Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].S(Cl)([Cl:23])=O.Cl>Cl.C(N(CC)CC)C.C(Cl)(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([Cl:23])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 663 %

Procedure:
There are mixed 14.1 grams (0.05 mole) of the acid from step (a), 0.1 grams triethylamine hydrochloride and 150 milliliters chloroform, followed by stirring and heating to reflux. Then 6.5 grams (0.055 mole) thionyl chloride was slowly added, dropwise. After the addition was complete, the reaction mass was heated under reflux until evolution of HCl had ceased (about 30 minutes). The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum distillation yielding 100 grams (66.7% of theoretical yield) of 2-(3-trifluoromethylphenoxy) nicotinoyl chloride.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH3:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[N:18]([CH3:19])[C:17]([S:20][CH3:21])=[N:16][N:15]=2)=[CH:10][N:9]=1.S([O-])(O)(=O)=[O:23].[Na+].[OH2:28]>C(O)(=O)C>[CH3:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[N:18]([CH3:19])[C:17]([S:20]([CH3:21])(=[O:23])=[O:28])=[N:16][N:15]=2)=[CH:10][N:9]=1
Reactant: CSc1nnc(-c2cnc(C)cn2)n1C
Reactant: O=S(=O)([O-])O
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnc(-c2nnc(S(C)(=O)=O)n2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of potassium permanganate (3.38 g, 17.0 mmol) in water (95 mL) was added to a solution of 2-methyl-5-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyrazine (1.853 g, 11.52 mmol) in glacial acetic acid (45 mL). The resulting mixture was stirred at room temperature overnight. Solid sodium hydrogen sulfate was added in portions until the dark color disappeared giving a clear colorless solution. The product was partitioned between chloroform (350 mL) and water (50 mL), and the aqueous layer was extracted with chloroform (3×150 mL). The combined organic layer was neutralized with aq. NaOH (40 is mL, 6M) and saturated sodium bicarbonate (250 mL) until gas evolution ceased and pH ˜7. The organic layer was washed with brine (100 mL) and dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (2.715 g, 93%, white solid). 1H NMR (300 MHz): 9.44 (s, 1H), 8.55 (s, 1H), 4.36 (s, 3H), 3.62 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH:14]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Product: O=C(O)c1ccc(NC(=O)C2CCC2)cc1[N+](=O)[O-]

Procedure:
4-Cyclobutanecarbonylamino-2-nitro-benzoic acid was prepared as described in Example 3 from 10.9 g (0.06 mol) of 4-amino-2-nitro-benzoic acid and 7.83 g (0.066 mol) of cyclobutanecarboxylic acid chloride.
Reaction SMILES: Br[C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C>[N+:7]([C:6]1[S:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc2ccccc2c1Br
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc2ccccc2c1Nc1ccccc1
Yield: 95.9 %

Procedure:
A mixture solution of 3-bromo-2-nitrobenzo[b]thiophene (14 g, 54 mmol), aniline (14 ml, 154 mmol) and triethylamine (11 ml, 79 mmol) in DMF (150 ml) was heated at 120° C. for 30 min before quenching with water. The solid was isolated by filtration, washed with water and recrystallized from DCM/hexane to yield 2-nitro-N-phenylbenzo[b]thiophen-3-amine (14 g, 96%) as a yellow solid.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][NH2:6].[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13]>O>[NH2:6][CH2:5][C:4]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:3]
Reactant: COC(=O)CN
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Product: NCC(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
The same procedures used in Example 9 were repeated except that glycine methyl ester hydrochloride (hereunder referred to as Gly-OMe.HCl) was dissolved in L-Gln-TBP prepared by converting L-glutamine (L-Gln) into its ionic liquid form according to the same method used in Example 9 such that the concentration of the former was adjusted to 900 mmol/kg-L-Gln-TBP (the amount of water relative to the total mass of the reaction system: 14% by mass) and that the reaction time was changed from 20 hours to 23 hours to form the intended dipeptide, i.e., glycyl glutamine (Gly-Gln) and in this respect, the formation of such a desired dipeptide was confirmed according to the HPLC technique.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18](N=[N+]=[N-])=[O:19])=[CH:12][C:11]([Br:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2].S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[CH2:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:19])=[CH:12][C:11]([Br:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)N=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)OCc1ccccc1
Yield: 86.1 %

