Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:13])[C:5]([Cl:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[Cl:13][C:4]1[C:5]([Cl:12])=[C:6]([C:10]#[N:11])[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2c(Cl)c(Cl)c(C#N)c(C#N)c2Cl)cc1

Procedure:
To a 250 mL flask, 4.8 g of tetrachlorophthalonitrile, 3.98 g of methyl 4-hydroxybenzoate, 5 g of potassium carbonate (K2CO3), and 55 mL of acetonitrile are added, followed by heating for 12 hours while refluxing. After completion of the reaction, 30 mL of ethyl acetate is added and filtered to remove the solvent. To the obtained solid, a suitable amount of dichloromethane is added to dissolve the solid, followed by adding hexane for crystallization. The obtained solid is filtered and dried under vacuum to obtain a compound, methyl 4-(2,3,6-trichloro-4,5-dicyano-phenoxy)benzoate. The first step reaction may be represented by Reaction Scheme 1:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:46]2[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:45])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:43])[CH3:42])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][CH:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]2[NH:3][C:4](=[O:7])[O:5][N:53]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:45])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:42])[CH3:43])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][CH:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogen carbonate (0.59 g) and dimethyl sulfoxide (2.5 mL) was stirred at 50° C. for 30 min, 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.22 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.091 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.084 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.23 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8](Cl)=[N:9][CH:10]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[NH:20][CH3:21].CS(O)(=O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([N:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=2)[CH3:21])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Reactant: CNc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N(C)c2cccc(Cl)c2)c2ccn(C)c12
Yield: 47.7 %

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (0.5 g) in 1,4-dioxane (5 ml) was added 3-chloro-N-methyl aniline (0.629 g) and methanesulfonic acid (0.289 ml). The mixture was irradiated under microwave conditions at 180° C. for 30 min. 1,4-dioxane was removed in vacuo and the residue purified by MDAP to give the title compound (350 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[C:20](=[O:24])[CH:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:26])[F:27]
Reactant: O=c1cc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: Cn1cc(CCl)cn1
Product: Cn1cc(Cn2ccc(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)cc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2 (1H)-pyridinone and 4-(Chloromethyl)-1-methyl-1H-pyrazole. LC-MS (ESI): m/z 504 [M+H]+; 3.68 min (ret time).
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=1.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:28]2[CH:34]=[CH:33][S:32][C:29]2=[N:30][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH:25][C:26]2[C:27]([N:35]3[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]3)=[C:28]3[CH:34]=[CH:33][S:32][C:29]3=[N:30][CH:31]=2)=[O:24])[N:21]=1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3sccc23)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3sccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (88.5 mg, 0.662 mmol) in DCM (1.0 mL) was added slowly to a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (from step 2 in Example 2, 56.9 mg, 0.236 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 2 h. A solution of tert-butyl [(3S)-1-(5-aminothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (73.3 mg, 0.210 mmol) in DCM (2.0 mL), followed by pyridine (162.6 mg, 2.056 mmol) was then added and the mixture was stirred at room temperature for a further 2 h. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark oil (118.2 mg, 98%). LCMS calc. for C27H28F2N5O3S2 (M+H)+: m/z=572.2. found 572.2.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[C:1]([NH:8][C@H:9]([C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (210 μl) was condensed with Boc-3-cyclohexyl-L-alanine (590 mg, manufactured by Bachera Fein Chemikalien AG, Switzerland) to give N-(Boc-3-cyclohexyl-L-alanyl)morpholine (702 mg) as a colorless oily product (yield 95%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (210 mg) to yield the title compound (compound 75; 379 mg) as a colorless oily product (yield 76%).
Reaction SMILES: [Se](=O)=O.C[C@H]1[C@H](O)C(=O)O[CH2:31][C@:23]23[C@H:28]([O:29][C@H:20]4[C@:21]5(O[CH2:38]5)[C@:22]2([CH3:37])[C@@H:18]([CH2:19]4)OC(=O)C=CC=CC(=O)OCC1)[CH:27]=[C:26]([CH3:30])[CH2:25][CH2:24]3>>[CH3:38][CH:21]1[C@@:22]2([CH3:37])[C@:23]3([CH3:31])[C@H:28]([O:29][C@@H:20]1[CH2:19][CH2:18]2)[CH:27]=[C:26]([CH3:30])[CH2:25][CH2:24]3
Reactant: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)C=CC=CC(=O)OCC[C@@H](C)[C@H](O)C(=O)OC[C@@]2(CC1)[C@]4(C)[C@]31CO1
Agent: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)/C=C\C=C\C(=O)OCC[C@@H](C)[C@H](O)C(=O)OC[C@@]2(CC1)[C@]4(C)[C@]31CO1
Agent: O=[Se]=O
Product: CC1=C[C@H]2O[C@@H]3CC[C@@](C)(C3C)[C@@]2(C)CC1

