Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2=CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Solvent: CO
Product: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (981 mg, 1.89 mmol) in dry MeOH (30 mL) was deoxygenated by bubbling nitrogen through solution for 5 min, then 10% palladium on charcoal (202 mg) was added, nitrogen was bubbled for another 5 min, then it was displaced by hydrogen, and the mixture was stirred at room temperature overnight. The mixture was filtered through celite washing with MeOH, and filtrate was concentrated under reduced pressure to give 928 mg (95%) of crude 5-(1,4-dioxa-spiro[4.5]dec-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester, which was used in the following step without purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[C:13]([O:12][C:10](=[O:11])[CH2:9][O:8][C:7]1[CH:17]=[CH:18][CH:19]=[C:5]([CH2:4][NH2:1])[CH:6]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN=[N+]=[N-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.2 %

Procedure:
To a mixed liquid of 5.16 g of t-butyl [3-(azidomethyl)phenoxy]acetate and 50 ml of THF were added 6.17 g of triphenylphosphine and 1.04 ml of water, followed by stirring at room temperature for 4 days. The solvent was evaporated and diisopropyl ether was added thereto. The precipitated solid was separated by filtration and the solvent was evaporated again. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-saturated aqueous ammonia) to obtain 4.10 g of t-butyl[3-(aminomethyl)phenoxy]acetate as a pale yellow oily substance.
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.C([O-])(=O)C.[Zn+2:17].C([O-])(=O)C>O>[C:1]1([P:7](=[O:8])([O-:10])[O-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zn+2:17]
Reactant: O=P(O)(O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
1.58 g (10.0 mmol) of phenylphosphonic acid (manufactured by Nissan Chemical industries, Ltd.), 2.20 g (10.0 mmol) of zinc acetate dihydrate and 72 g of water were mixed, stirred at 80° C. for 3 hours, then the resulting slurry was filtered, acetic acid in the wet cake was fully washed away with water, and thereafter, dried at 150° C. to obtain 2.17 g (yield 98%) of the aimed product as white crystal. Decomposition temperature: 541° C. The average particle diameter was 4.4 μm with a laser diffraction type particle size distribution meter (manufactured by Seishin Enterprise Co., Ltd., PRO-7000S).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6]C)=O.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]2[C:3]=1[C:4]([OH:6])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:1]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1c(N)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cccc(Cl)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of methyl 2-amino-6-chlorobenzoate (3.00 g, 16.2 mM) and dimethyl acetylenedicarboxylate (2.64 g, 18.6 mM) in t-butanol (25 mL) was refluxed under a nitrogen atmosphere for 18 hr. The reaction mixture was cooled to room temperature and potassium t-butoxide (2.09 g, 18.6 mM) was added in one portion whereupon a precipitate formed. After refluxing this mixture for 1.5 hr, it was cooled to room temperature and filtered to separate the solids. The solids were dissolved in water and the resulting solution acidified with 1N H2SO4 to form a precipitate. The mixture was filtered and the collected solids were washed with water and air dried to give dimethyl 5-chloro-4-hydroxyquinoline-2,3-dicarboxylate (3.84 g, 80.2%) as a tan solid. An 0.25 g portion of this material was recrystallized from ethyl acetate to provide an analytical sample (0.152 g) of the title compound as an off-white solid, mp 174°-176° C.; MS(CI): 296 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:22])[CH2:3][CH2:2]1.[ClH:23]>C(O)C.O1CCOCC1>[ClH:23].[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:22])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1COC2(CCNCC2)CN1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
1,1-Dimethylethyl 4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate was dissolved in ethanol (300 mL) and cooled over an ice bath. A 4M solution of hydrogen chloride in dioxane (300 mL) was added, such that the temperature remained low. The ice bath was removed and the mixture was stirred at ambient temperature overnight. The solid was collected, washed with a little ethanol and diethyl ether to give the title product (47.1 g, 58%). The mother liquors were treated with diethyl ether (1.2 L), stirred for 30 min, and the solid was collected and dried to give a total combined yield of 78% of the title product (63.69 g) over the three steps. MS(ES)+ m/e 211.0[M+H+]; 1H NMR (400 MHz, DMSO-d6) δ 9.17-8.64 (m, 2 H), 4.04 (s, 2 H), 3.14 (d, J=13.1 Hz, 2 H), 3.01-2.85 (m, 2 H), 2.83-2.71 (m, 1 H), 1.96-1.83 (m, 2 H), 1.83-1.68 (m, 2 H), 0.76-0.67 (m, 2 H), 0.64-0.55 (m, 2 H).
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:18]1(/[CH:22]=[CH:23]/[C:24](OCC)=[O:25])[CH2:21][CH2:20][CH2:19]1>ClCCl.O>[CH2:2]([N:9]1[CH:22]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH2:23][C:24](=[O:25])[O:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ONCc1ccccc1
Reactant: CCOC(=O)/C=C/C1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CC(C2CCC2)N(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
N-benzylhydroxylamine hydrochloride (0.77 g, 4.82 mmol) and triethylamine (0.76 mL, 5.45 mmol) were successively added to a solution of (E)-ethyl 3-cyclobutylacrylate, 46a, (0.65 g, 4.19 mmol) in dry dichloromethane (23.5 mL). The reaction mixture was allowed to stir at room temperature under an atmosphere of nitrogen for 3 days. The mixture was diluted with 75 mL of water and the layers were separated. The aqueous phase was reextracted twice more with dichloromethane (50 mL). The combined organic phases were dried over MgSO4, filtered and evaporated to dryness. The residue was purified via silica gel chromatography (0-100% EtOAc/Hexanes gradient) to afford 834 mg (86%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 4.64 (s, 1H), 3.82 (q, J=13.5 Hz, 2H), 3.37-3.18 (m, 1H), 2.80-2.52 (m, 2H), 2.33 (dd, J=14.5, 5.1 Hz, 1H), 2.22-2.09 (m, 1H), 2.01-1.68 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[I:9](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>C(O)(=O)C.O>[I:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(N)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)ccc1I
Temperature: 80 °C
Yield: 384.2 %