Procedure:
3-(3-Azidocarbonyl-propyl)-5-bromo-1H-indole-2-carboxylic acid ethyl ester (1.28 g, 3.4 mmol, 1.0 equiv), TsOH hydrate (65 mg, 0.34 mmol, 0.1 equiv), and benzyl alcohol (0.74 mL, 6.8 mmol, 2.0 equiv) were refluxed in 30 mL of benzene for 16 h. The solution was then poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with 2×50 mL of diethyl ether. The pooled organic fractions were dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography on silica gel using 0% EtOAc in hexanes graded to 20% EtOAc in hexanes to provide 5-bromo-3-[3-benzyloxycarbonyl-propyl]-1H-indole-2-carboxylic acid ethyl ester (1.3 g, 75%). This material was used without further manipulation.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][N+:24]([O-])=[C:23]3C[CH2:29][C@@H:30](C)[C:22]=23)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:5]([O:4][CH:2]1[C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:16][CH2:17]3)[C:22]=2[C@H:30]([CH3:29])[CH2:1]1)(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CCc2c1c(N1CCN(C(=O)OC(C)(C)C)CC1)nc[n+]2[O-]
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 1.67 h
Yield: 99.8 %

Procedure:
Ac2O (77.0 mL, 816 mmol) was added to (R)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (21.0 g, 62.8 mmol). The reaction mixture was heated under nitrogen in a 90° C. sand bath and stirred for 100 minutes. The reaction mixture was cooled to room temperature, and excess acetic anhydride was removed by rotary evaporation. The resulting oil was dissolved in DCM, which was then poured carefully into ice saturated Na2CO3. The mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered and concentrated to give (5R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (23.6 g, 100%) as a foam. LC/MS (APCI+) m/z 377.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[NH2:22][CH:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:22][CH:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: CCOC(=O)CC(C)N
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Triethylamine (12.8 mL, 91.8 mmol) was added to a solution of 4-chloro-3-nitroquinoline (8.0 g, 38 mmol) in DMF (100 mL). The resulting solution was stirred for five minutes at room temperature, and then ethyl 3-aminobutyrate (6.2 mL, 42 mmol) was added. The reaction was stirred overnight at room temperature and poured into deionized water (320 mL). The mixture was extracted with ethyl acetate (1×125 mL and 2×100 mL). The combined extracts were washed with brine (3×120 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide 11.5 g of ethyl 3-[(3-nitroquinolin-4-yl)amino]butanoate as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:18])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:8][N:9]=1)[C:5]#[N:6].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:3]1[C:2]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[N:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:4]=1[C:5]#[N:6]
Reactant: Cc1ccccc1N
Reactant: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc(-c2cnc(Nc3ccccc3C)c(Cl)c2C#N)c1
Temperature: 180 °C

Procedure:
A mixture of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (50 mg, 0.179 mmol, from Step 3 of Example 128) and o-toluidine (384 mg, 3.58 mmol) in DMSO (1 mL) was heated to 180° C. under microwave for 1 h. LCMS and HPLC analysis indicated that the reaction was ˜25% complete. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with 1 N HCl (5 mL), water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Purification by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave 3-chloro-5-(3-methoxyphenyl)-2-(o-tolylamino)isonicotinonitrile as yellow solid, assumed as TFA salt (7 mg, 8% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.13 (1H, s), 7.38-7.54 (2H, m), 7.28-735 (1H, m), 7.15-7.27 (2H, m), 7.07-7.14 (2H, m), 6.97-7.05 (1H, m), 3.87 (3H, s), 2.27 (3H, s); MS (ES+) m/z: 350 (M+H); LC retention time: 3.848 min (analytical HPLC Method A).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:3]=12.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCCCO.O.C(Cl)Cl>[CH:26]1([NH:32][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:14]=[CH:15][C:3]=23)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Solvent: CCCCO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1NC1CCCCC1
Temperature: 110 °C
Yield: 72.7 %

Procedure:
To a solution of ethyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.28 g, 5.42 mmol) in n-BuOH (21 mL) was added cyclohexanamine (1.24 mL, 10.8 mmol). The resulting solution was heated at about 110° C. for about 18 h. The reaction mixture was cooled to ambient temperature and diluted with water and DCM (50 mL each). The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, and concd to dryness under reduced pressure. The residue was triturated with heptane and the precipitates were filtered to give ethyl 4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.74 g, 73%) as a light yellow solid: LC/MS (Table 1, Method b) Rt=3.18 min; MS m/z: 442 (M+H)+.
Reaction SMILES: [C:1]1([S:7][O:8][C:9](=[O:21])[CH2:10][CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.C1COCC1.O>[C:1]1([S:7][O:8][C:9](=[O:21])[CH2:10][CH:11]([OH:13])[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CC(=O)OSc1ccccc1)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(O)CC(=O)OSc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
To 3.26 g (10.4 mmol) of (-)-3-t-butyldimethylsilyloxybutyric acid phenylthio ester was added 50 ml of acetic acid: THF:water (3:1:1) and the mixture was stirred at 50° C. for 24 hours. The resultant was concentrated and distilled (128° to 130° C./0.8 mmHg) to give 1.91 g of (-)-3-hydroxybutyric acid phenylthio ester (yield: 94%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].O1CCCC1.[BH4-].[Na+]>O>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: COc1ccc(C=O)cc1Oc1cccc(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CO)cc1Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed (16) (1.09 g, 4.27 mmol), tetrahydrofuran (10 mL), water (10 mL) and sodium borohydride (485 mg, 12.8 mmol). The mixture was stirred at room temperature for 2 hours and then quenched with water (60 mL). After extractions with ethyl acetate (3×50 mL), the organic portions were combined, washed with brine (75 mL), dried (MgSO4), concentrated. The resulting solid was dried in a high vacuum oven for 5 hours at 45° C. and 945 mg (86% yield) of (17) was isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[C:18]1(C)C=CC=C[C:19]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C(C([SnH3])=C(CCCC)CCCC)CCC>COCCOC.C(Cl)(Cl)Cl.CO>[CH:18]([C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1)=[CH2:19]
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: CCCCC([SnH3])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: COCCOC
Product: C=Cc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Yield: 186.9 %

