Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([O-:11])=[O:10].Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 84 °C
Yield: 49 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 178 mg of p-nitroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 4 hours under a nitrogen atmosphere. A precipitate was formed which was collected by filtratio. 6-Chloro-N-(4-nitrophenyl)pyrimidin-4-amine hydrochloride in the form of bright yellow crystals was obtained.
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8](Cl)=[O:9])=[O:4].[C:17]([O:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:36]([NH2:37])[C:35](=[O:38])[N:26]2[C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:19])[CH3:18].C1OC1C>C(OCC)(=O)C>[C:17]([O:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:36]([NH:37][C:8](=[O:9])[C:7](=[N:6][O:5][C:3](=[O:4])[CH:2]([Cl:16])[Cl:1])[C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[C:35](=[O:38])[N:26]2[C:27]=1[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])(=[O:19])[CH3:18]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Agent: CC1CO1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3cccs3)[C@H]2SC1

Procedure:
A solution of 2-dichloroacetoxyimino-(thien-2-yl)acetyl chloride (syn-isomer) in ethyl acetate (300 ml.) was added to a stirred solution of t-butyl 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (43 g) and propylene oxide (34 ml.) in ethyl acetate (400 ml.) at 20°. Initially a solid precipitated out but it gradually redissolved. The temperature was maintained between 20° and 30° by alternately cooling and warming the solution. After 4 hours the solution was washed with 2 N-hydrochloric acid, saturated sodium bicarbonate solution, water and brine, and was dried and concentrated under reduced pressure to give the title ester as an oil that was used directly in the next stage.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([O:24][CH2:25][C:26]([NH2:28])=[O:27])=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([O:24][CH2:25][C:26]([NH2:28])=[O:27])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(OCC(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2cccs2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give 2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinyl]oxy}acetamide hydrochloride (0.11 g, 91.7%) as an amorphous solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccc3oc4ccccc4c3c2)cc1

Procedure:
N-phenyldibenzo[b,d]furan-2-amine (5.0 g, 19.3 mmol), and 1-bromo-4-iodobenzene (10.9 g, 38.6 mmol) were mixed in 100 mL of toluene. The solution was bubbled with nitrogen for 15 min. Pd(OAc)2 (0.22 g, 1.0 mmol), triphenylphosphine (0.51 g, 1.9 mmol) and sodium t-butoxide (2.2 g, 23.1 mmol) were added. The mixture was refluxed overnight under nitrogen.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH:34]([OH:41])[CH2:35][CH2:36][NH:37][CH:38]([CH3:40])[CH3:39]>>[OH:41][CH:34]([CH2:35][CH2:36][NH:37][CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: CC(C)NCCC(O)CCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCNC(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by the procedure analogous to Example 1. MS (APCI, m/z): 504 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]([CH2:10][CH2:11]O)[C:4]([CH3:13])=[CH:3]1.CC12[O:23][CH2:22][CH2:21]C1C(C)(C)CC=C2.CC12OCCC1C(C)(C)CC(=O)C2>>[CH3:13][C:4]1[CH:5](/[CH:10]=[CH:11]/[C:22]([CH3:21])=[O:23])[C:6]([CH3:9])([CH3:8])[CH2:7][CH2:2][CH:3]=1
Reactant: CC1(C)CC=CC2(C)OCCC12
Reactant: CC1=CC(=O)CC(C)(C)C1CCO
Agent: CC1(C)CC(=O)CC2(C)OCCC12
Product: CC(=O)/C=C/C1C(C)=CCCC1(C)C