Procedure:
To a stirred solution of 6-methyl-pyridin-2-ylamine (30 g, 278 mmol, 1 eq) in acetic acid (167 mL) was added periodic acid (12.7 g, 55.6 mmol, 0.2 eq) followed by addition of sulphuric acid (4.8 mL, 90.8 mmol, 0.34 eq), water (33 mL) and iodine (28.7 g, 111 mmol, 0.4 eq) at room temperature. Resulting reaction mixture was heated at 80° C. for 6 hours. After complete consumption of starting material, reaction mixture was cooled and poured into sodium thiosulfate solution (200 mL), reddish oil was settled down at the bottom. Reaction mixture was decanted from reddish oil, and filtrate was basified with 50% sodium hydroxide solution (100 mL), yellow colored solid was formed. Resulting solid was extracted with diethyl ether (2×200 mL) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown semi solid (60 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 15% EtOAc in hexane to get title compound as faint brown solid (50 g, 77%). 1H NMR (400 MHz, CDCl3) δ: 2.52 (s, 3H), 4.43 (bs, 2H), 6.09 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.44 Hz, 1H). LC-MS (m/z): 235.3 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:21])[CH3:2].[CH3:22][O:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:25][CH2:24][O:23][CH3:22])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:21])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(Nc3ccc(O)cc3)nc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OCCOC)cc3)nc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 8-ethyl-2-(4-hydroxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (92 mg, 0.33 mmol), 2-methoxyethyl bromide (55 mg, 0.40 mmol) and potassium carbonate (360 mg, 2.61 mmol) in 5 mL of dimethylformamide was heated at reflux for 5 minutes. After cooling to room temperature, water was added, and the resultant solid collected by filtration. The solid was dissolved in ethyl acetate and the solution dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography eluting with ethyl acetate to provide 92 mg (56%) of 8-ethyl-2-[4-(2-methoxyethoxy)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one, mp 169-171° C.
Reaction SMILES: C([N:3]([C@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][N+:14]([O-:16])=[O:15])[CH2:9][CH2:8]1)[C:4](=[O:6])[CH3:5])C.C(N[C@H]1CC[C@H](O[N+]([O-])=O)CC1)C>>[C:4]([NH:3][C@H:7]1[CH2:8][CH2:9][C@H:10]([O:13][N+:14]([O-:16])=[O:15])[CH2:11][CH2:12]1)(=[O:6])[CH3:5]
Reactant: CCN(C(C)=O)[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: CCN[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Product: CC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1

