Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][CH:4]=1)=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>ClCCl.O.C(O[Ti](OCC)(OCC)OCC)C>[C:16]([S@@:19](/[N:21]=[CH:1]/[C:3]1[S:7][C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][CH:4]=1)=[O:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(/C=N/[S@@](=O)C(C)(C)C)s1
Temperature: 25 °C

Procedure:
tert-Butyl 5-formylthiophene-2-carboxylate (2 g, 9.42 mmol) and (S)-2-methylpropane-2-sulfinamide (1.370 g, 11.31 mmol) were dissolved in dichloromethane (100 ml). The mixture was chilled in an ice bath to which was added tetraethoxytitanium (8.7 ml, 41.5 mmol). The mixture was allowed to warm to room temperature overnight with stirring. The mixture was poured into a large Erlenmeyer flask with 200 mL dichloromethane and was diluted with 18 mL H2O. After vigorous stirring for 30 minutes the suspension was filtered through diatomaceous earth and the filtrate was concentrated. Purification using normal phase chromatography provided the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:18])[NH:6][C:7](=[O:17])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:3])[CH3:2].[C:19]([CH:23]1[CH2:27][C:26](CBr)=[C:25]([CH2:30][O:31][SiH](C)C)[CH2:24]1)(C)(C)C>>[OH:31][CH2:30][CH:25]1[CH2:24][C:23]([CH2:19][N:8]2[C:9]([S:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:18])[NH:6][C:7]2=[O:17])=[CH:27][CH2:26]1
Reactant: C[SiH](C)OCC1=C(CBr)CC(C(C)(C)C)C1
Reactant: CC(C)c1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Product: CC(C)c1c(Sc2ccccc2)n(CC2=CCC(CO)C2)c(=O)[nH]c1=O
Yield: 29.5 %

Procedure:
5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and [(4-t-butyldimethylsilyl-oxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound (67 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 87 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 87%). 1H NMR (200 MHz, CDCl3): δ 3.13-3.16 (m, 4H), 3.78-3.81 (m, 4H), 4.15 (s, 3H), 7.02-7.06 (m, 3H), 7.23-7.42 (m, 4H), 7.82-7.83 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH2:31]([NH:33][S:34](Cl)(=[O:36])=[O:35])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:34](=[O:36])(=[O:35])[NH:33][CH2:31][CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Reactant: CCNS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and nitrogen were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 6.86 g, 19.6 mmol), Et2O (100 mL), and NEt3 (3.25 mL, 23.4 mmol), respectively. The solution was cooled to 0° C. and treated rapidly with a solution of (ethyl amino)sulfonyl chloride (3.37 g, 23.4 mmol) in Et2O (10 mL). The reaction was stirred for 30 minutes and then filtered. The solids were washed with Et2O, and the filtrate was concentrated. The resulting residue was dried in a high vacuum oven at 40° C. overnight to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 1.23 (t, 3 H) 2.19 (s, 3 H), 2.35 (s, 3 H), 3.30 (m, 2 H), 4.75 (br t, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.32 (d, 2 H), 7.39 (d, 2 H).