Procedure:
Identification has been carried out by mass spectrum as stated above. The composition can be characterized by the presence of compounds 1 [2-(4-hydroxy-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and 2 [2-(4-keto-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and especially 3 [1,5,5-trimethyl-9-oxa-bicyclo[4.3.0]non-2-ene] and 4 [1,5,5-trimethyl-9-oxa-bicyclo[4.3.0]nonan-3-one]. (See Table A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14](O)=[O:15])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:29]1C=CN=C1)=O.O.N>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([NH2:29])=[O:15])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(CC(=O)O)sc2-c2ccc(F)cc2)cc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(CC(N)=O)sc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 78.2 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetic acid (4.1 g) and 1,1'-carbonyldiimidazole (1.8 g) in tetrahydrofuran (50 ml) was stirred and refluxed for 1 hour. The mixture was added dropwise to an ice-cooled mixture of ammonia water (28%; 5 ml) and tetrahydrofuran (10 ml). The resulting mixture was stirred overnight, diluted with water, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, water, and dilute hydrochloric acid, successively. The organic layer was dried and concentrated, and the residue was recrystallized from a mixture of chloroform, ethyl acetate and ethanol to give crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetamide (3.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].C([Sn](CCCC)(CCCC)[CH:25]=[CH:26][O:27][CH2:28][CH3:29])CCC>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:26]([O:27][CH2:28][CH3:29])=[CH2:25])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (17.8 g, 46.1 mmol), tetrakis-(triphenylphosphine)-palladium (2.67 g, 2.30 mmol), and tributyl-(ethoxyvinyl)-tin (25.0 g, 69.2 mmol) in dioxane (100 mL) was heated to 110° C. for 20 h under nitrogen. The mixture was allowed to cool to r.t., and then filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (silica gel 60, hexanes/EtOAc 3:1) to give crude 2-acetylamino-5-(1-ethoxy-vinyl)-4-trifluoromethyl-benzoic acid methyl ester as an orange solid, m.p. 65-73° C., ESI-MS: m/z 332 [M+H]+. This crude product was used without further purification in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15](=[O:17])[CH3:16])[C@@H:10]([CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19].CCOCC>C(Cl)Cl>[ClH:19].[CH3:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]([CH3:18])[N:11]1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N1[C@H](C)CN(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N1[C@H](C)CNC[C@@H]1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(3S,5R)-4-Acetyl-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.75 mmol) was dissolved in DCM (10 ml) and acidified with HCl/Et2O. The mixture was stirred at room temperature for two days. The resulting solid was filtered to give 190 mg of 1-((2R,6S)-2,6-dimethyl-piperazin-1-yl)ethanone hydrochloride. The mother liquors were treated with HCl/Et2O for 4 h and the resulting solid was filtered to give additional 43 mg of the title compound as hydrochloric salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]C)[C:5](N)=[N:6][CH:7]=1.N(OC(C)(C)C)=O>C(O)(=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][C:5]2=[N:6][CH:7]=1
Reactant: CSc1ccccc1-c1cc(Cl)cnc1N
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1cnc2sc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Solution of 5-chloro-3-(2-(methylthio)phenyl)pyridin-2-amine (5.2 g, 19.3 mmol) in 50 mL of glacial acetic acid and 20 mL of THF was cooled down to −10° C. and tert-butyl nitrite (4.6 mL) was added dropwise. The reaction mixture was stirred overnight at 0° C., warmed to room temperature, diluted with 100 mL of water. Solid material was filtered and dried, providing 2.5 g of pure 3-chlorobenzothieno[2,3-b]pyridine.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:6][CH:5]([OH:7])[CH2:4]1)#[N:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=O)=O>ClCCl>[Si:29]([O:7][CH:5]1[CH2:6][C:3]([C:1]#[N:2])([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:4]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#CC1(c2ccc(F)cc2)CC(O)C1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC1CC(C#N)(c2ccc(F)cc2)C1
Temperature: 25 °C
Yield: 104 %