Procedure:
The trichothecene therapeutic agent 16-oxo verrucarin A is prepared by selenium dioxide oxidation of verrucarin A. The MAb hydrazide is then reacted with 16-oxo verrucarin A at 4° C. overnight with agitation, thereby yielding a unique Schiff base-linked targeting protein, having the following structure: ##STR21##
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>CO.C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:1][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]4[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with 1-(4-fluorophenyl)piperazine (90 mg, 0.50 mmol) as described in General Procedure X to afford Iaa (69.0 mg, 55.6%) as an ivory colored solid, tlc Rf=0.4 (10% MeOH/CH2Cl2−0.20% Et3N), m/z obs=461 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([NH:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](OC=O)(=[O:26])C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([N:16]([CH:24]=[O:26])[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CCCc1ccccc1)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of (2R,3S)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (21.4 g, 66.7 mmol) in pyridine (100 mL) at 0° C. is added formic acetic anhydride (30 mL). The resulting solution is allowed to warm to 25° C., stirred for 6 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (300 mL) and washed sequentially with 1 M hydrochloric acid (200 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-(3-Phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (18.9 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+:15].[OH-]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Agent: [OH-]
Product: Nc1cc(-c2ccccc2)c(Cl)nn1
Temperature: 140 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
3,6-dichloro-4-phenylpyridazine (J. Med. Chem. 2005, 48, 7089; 5.93 g, 26.3 mmol) was divided into 6 microwave tubes, and concentrated NH4OH (7 mL) was added to each. After sealing, each was heated at 140° C. for 1 h. The microwave tubes were uncapped, the precipitates were filtered and washed with cold water. The precipitates from all reactions were combined, and Et2O (150 mL) was added. After stirring overnight, the remaining solid was filtered, rinsed with Et2O and dried to give 6-chloro-5-phenylpyridazin-3-amine (3.06 g, 56%)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([Cl:3])=[O:18])[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
20 mL of thionyl chloride was added dropwise to a mixture containing 20.0 g (0.1 mol) of trans-4-pentylcyclohexanecarboxylic acid represented by the following formula (b-i), 0.5 mL of pyridine and 300 mL of toluene in a nitrogen atmosphere, and the mixture was stirred under heating to 80° C. or less for 1 hour. The solvent was distilled off under reduced pressure to provide trans-4-pentylcyclohexanecarboxylic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[Cl:15])[CH:3]=1.[F:16][C:17]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[Cl:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:17]=2[F:16])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: COc1ccc(C(=O)O)c(F)c1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
4-Amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenol (2.0 g, 8.94 mmol) was suspended in anhydrous CH2Cl2 (75 mL). The suspension was made to dissolve by the adding anhydrous DMF (5 mL) and briefly heating the solution using a heat gun (˜50° C.). 2-Fluoro-4-methoxybenzoic acid (1.52 g, 8.94 mmol), DIEA (2.34 mL, 13.4 mmol) and HATU (4.08 g, 10.7 mmol) were added to the solution. The reaction was stirred at room temperature for 2 hours. After this time, the reaction was extracted (120 mL each of H2O/CH2Cl2). The aqueous layer was extracted once more with CH2Cl2 (120 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (0,20,40,50,70% EtOAc/Hexanes) to yield N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (2.88 g, 7.66 mmol, 77.1%) as a colorless oil that turned solid upon standing. LCMS m/z 376.1 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 3.76 (s, 3 H), 3.90 (s, 3 H), 6.87 (dd, J=33.09, 2.53 Hz, 1 H), 6.87 (dd, J=11.49, 2.40 Hz, 1H), 7.00 (d, J=8.59 Hz, 1 H), 7.54 (s, 1 H), 7.55 (d, J=2.53 Hz, 1 H), 7.66 (dd, J=8.84, 2.53 Hz, 1 H), 7.76 (t, J=8.72 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[N:17]1[C:22](=[O:23])[C:21]3=[CH:24][S:25][CH:26]=[C:20]3[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]1=[O:34])=[CH:14][C:13]([C:35]([F:38])([F:37])[F:36])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:45][C:46]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:47]=1[CH2:48]Br.C(OCC)(=O)C>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:48][C:47]2[CH:50]=[C:51]([F:54])[CH:52]=[CH:53][C:46]=2[F:45])[C:10]2[C:15]([C:16]=1[N:17]1[C:22](=[O:23])[C:21]3=[CH:24][S:25][CH:26]=[C:20]3[N:19]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C:18]1=[O:34])=[CH:14][C:13]([C:35]([F:36])([F:37])[F:38])=[CH:12][CH:11]=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)c1[nH]c2ccc(C(F)(F)F)cc2c1-n1c(=O)c2cscc2n(C(=O)OC(C)(C)C)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1c(-n2c(=O)c3cscc3n(C(=O)OC(C)(C)C)c2=O)c2cc(C(F)(F)F)ccc2n1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(1-tert-butoxycarbonyl-2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 51 (30 mg, 0.054 mmol) in anhydrous THF (1 mL) and anhydrous DMF (1 mL) was added potassium tert-butoxide (9 mg, 0.080 mmol) and 2,5-difluorobenzyl bromide 5J (14.6 mg, 0.071 mmol). The reaction mixture was stirred at room temperature for 3 hours. Ethyl acetate (50 mL) was added and the organic layer was washed with saturated ammonium chloride solution and brine. The organic layer was dried over sodium sulfate. The organic solvent was removed under reduced pressure to provide 3-(1-tert-butoxycarbonyl-2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-1-(2,5-difluorobenzyl)-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5K which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:33][C:34]([F:45])([F:44])[CH2:35]OS(C(F)(F)F)(=O)=O>C1COCC1>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:35][C:34]([F:45])([F:44])[F:33])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1csc(C2CCN(CC(F)(F)F)CC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reaction time: 2 h
Yield: 68.9 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-159) (0.072 g, 0.21 mmol) was dissolved in dry THF (5 mL) and DIPEA (0.66 mmol) was added followed by 2,2,2-trifluoroethyltrifluoromethanesulphonate (0.26 mmol) and the resulting mixture stirred for 2 hours. 2,2,2-Trifluoroethyltrifluoromethanesulphonate (0.26 mmol) was added and the mixture refluxed overnight. The solvent was evaporated and the resulting gum was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.06 g). LCMS m/z 415.13 [M+H]+ RT=12.16 min (Analytical Method 2).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[CH:7][C:6]=1[OH:13])([OH:4])(=[O:3])=[O:2].[Cl:14]Cl>O.S(=O)(=O)(O)O>[S:1]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:14])[C:6]=1[OH:13])([OH:4])(=[O:2])=[O:3]
Reactant: Cc1cc(O)c(S(=O)(=O)O)cc1Cl
Reactant: ClCl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl