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:8]=1
Reactant: Cc1ccnc(OCc2ccc(CC(Cl)=NO)cc2)c1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccnc(OCc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (4-(4-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (270 mg, 0.930 mmol) described in Manufacturing Example 43-1-5 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (189 μL, 1.36 mmol) at room temperature, which was stirred at room temperature for 4 hours. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (28.9 mg, 20.6%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>ClCCl>[C:17]([O:10][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])(=[O:19])[CH3:18]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1cc(C)cc(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
In dichloromethane (150 mL) was dissolved 15.09 g (0.1108 mol) of 2,3,5-trimethylphenol, and 17.82 mL (0.2204 mol) of pyridine, then 20.78 mL (0.2202 mol) of acetic anhydride were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 20.08 g (0.1127 mol, Yield: quantitative) of 2,3,5-trimethylphenyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH2:31])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH:31][S:36]([CH:33]2[CH2:35][CH2:34]2)(=[O:38])=[O:37])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Reaction time: 16 h
Yield: 67 %

Procedure:
1.5 g of crude tert-butyl(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}phenyl)carbamate (2.7 mmol, 1 eq.) were dissolved in 10 mL pyridine and 457 mg cyclopropyl sulfonyl chloride (3.3 mmol, 1.2 eq.) and stirring was continued at that temperature for 16 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between DCM and water, the aqueous layer was reextracted with DCM. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography yielding 1.19 g of the target compound (67% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2SC)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:31][S:32]([O-:34])=O.[K+].[C:36](#N)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:32]([CH3:36])(=[O:34])=[O:31])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#N
Reactant: O=S([O-])OO
Reactant: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
2-(2′-Methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.4 mmol) was dissolved in 10 mL acetonitrile, added oxone (2.98 g, 4.8 mmol) in one portion and stirred at ambient temperature for 1 week and then concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 20% moving to 40% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound. (0.80 g, 75%) APCI (AP−): 443.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].Cl.[F:24][C:25]([F:35])([F:34])[C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:31]1[CH2:32][CH2:33][C@H:29]([NH:28][C:26](=[O:27])[C:25]([F:35])([F:34])[F:24])[CH2:30]1)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: O=C(N[C@H]1CCNC1)C(F)(F)F
Reactant: CCOC(=O)c1c2n(c3c(F)c(F)c(F)cc3c1=O)C(C)S2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3c(F)c(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.34 g of ethyl 6,7,8-trifluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 2.66 g of (S)-3-trifluoroacetylaminopyrrolidine hydrochloride [[α]D20 -28.6° (c=1, MeOH)], 1.80 g of 1.8-diazabicyclo[5,4,0]-7-undecene and 30 ml of N,N-dimethylformamide was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, and water was added to the residue. The precipitate was collected by filtration and was chromatographed on silica gel using chloroform-methanol (8:2) to give the desired compound, which was recrystallized from methanol to give 0.80 g of pale yellow needles, m.p. 219°-224° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13]([CH3:23])=[C:12]([O:24][CH3:25])[C:11]3=[O:26])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])(=O)C.[NH4+]>CO>[NH:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13]([CH3:23])=[C:12]([O:24][CH3:25])[C:11]3=[O:26])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC1=C(C)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: COC1=C(C)[C@H](c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
20 mg/5 ml of 1-(1H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one (which may be prepared in accordance with Example 8) were subjected to semi-prep chiral chromatography on a 250/21 Chirobiotic Tag (Supplier: Supelco), 5μ, detection: UV @ 214 nm, Mobile phase: 40% Ammonium acetate buffer (pH 4.0, 40 mM)/60% MeOH, isocratic, 10 ml/min, r.t., yield 8 mg as second eluting enantiomer, optical rotation c=0.5 g/100 ml (MeOH) αD2032 214.1°