Procedure:
trans-N-ethyl-N-acetyl-4-nitroxycyclohexylamine from trans-N-ethyl-4-nitroxycyclohexylamine melting point: 68°-69° C. (ether), yield: 35% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:12]([C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH3:24])[C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH:32]1[CH:37]=[CH:36][C:35]([Se:38]Br)=[CH:34][CH:33]=1.CN(C)C=O>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[N:12]([C@@H:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[CH3:24])[C:13](=[O:22])[CH:14]([Se:38][C:35]3[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=3)[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: Br[Se]c1ccccc1
Reactant: C[C@H](c1ccc(Cl)cc1)N(C(=O)C=Cc1ccccc1)[C@H](C(N)=O)c1ccc(Cl)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)C([Se]c2ccccc2)C(c2ccccc2)NC(=O)[C@@H]1c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
Silver triflate (1.69 g, 6.6 mmol) was added to a stirred solution of (S)-α-(4-chlorophenyl)-α-[(R)-N-[1-(4-chlorophenyl)ethyl]-N-(cinnamoyl)amino]acetamide (1.5 g, 3.3 mmol), in acetonitrile (120 mL). To the resulting solution was successively added benzeneselenyl bromide (1.54 g, 6.53 mmol) and dimethylformamide (5.2 mL). After 6 h, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and 1N sodium hydrogenocarbonate (70 mL), dried (Na2SO4), and evaporated. Purification by column chromatography (AcOEt/hexanes, 1:3) afforded the title compound, which was recrystallized from Et2O to give colorless prisms (855 mg, 43%): 1H NMR (400 MHz, CDCl3) δ 1.68 (d, J=7.0 Hz, 3H, CH3), 4.29 (d, J=12.2 Hz, 1H, CH), 4.79 (d, J=12.2 Hz, 1H, CH), 5.28 (s, 1H, CH), 6.21–6.25 (m, 3H, ArH), 6.31 (q, J=7.0 Hz, 1H, CH), 6.71–6.76 (m, 4H, ArH), 6.93–7.11 (m, 6H, NH+5ArH), 7.34–7.40 (m, 4H, ArH), 7.50 (d, J=8.4 Hz, 2H, ArH). Mass spectrum (LCMS, ESI pos.): Calcd for C31H26Cl2N2O2Se: 608.0; found: 609.0 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[OH-].[K+]>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:19][CH2:20][N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:1]2=[O:2])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Yield: 66.4 %

Procedure:
With stirring, 15 g of phosgene are introduced at 5° to 10° C in the course of 1 hour into a suspension of 10 g of 1-benzyl-4-(2-phenylamino-1-ethylamino)-piperidine in 100 ml of toluene and 48.5 ml of 3N potassium hydroxide solution. After stirring for 2 hours at 5° to 10° C, the reaction mixture is made alkaline with 43 ml of 6N potassium hydroxide solution and brought to room temperature. After it has been stirred for a further 15 hours at room temperature, the reaction mixture is filtered with suction and the residue is recrystallised from isopropanol-methanol to yield 7.2 g of 1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:5]>C1COCC1>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]=[O:5])[C:7]=1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CON(C)C(=O)c1cccc(F)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2c(F)cccc2C=O)CC1
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Cp2Zr(H)Cl (1.45 g, 5.61 mmol, 1.5 eq.) was suspended in THF (25 mL) under N2 at room temperature in a flame-dried flask. To this suspension was added tert-butyl 4-(2-(N-methoxy-N-methylcarbamoyl)-6-fluorophenyl)piperidine-1-carboxylate (1.37 g, 3.739 mmol) in THF (50 mL). The reaction was stirred under N2 for 15 min until the mixture turned clear (monitored by TLC: no SM detected). SiO2 was then added and the mixture was concentrated and purified by ISCO flash chromatography (SiO2, 5 to 30% EtOAc in Hexanes) to give 652 mg of tert-butyl 4-(2-fluoro-6-formylphenyl)piperidine-1-carboxylate as a white solid (57% over 2 steps). LC/MS ES+1: 308.17.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[CH3:8][N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)=[CH:24][CH:23]=[C:22]([CH3:34])[N:21]=2)=[CH:16][CH:15]=1)[CH3:10]>ClCCCl>[CH3:10][N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)=[CH:24][CH:23]=[C:22]([CH3:34])[N:21]=2)=[CH:18][CH:19]=1)[CH3:8]
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN(C)C)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN(C)C)cc2)n1
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
The AlCl3 (7 g, 52 mmol) was stirred in 150 mL of DCE at 0° C., ethanethiol (5.5 mL, 75 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-methylpyridine (2.7 g, 7.5 mmol) in 50 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 25 mL THF at 0° C., followed by 25 mL 1N HCl and worked up. The crude product was recrystallised from hot EtOAc/ pet. ether to give 0.9 g (34 % yield) of white solid: mp 155°-157° C.; 1H NMR (CDCl3) d 2.37 (s, 6H, NCH3), 2.62 (s, 3H, pyr-CH3), 2.78-2.81 (t, 2H, J=5 Hz, CH2N), 4.05-4.07 (t, 2H, J=5 Hz, OCH2), 6.64-6.69 (m, 4H, ArH), 6.94-6.96 (d, 2H, J=8 Hz, ArH), 7.09-7.12 (d, 1H, J=8 Hz, ArH), 7.24-7.27 (comp, 2H, ArH), 7.52-7.55 (d, 1H, J=8 Hz, ArH); MS(FD) 348 (M+). Anal. Calcd for C22H24 N2O2 : C, 75.84; H, 6.94; N, 8.04. Found: C, 75.70; H, 6.98; N, 8.00.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:14]1([S:20][CH2:21][N:5]2[C:4](=[O:13])[C:3]3[C:9](=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[S:6]2(=[O:8])=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Yield: 46.3 %

