-aminobenzimidazole and 1.91 g (0.00745 mol) of 2-bromo-4-chlorophenyl chloromethyl ether in 5 ml of sulfolane is allowed to stand at room temperature for 22 hours. A solid precipitate forms within 5 minutes of mixing the two reagents. The product mixture is diluted with 10 ml of cold 2-propanol, and filtered, and the solid product is washed with two portions of cold 2-propanol. Drying in vacuo over P2O5 gives 2.28 g (100% crude yield) of the product as a white solid: mp 230° sinters, melts 233°-234° dec. The product is dissolved in 400 ml of hot 95% ethanol, and the solution is concentrated to a volume of 200 ml. The solution is allowed to cool slowly while precipitating a white floculant solid which is isolated from the chilled mixture to give 1.11 g (49% yield) of the named product: mp 235°-236°dec.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O.CS(O)(=O)=O>C[O-].[Na+]>[O:12]=[C:11]1[O:13][CH:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]1=2
Reactant: COP([O-])OC
Reactant: O=Cc1ccccc1C(=O)O
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl phosphite (11 g, 0.1 mol) then 2-formylbenzoic acid (10.51 g, 0.07 mol) or equivalent were added dropwise at 0° C. under nitrogen to a stirred solution of sodium methoxide [from sodium (2.3 g) in methanol (80 ml)], the mixture was stirred at ambient temperature for 30 minutes, then it was quenched by the addition of methanesulphonic acid (10.6 g, 0.11 mol). The methanol was removed in vacuo, the residue was partitioned between dichloromethane (200 ml) and water (50 ml), then the dichloromethane solution was washed with water (2×50 ml) and dried (MgSO4). The solvent was removed in vacuo to leave dimethyl 3-oxobenzo[c]furan-1-ylphosphonate or equivalent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23].C(N(CC)CC)C>ClCCl>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[S:18][C@@H:16]([C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17]
Reactant: CN(C)C(=S)Cl
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](SC(=S)N(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.3 %

Procedure:
(2R,3R)-2-(2,4-difluorophenyl)-3-mercapto1-[1H-1,2,4-triazol-1-yl]-2-butanol (0.10 g) was allowed to react with N,N-dimethylthiocarbamoyl chloride (0.13 g) in dichloromethane (3.0 ml) in the presence of triethylamine (49 ml) by the same manner as in Example 2. The compound (32), i.e., [(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl] N,N-dimethyldithiocarbamate (0.08 g) was obtained as colorless oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.[CH2:35]([N:42]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.CN(C=O)C.C(N(CC)CC)C>[CH2:35]([N:42]1[CH2:46][CH2:45][CH:44]([NH:47][C:21]([C:17]2[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=2[CH3:20])=[O:23])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NC1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Yield: 52.4 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were added to DMF (500 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then 1-benzylpyrrolidine-3-amine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 170.3 g (524 mmol) of N-(1-benzylpyrrolidin-3-yl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 52.4%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].O.Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:4]
Reactant: CCOC(=O)CNC
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccsc1C(=O)OC
Reaction time: 0.33 h

Procedure:
20 G. of 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester are dissolved in absolute chloroform, whereupon 21 g. of sarcosine ethyl ester are added dropwise during 10 minutes. In so doing, the mixture warms up to 50° C. After 20 minutes, the mixture is cooled, shaken once each time with water, 0.5 -N hydrochloric acid and a sodium bicarbonate solution, dried and evaporated. The remaining oil is brought to crystallization with ethanol. There is obtained 3-(N-carbethoxymethyl-N-methyl-sulfamoyl)-thiophene-2-carboxylic acid methyl ester of melting point 84°-85° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19]N2CCSCC2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:5]>C(Cl)Cl.CO>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(NCCCCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
The same procedure is used as in (1). Rf value: 0.51 (silica gel; methylene chloride/methanol=19:1)
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:24]([C:26]1[C:31]2[N:32]([CH2:35][C:36](O)=[O:37])[CH:33]=[N:34][C:30]=2[CH:29]=[CH:28][CH:27]=1)#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH:23][C:36](=[O:37])[CH2:35][N:32]2[C:31]3[C:26]([C:24]#[N:25])=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]=[CH:33]2)[CH3:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(N)c1ccc(C(C)(C)C)nc1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C(C)(C)C)nc1

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butylpyridin-3-yl)ethyl]amine (intermediate 25) (93 mg, 0.52 mmol), 7-cyanobenzimidazole-1-acetic acid (100 mg, 0.5 mmol), HATU (198 mg, 0.52 mmol) and DIPEA (226 μL, 1.3 mmol). Water is added and the reaction is concentrated then purified by reverse phase chromatography. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.26 (s, 9 H), 1.39 (d, J=7.03 Hz, 3 H), 4.87-4.97 (m, 1 H), 5.12-5.27 (m, 2 H), 7.32 (dd, J=8.01, 7.62 Hz, 1 H), 7.35 (d, J=8.20 Hz, 1 H), 7.66 (dd, J=8.30, 2.25 Hz, 1 H), 7.69 (dd, J=7.52, 0.88 Hz, 1 H), 7.99 (dd, J=8.20, 0.98 Hz, 1 H), 8.32 (s, 1 H), 8.45 (d, J=2.54 Hz, 1 H), 8.85 (d, J=7.42 Hz, 1 H). MS [MH+] calc. 362.1981 found 362.3.