Procedure:
A solution containing 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (150 mg, 0.508 mmol), tris(dibenzylidineacetone)dipalladium (0) (22 mg, 0.024 mmol), tri(o-tolyl)phosphine (63 mg, 0.206 mmol), lithium chloride (103 mg, 2.43 mmol), and tri-n-butylvinylstannane (188 mg, 0.592 mmol) in 1,2-dimethoxyethane (10 ml) was heated under reflux overnight. The solution was evaporated, and the residue was taken up in chloroform and filtered. The filtrate was evaporated then purified by HPLC using a gradient of 0-25% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (93 mg, 0.385 mmol, 76%) as a pale solid: electrospray MS (m/z, relative intensity) 243 ([MH]+, 100).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=CC(C(F)(F)F)=CC=2Cl)N=C(C#N)[C:3]=1S(C(F)(F)F)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:35][CH2:36]CCCCC.C(OCC)(=O)C.O>C(#N)C>[Cl-:13].[Cl:13][CH2:12][CH2:7][NH+:6]([CH2:2][CH3:3])[CH2:35][CH3:36]
Reactant: CCCCCCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC[NH+](CC)CCCl
Product: [Cl-]

Procedure:
(0.19 g, 1.1 mmol) was added to a mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinylpyrazole (0.4 g, 0.92 mmol) and tripotassium phosphate (0.77 g, 3.7 mmol) in acetonitrile (6 ml), and the mixture heated under reflux for 6 hours. After extractive workup (heptane-ethyl acetate, water) and chromatography the title product was obtained (0.15 g); 1H-NMR: 0.87 (3H), 2.40 (2H), 2.53 (2H), 2.98 (2H), 7.80 (2H); 19F-NMR: −64.2; −74.5 ppm.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH:7]2[C:12]3=[C:13]4[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:14]4=[C:15]([C:16]4[S:17][CH:18]=[C:19]([C:21]([O:23]CC)=[O:22])[N:20]=4)[N:11]3[CH2:10][CH2:9][S:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O>C1COCC1>[CH3:7][CH2:12][CH2:13][CH:14]([CH3:26])[CH3:15].[Cl:1][C:2]1[O:6][C:5]([CH:7]2[C:12]3=[C:13]4[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:14]4=[C:15]([C:16]4[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=4)[N:11]3[CH2:10][CH2:9][S:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCSC3c2ccc(Cl)o2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C)C
Product: Cn1c(=O)c2c(-c3nc(C(=O)O)cs3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)SCC3
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 2-(10-(5-chlorofuran-2-yl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazin-5-yl)thiazole-4-carboxylate (Example 15 Step 1)(72 mg, 0.142 mmol) and lithium hydroxide monohydrate (5.96 mg, 0.142 mmol) were suspended in THF (5 mL) and the mixture stirred at room temperature for 24 hours. Two portions of lithium hydroxide monohydrate (5.96 mg, 0.142 mmol) were added during this period. Water (2 mL) was then added and the mixture stirred for a further 30 mins. The resulting mixture was evaporated under vacuum. The residue was partitioned between water (20 ml) and DCM (20 mL) and brought to pH 1 with HCl(aq). The phases were separated and the aqueous phase was extracted with DCM (2×20 ml). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. The residue was re-suspended in DCM (5 ml) and loaded to a Isolute PE-AX ion exchange cartridge (1 g). The cartridge was eluted with DCM (50 ml), 1:1 MeOH:DCM (20 ml) and 4 M HCl/dioxane. The acidic eluent was evaporated under vacuum and the residue triturated with TBME:iso-hexane to afford the title compound.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH2:10]([N:12]([CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[NH:18])=[O:17])[CH3:11].O.[OH-].[Na+]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:28]([N+:12]([CH2:10][CH3:11])([CH3:6])[CH2:13][CH2:14][CH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[NH:18])=[O:17])[CH3:29]