Procedure:
According to the present invention there is provided a process for preparing 2-nitro-4,6-dichloro-5-methylphenol comprising sulphonation of 4-chloro-5-methyl-phenol with concentrated sulphuric acid at elevated temperature to form 2-sulpho-4-chloro-5-methylphenol, thereafter diluting the reaction mixture with water to a sulphuric acid content of 20 to 30%, chlorinating the resulting 2-sulpho-4-chloro-5-methylphenol with chlorine at elevated temperature and normal or elevated pressure to form 2-sulpho-4,6-dichloro-5-methylphenol and reacting the 2-sulpho-4,6-dichloro-5-methylphenol with nitric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-:17])=[O:16])=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].N1C=CC=C[CH:36]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:36])=[O:16])=[CH:13][CH:12]=2)=[C:2]([NH:1][S:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:23]=2)(=[O:29])=[O:28])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1SCc1ccc(C(=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1ccncc1
Product: COC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Yield: 66 %

Procedure:
Following General Procedure B, the title compound (635 mg, 66%) was prepared from 4-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (535 mg, 1.74 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (486 mg, 1.74 mmol) in pyridine (5 ml).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:17]([C:19](=[S:21])[NH2:20])N.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:5]1([C:9]2([C:13]3[S:21][C:19]([NH2:20])=[N:17][N:14]=3)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: NNC(N)=S
Reactant: N#CC1(c2cccc(C(F)(F)F)c2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(C2(c3ccccc3)CCC2)s1
Temperature: 60 °C

Procedure:
To a T-vial containing 1-[3-(trifluoromethyl)phenyl]cyclobutanecarbonitrile (1 eq) and hydrazinecarbothioamide (1 eq) was added TFA (1 eq) dropwise at rt. Then the mixture was heated to 60° C. for 2 hrs and cooled to rt. Ethyl acetate and aq. NaHCO3 were added and extracted with ethyl acetate twice, the organic layers combined, dried with MgSO4, and concentrated to give the desired product which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1)#[N:2].[Cl-].[Ca+2].[Cl-]>[Fe]>[NH2:11][C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cc1c([N+](=O)[O-])cnc(C#N)c1C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Product: Cc1c(N)cnc(C#N)c1C
Yield: 43.2 %

Procedure:
2-Cyano-3,4-dimethyl-5-nitropyridine (0.15 g, 0.85 mmol), calcium chloride (0.05 g, 0.42 mmol), and iron powder (0.44 g, 7.8 mmol, 325 Mesh) were reacted as described in example 772B. Purification of the crude product by silica gel chromatography using 1:1 ether/CH2Cl2 as the eluent gave compound 773B (0.054 g, 50%) as a yellow solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=O.[CH2:11]([O:13][C:14]([C:16]1([NH2:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12].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>CN(C=O)C.O>[CH2:11]([O:13][C:14]([C:16]1([NH:25][C:8]([CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[O:10])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)C1CC2CCC1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1(NC(=O)C2CC3CCC2C3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of bicyclo[2.2.1]heptane-2-carboxylic acid (102 mg, 0.73 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (150 mg, 0.73 mmol), HATU (333 mg, 0.87 mmol) in anhydrous DMF (1 mL) is added DIPEA (1904, 1.10 mmol). The resulting solution is stirred at RT overnight. Water (10 mL) is poured into the reaction mixture and then extracted with EtOAc (3×5 mL). The combined organic layers are concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0-30% EtOAc in heptane) to give product (272) as yellow oil (148 mg, 62%).