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13](=[NH:15])[NH2:14])=[CH:5][CH:4]=1.[O-]CC.[Na+].C([O:30][C:31]([CH:33]=[CH:34][O-])=O)C.[Na+]>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13]2[NH:14][C:31](=[O:30])[CH:33]=[CH:34][N:15]=2)=[CH:22][CH:23]=1
Reactant: N=C(N)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C=C[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1ccnc(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)[nH]1
Yield: 11.7 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamide hydrochloride (188 mg, 0.515 mmol) in ethanol (8.0 mL) was added 21% sodium ethoxide in ethanol (0.192 mL, 0.515 mmol) and sodium 2-ethoxycarbonyl ethenolate (284 mg, 2.06 mmol) (prepared as in J. Med. Chem., (2001), 44(17), 2695-2700), and the reaction was heated to reflux overnight. The reaction was cooled and concentrated. The residue was slurried DCM (15 mL) and water (15 mL) for 20 minutes. The solids were filtered, dried and purified by silica gel chromatography (methanol/DCM=0/100→15/85) to give the product. HPLC gave 23 mg of the title compound as a yellow solid. (12% yield). LC/MS (FA) ES+ 381. 1H NMR (300 MHz, DMSO-d6) δ: 8.72-8.60 (m, 2H), 8.41 (d, 1H, J=5.7 Hz), 7.88-7.85 (m, 2H), 7.40-7.36 (m, 2H), 7.32-7.28 (m, 2H), 6.58 (d, 1H, J=5.7 Hz), 4.80 (s, 2H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1.[CH3:17]I>CS(C)=O>[CH3:17][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1)[C:11](=[O:16])[CH:12]=[C:13]([CH3:14])[CH3:15]
Reactant: CC(C)=CC(=O)Nc1cccc(Br)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)=CC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
28.7 g of powdered potassium hydroxide were suspended in 300 ml of dimethyl sulfoxide and a solution of 32.6 g of N-(3-bromophenyl)-3,3-dimethyl-acrylamide in 200 ml of dimethylsulfoxide (DMSO) was added dropwise thereto. The mixture was stirred at room temperature for 30 minutes and subsequently a solution of 27.5 g of methyl iodide in 150 ml of DMSO was added dropwise thereto. After 2.5 hours the mixture was poured on to 1 l of ice/water and extracted with ethyl acetate. The organic phase was washed repeatedly with water, dried and evaporated. The oily residue was distilled in a high vacuum. There were obtained 29.3 g of N-methyl-N-(3-bromophenyl)-3,3-dimethyl-acrylamide as a slightly yellow oil, boiling point 112°-114° C./67 Pa.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:14]([C:18]1[CH:30]=[CH:29][C:21]([O:22][C:23]2[C:27](Cl)=[N:26][S:25][N:24]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:27]2[C:23]([O:22][C:21]3[CH:29]=[CH:30][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=3)=[N:24][S:25][N:26]=2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(Oc2nsnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2nsnc2Oc2ccc(C(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a suspension formed by suspending 0.16 g of sodium hydride (60%) in N,N-dimethylformamide was added 0.6 g of 4-t-butylphenol and after stirring the mixture for one hour at 60° C., 0.81 g of 3-(4-t-butylphenoxy)-4-chloro-1,2,5-thiadiazole was added to the mixture followed by stirring for 12 hours at 100° C. After allowing to cool, the reaction mixture was poured in water and extracted with ether. The ether layer collected was washed twice each time with a diluted aqueous sodium hydroxide solution, water, and then a saturated aqueous sodium chloride solution. The ether layer thus washed was dried with anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to provide 0.84 g of 3,4-bis(4-t-butylphenoxy)-1,2,5-thiadiazole.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:1]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl bromide (2.29 mL, 19.3 mmol) was added dropwise to a cooled (0° C.) mixture of commercially available 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid (4.96 g, 19.3 mmol) and K2CO3 (6.67 g, 48.3 mmol) in 40 mL of DMF. The reaction mixture was permitted to warm to rt and stir for 3 days (the reaction was likely complete after only a few h). The reaction mixture was diluted with ether and washed four times with water, then once with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 30% ethyl acetate/hexanes) provided tert-butyl 4-[3-(benzyloxy)-3-oxopropyl]piperidine-1-carboxylate. 1HNMR (CDCl3, 500 MHz): δ 7.38 (m, 5H), 5.14 (s, 2H), 4.09 (br m, 2H), 2.65 (m, 2H), 2.41 (t, J=7.5 Hz, 2H), 1.63 (m, 4H), 1.47 (s, 9H), 1.40 (m, 1H), 1.10 (dq, J=4.0, 12 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)CO>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[N:12][C:3]=1[CH2:2][O:19][C:20]1[CH:21]=[CH:22][CH:25]=[CH:26][C:27]=1[CH2:13][OH:16]
Reactant: ClCc1ncc2ccccc2n1
Reactant: OCc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccccc1OCc1ncc2ccccc2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 93.1 %