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC[N+](C)(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium fluoroborate (3.81 g, 25.6 mmol) was added to a solution of N,N-diethyl-3-[S-(4-nitrophenyl)sulfonimidoyl]-1-propanamine (7.7 g, 25.6 mmol) in methylene chloride (50 mL) maintained at -20° C. After 15 min the reaction mixture was warmed to 0° C. for 30 min and then to ambient temperature for 1 h. Water (100 mL) was added to the reaction mixture, and the reaction mixture was made basic with 10% sodium hydroxide. The biphasic mixture containing insoluble material was filtered. The solid that was collected by filtration was recrystallized from a methanol/ethanol mixture. The white solid that formed was collected by filtration to give 0.51 g(4.9%), mp 125°-126.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:20]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[O:21])=[CH:8][CH:7]=[CH:6][N:5]2[C:27]=1[CH3:28].ClC1[CH:31]=[C:32](C=CC=1)[C:33]([O:35]O)=[O:34].[C:40](=[O:43])([OH:42])[O-:41].[Na+]>ClCCl>[C:33]([OH:35])(=[O:34])/[CH:32]=[CH:31]/[C:40]([OH:42])=[O:43].[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:20]([O:22][CH2:23][CH2:24][S:25]([CH3:26])=[O:41])=[O:21])=[CH:8][CH:7]=[CH:6][N:5]2[C:27]=1[CH3:28].[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:20]([O:22][CH2:23][CH2:24][S:25]([CH3:26])=[O:34])=[O:21])=[CH:8][CH:7]=[CH:6][N:5]2[C:27]=1[CH3:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C([O-])O
Reactant: CSCCOC(=O)Nc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCS(C)=O)c1CNc1cccn2c(C)c(C)nc12
Product: O=C(O)/C=C/C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of 2,3-dimethyl-8-{2-[(2-methylsulfanylethoxy)carbonylamino]-6-methylbenzylamino}imidazo-[1,2-a]pyridine (1.0 g) in anhydrous dichloromethane (25 ml) is cooled to 0° C. and treated in portions with m-chloroperoxybenzoic acid (800 mg) and then stirred at 0° C. for a further 15 min. Aqueous sodium bicarbonate solution (25 ml) is then added, the mixture is stirred for a further 10 min, the organic phase is separated off and the aqueous phase is extracted with dichloromethane (3×20 ml). The combined organic phases are washed with water (50 ml), dried over magnesium sulfate and concentrated. To separate off the sulfone, the residue is chromatographed on silica gel (eluent: ethyl acetate/methanol/ammonia=19:1:0.1). The fractions of Rf =0.15 are collected and concentrated. The residue is taken up in a hot solution of fumaric acid (150 mg) in acetone (20 ml) and then cooled to 4° C. After filtration and drying in a high vacuum, 0.54 g (46%) of the title compound is isolated as a pale beige crystallizate. M.p. 137-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[Br:31][CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH3:33]>ClCCl>[Br:31][CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]5[CH2:22][CH2:23]5)=[O:20])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)[CH:7]=2)=[O:39])=[CH:36][CH:35]=1)[CH3:33]
Reactant: CC(Br)c1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C(C)Br)cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (51.8 mg, 0.163 mmol) and pyridine (0.05 mL, 0.6 mmol) in 2 mL dichloromethane was added a solution of the residue from Step 1 in 2 mL dichloromethane. The resulting mixture was stirred at room temperature for 1.5 hours, and then carried forward without purification.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N(C(C)(C)C#N)=NC(C)(C)C#N.N#N.[C:19](I)([F:22])([F:21])[F:20].FF.[I-:26]>C(OCC)(=O)C>[C:19]([CH2:3][CH:2]([CH2:1][OH:4])[I:26])([F:22])([F:21])[F:20]
Reactant: [I-]
Reactant: FC(F)(F)I
Reactant: C=CCO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: FF
Agent: N#N
Solvent: CCOC(C)=O
Product: OCC(I)CC(F)(F)F
Temperature: 60 °C

Procedure:
Into a 3-liter autoclave were poured 174 g (3.0 mol) of allyl alcohol, 49.2 g (0.3 mol) of α,α′-azobis isobutyronitrile (AIBN) and 300 ml of ethyl acetate. After decreasing the inside pressure (100 mmHg) on ice bath, N2 was introduced, and the inside pressure was decreased again. Thereafter, 588 g (3.0 mol) of CF3I was introduced and the mixture was slowly heated up to 60° C. After completion of the reaction, the reaction solution was cooled and washed with 1 mol/liter of an aqueous solution of HCl for separation of the solution. After that, refining by distillation was carried out, and 533 g (2.1 mol) of a fluorine-containing iodide (a): CF3CH2CHICH2OH was obtained.