Procedure:
3-cyano-3-(4-fluorophenyl)cyclobutan-1-ol (112, 19.8 g, 103.6 mmol) was dissolved in dichloromethane (200 mL) under argon, then 2,6-lutidine (27.78 g, 30.1 mL, 259 mmol) was added and the solution cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulphonate (32.9 g, 28.6 mL, 124.3 mmol) was added dropwise and the stirred reaction mixture was then allowed to warm up to room temperature overnight. The reaction mixture was washed successively with water, hydrochloric acid (0.1M), saturated sodium bicarbonate solution and brine before being dried over sodium sulphate. Filtration and evaporation gave 32.9 g of a yellow oil which was used in the next step without further purification. Rt=1.30 min (Method 18). Detected mass: 306.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[CH2:13].C([O-])(=O)C.[NH4+]>COCCOC.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CC(=O)OCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCCCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Microencapsulated Pd(OAc)2 (prepared as described in Example 1, 0.25 g, 2 mol %, based on palladium content) was added to a solution of 4-bromo nitrobenzene (1 mmol), butyl acrylate (1.5 mmol) and ammonium acetate (3 mmol) in 1,2-dimethoxyethane (5 mL) and stirred at 90° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with ether (50 mL) and filtered through a polyethylene frit (20-micron porosity). The filtrate was washed with water (2×20 mL), brine (20 mL) and dried (MgSO4). Evaporation under reduced pressure and purification by column chromatography gave butyl 4-nitro-trans-cinnamate 87%; IR: 1709, 1643, 1519 and 1343; 1H NMR (400 MHz; CDCl3): 8.24 (2H, d, J 8.8), 7.7 (1H, d, J 15.6), 7.67 (2H, d, J 8.5), 6.55 (1H, d, J 16.1), 4.23 (2H, t, J 7), 1.7 (2H, qn, J 7.6), 1.44 (2H, sext, J 7.6) and 0.97 (3H, t, J 7.4); 13C NMR (CDCl3): 166.0, 148.4, 141.5, 140.6, 128.5, 124.1, 122.6, 64.8, 30.6, 19.1 and 13.6.
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-])=O)[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)C>[NH2:22][C:19]1[CH:18]=[C:17]([Br:25])[C:3]([O:4][C:5]2[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=2)[CH:10]=[O:11])=[C:2]([Br:1])[C:20]=1[CH3:21]
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(N)cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Yield: 27 %

Procedure:
5-(2,6-Dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 8D (100 mg, 0.21 mmol), Na2S2O4 (553 mg, 3.2 mmol), NaHCO3 (0.2 mL, saturated aqueous solution) and ethanol (1.8 mL) were mixed in a microwave safe reaction vial. The vial was sealed and irradiated for 5 minutes at 140° C. NaHCO3 (5 mL, saturated aqueous solution) was added to the reaction mixture and the organic phase removed in vacuo. The obtained suspension was extracted with CHCl3 and the two phases were separated with phase separator (IST). The organic phase was concentrated and filtration through a pad of silica gave 25 mg (27%) of 5-(4-amino-2,6-dibromo-3-methylphenoxy)-2-hydroxy-3-isopropylbenzaldehyde as white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:32][C:33]1[S:34][CH:35]=[N:36][N:37]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([NH:32][C:33]1[S:34][CH:35]=[N:36][N:37]=1)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 78.9 %