Procedure:
To a solution of 2-Chloromethylquinazoline (5.00 g, 28 mmol) in DMF (50 ml) were added potassium carbonate (4.26 g, 31 mmol) and tetra-n-butylammoniumbromide (903 mg, 2.8 mmol). 3-Hydroxybenzylalcohol (3.48 g, 28 mmol) was added to the resultant mixture, and the mixture was stirred at room temperature for five days. Subsequently, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the resultant mixture, and the organic phase was extracted from the mixture. The organic phase was dried over sodium sulfate anhydrate, concentrated under reduced pressure, and recrystallized from a chloroform-n-hexane mixture, to thereby obtain the title compound as pale yellow powder (6.94 g, yield: 93.1%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C@H:7]2[NH:14]C(=O)OC(C)(C)C.CO.Cl>O>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C@H:7]2[NH2:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2c1ccc(F)c2Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1(C)C[C@@H](N)c2ccc(F)c(Cl)c2O1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
The crude (R)-tert-butyl 8-chloro-7-fluoro-2,2-dimethylchroman-4-ylcarbamate (4.47 g, 13.5 mmol), MeOH (36 mL), and concentrated HCl (4 mL) were heated to 50° C. After 2 h, complete deprotection observed by LCMS. The reaction mixture was cooled, stirred for 8 h, then diluted with methyl tert-buthy ether (60 mL) and water (40 mL). The mixture was paritioned and the organic layer was extracted with water (50 mL). The aqueous layer was basified with 2N NaOH (40 mL) and extracted with dichloromethane (2×40 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated to give the title compound (2.87 g, 12.50 mmol, 92% yield). MS (ESI+) m/z 230 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:26](Cl)=[O:27].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:26](=[O:27])[C:25]1[CH:24]=[C:23]([F:22])[CH:31]=[C:30]([F:32])[CH:29]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)c1cc(F)cc(F)c1
Yield: 59 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 3,5-difluorobenzoyl chloride (0.219 g, 1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol) and triethylamine (0.251 g, 2.48 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-3,5-difluorobenzamide (0.280 g, 59% yield). 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 2H), 7.29 (s, 1H), 6.91 (t, J=2.4 Hz, 1H), 3.58 (q, J=5.7, 5.1 Hz, 2H), 3.51 (t, J=4.8 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.7, 161.5, 161.4, 137.6, 110.7, 106.9, 50.7, 39.9 ppm; HRMS (ESI) calcd for C9H8F2N4O2S (M+) 226.0666. found 226.0662.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].O>CN(C=O)C>[CH:11]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([O:23][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])[CH3:12].[CH:11]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([O:23][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(Oc2cc(Cl)ccn2)CC1
Product: CC(C)OC(=O)N1CCC(Oc2ccnc(Cl)c2)CC1
Temperature: 90 °C

Procedure:
2,4-Dichloropyridine (0.52 g, 3.5 mmol) in 2 mL of DMF was added to a suspension of sodium hydride (60% in oil, 0.16 g, 3 eq) and 2a (0.55 g, 3 mmol) in 8 mL of DMF. The mixture was heated at 90° C. The mixture was allowed to cool to room temperature, water was added to quench the excess sodium hydride and the solution was extracted with ethyl acetate twice, washed with a saturated solution of sodium bicarbonate, dried and evaporated. The crude material was purified on silica gel (eluent: 20% then 50% of ethyl acetate in hexane) to give 10a and 10b (0.55 g of the more polar product and 84 mg of the less polar product).
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([CH2:23]O)=[CH:18][N:17]=2)([O-:7])=[O:6].CN(C=O)C>C(Cl)Cl>[Cl:3][CH2:23][C:19]1[CH:20]=[C:21]2[N:22]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N+:5]([O-:7])=[O:6])[S:15][C:16]2=[N:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CO)cnc2s1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CCl)cnc2s1
Reaction time: 1 h
Yield: 95 %

Procedure:
Thionyl chloride (3.1 mol, 227 mL) was slowly added to a room temperature suspension of (2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methanol (0.62 mol, 180 g) in CH2Cl2 (1.8 L). DMF (5 mL) was added and the reaction became homogeneous. The reaction was stirred for 1 h, then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (150 mL) and concentrated under reduced pressure. The crude product was chased with hexane (200 mL×3)) and dried under vacuum for 16 h to give 6-(chloromethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a tan solid (180 g, 94% yield).