Procedure:
A mixture of 1.0 g (0.005 mol) of 4-methylsaccharin, 0.33 g (0.001 mol) of TBAB and 1.2 g (0.0075 mol) of chloromethyl phenyl sulfide in 25 ml of toluene was heated under reflux for about sixteen hours and then cooled, diluted with ethyl acetate and the solution washed with aqueous bicarbonate and water. The organic layer was dried and taken to dryness to give 0.74 g of 2-phenylthiomethyl-4-methylsaccharin.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].C(N(CC)CC)C.C(O)C.[Cl:20][C:21](Cl)=[CH:22][C:23](=O)[C:24]([F:27])([F:26])[F:25]>ClCCl.CN(C)C=O>[Cl:20][C:21]1[N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:3]=[C:23]([C:24]([F:27])([F:26])[F:25])[CH:22]=1
Reactant: O=C(C=C(Cl)Cl)C(F)(F)F
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Reaction time: 2 h

Procedure:
To a mixture of ethyl hydrazinoacetate hydrochloride (2.8 g, 18.1 mmol) and triethylamine (9.2 g, 91 mmol) in a solution of ethanol (20 mL) and N,N-dimethylformamide (1 mL), a solution of crude 4,4-dichloro-1,1,1-trifluoro-3-buten-2-one in dichloromethane (20 mL) was added dropwise while keeping the temperature of the reaction mixture below 10° C. After stirring a further 2 h at below 10° C., the reaction mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether, and the mixture was filtered. The resulting filtrate was concentrated to give 4.34 g of the title compound as a solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH3:12])=[CH:4][CH:3]=1.C(O)C.C(=O)=O.FC(F)(C1C=C2C(=CC=1)N=CC=C2)C1N2N=C(C3C=CC(CCNC(=O)OC(C)(C)C)=CC=3)C=CC2=NN=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: CC(C(=O)NNc1ccc(Cl)nn1)c1ccc2ncccc2c1
Agent: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cc1
Agent: O=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12

Procedure:
A solution of N′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (2700 mg, 8238 μmol) in TFA (20 mL) was heated to 120° C. with microwaves (2 bar; 10 watts) for 40 min. The solution was concentrated under reduced pressure then partitioned between 9:1 CHCl3/IPA (75 mL) and 1 M NaOH (100 mL). The aqueous layer was further extracted with 9:1 CHCl3/IPA (2×20 mL). The combined organics were dried over MgSO4 then concentrated to an amber oil under reduced pressure. The product was isolated as off white crystalline solid from ACN. MS (ESI pos. ion) m/z: 310 (MH+). Calc'd exact mass for C16H12ClN5: 309. Enantiomer resolved with: Chiralpak AD-H (3×25 cm) column using 45% ethanol (0.1% DEA)/CO2 The following compounds were prepared using same method as tert-Butyl 2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate and resolved from racemic mixtures:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>>[C:42]([O:41][C:39]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)CCCCCCCBr
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCCCC(=O)OC(C)(C)C)C(C)(C)CCC2(C)C
Yield: 80.7 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 3.82 g (9.34 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate obtained in Example 13(f) with 3 g (10.7 mmol) of tert-butyl 8-bromooctanoate obtained above, 4.36 g (77%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.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>[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine-2HCl (70 mg, 0.206 mmol), (3-fluorophenyl)acetic acid (31.8 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at rt for overnight. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered to give the product. LC/MS (ES) m/z=403.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.26 (t, J=8.46 Hz, 2H), 3.93 (s, 5H), 4.25 (t, J=8.46 Hz, 2H), 7.11 (s, 1H), 7.13-7.17 (m, 2H), 7.39 (d, J=6.82 Hz, 1H), 7.44 (d, J=8.34 Hz, 1H), 7.51 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).