Procedure:
10 g of N-benzyloxycarbonyl-DL-valine, 4.1 g of triethylamine, 150 ml of chloroform, 4.4 g of ethyl chlorocarbonate and 4.1 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 10.5 g (yield: 79%) of 2-(N-benzyloxycarbonyl-DL-valylamino)-1,3,4-thiadiazole as white crystals having a melting point of 162°-164° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])[C:6]=2[CH:5]=[C:4]([N+:22]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])[C:6]=2[CH:5]=[C:4]([NH2:22])[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc(N)cc21
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (2.83 g, 6.86 mmol) in Methanol (40 mL) in a 250 ml round bottomed flask was added Tin(II)chloride dihydrate (9.29 g, 41.1 mmol) and HCl (1.875 mL, 61.7 mmol). The reaction mixture was left to stir at 50° for 3 h. The solvent was removed and diluted with water (100 mL) and this solution was decanted into a 250 mL Erlenmeyer flask. The brown residue remaining in the round bottomed flask was dissolved in 100 mL of EtOAc, washed with 1N NaOH, brine, dried and evaporated to yield a brown solid which was the expected compound 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-amine (2.49 g, 6.51 mmol, 95% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.45-2.48 (m, 3H) 5.33 (s, 2H) 5.47 (s, 1H) 5.58-5.62 (m, 1H) 6.28-6.33 (m, 2H) 6.93 (d, J=1.77 Hz, 1H) 6.98 (s, 1H) 7.28 (s, 1H) 7.32 (d, 2H). LC/MS: MS (ES+) m/e 383 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=[C:4]([CH:14]=O)[CH:3]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].O.CCOC(C)=O>C1COCC1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH3:16][C:17]([S@:20](/[N:22]=[CH:14]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1)=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)ncc1OCC(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A mixture of 4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde (1.6 g, 7.3 mmol, Step-5), (R)-2-methylpropane-2-sulfinamide (1.33 g, 11.0 mmol), and titanium tetraethoxide (2.50 g, 11.0 mmol) in THF (30 mL) is refluxed with stirring for 2 hours. After cooling to 0° C., water (30 mL) and EtOAc (80 mL) are added to the mixture, and this is filtered through a pad of Celite. The filtrate is washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.14 g (48% yield) of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:8]([NH:19]C(=O)OC(C)(C)C)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:27]>CO>[ClH:27].[Br:1][C:2]1[C:3]([C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[NH2:19])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Agent: Cl
Solvent: CO
Product: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a solution of (S)-tert-butyl ((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (2.0 g, 4.64 mmol) in MeOH (10 mL) was added hydrogen chloride (3.48 mL, 13.91 mmol) (4.0 M in 1,4-dioxane). The reaction was stirred for 27 h at rt under N2. The reaction was concentrated in vacuo to give the amine which was used without further purification in subsequent steps. MS (ESI pos. ion) m/z: 331.0, 332.9 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[I:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
5-Iodosalicylic acid (528 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-iodosalicylate (457 mg, yield 78%).
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](C(OCC)=O)=[CH:11]2.C(OC)(=O)C=C.Cl>C1C=CC=CC=1.O>[Br:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:12][CH2:1][C:2](=[O:5])[C:3]3=[CH:11][C:10]=2[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C=CC(=O)OC
Solvent: c1ccccc1
Product: O=C1CCn2c1cc1cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of KOtBu (1.0 g, 8.9 mmol) in benzene (20 mL) was added ethyl 5-bromo-1H-indole-2-carboxylate (2.3 g, 8.6 mmol) as a solution in benzene (40 mL) at room temperature. To the resulting white slurry was added methyl acrylate (1.5 mL, 17.1 mmol). The combined solution was heated at 80° C. for 1 h then cooled to room temperature and stirred for an additional 16 h. The reaction mixture was then poured into H2O (100 mL) and the pH was adjusted to 4 with concentrated HCl. The aqueous phase was then extracted with CH2Cl2 (2×200 mL). The combined organic phases were washed with H2O, dried over Na2SO4, filtered and concentrated. The crude residue was then dissolved in EtOH (30 mL), 4M HCl (10 mL) was added, and the mixture was heated to reflux. After stirring at reflux for 3.5 h, the reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHCO3. The aqueous phase was then washed with Et2O (2×100 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated to afford the title compound as an off white solid (1.3 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](=[S:25])[NH2:8]
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(N)=S)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 5 h

Procedure:
3,4,5-Trimethoxybenzamide (5.0 g) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (5.24 g) were added to toluene, and the mixture was stirred at 70° C. After 5 hours, the reaction mixture was cooled back to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to obtain yellow crystals, and the crystals were further recrystallized from ethyl acetate-hexane to obtain the title compound.