Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2>C1COCC1.CO.[Pt](=O)=O>[CH3:1][CH:2]1[CH2:11][N:10]2[C:5](=[N:6][S:7](=[O:13])(=[O:12])[CH2:8][CH2:9]2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:3]1
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3ccccc3)cc2)=C1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1CC(c2ccc(Oc3ccccc3)cc2)C2=NS(=O)(=O)CCN2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a suspension of NaH (60%, 229 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.361 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 5-methyl-3-(4-phenoxyphenyl)pyridin-2-amine (316 mg) in THF (dry) (20 mL) was added at 0° C. and the mixture was stirred at room temperature for 30 min. The mixture was quenched with water. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give 7-methyl-9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (158.2 mg) as a white solid. Platinum(IV) oxide (30.0 mg) was added to a solution of 7-methyl-9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (141 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Platinum(IV) oxide (30.0 mg) was added and the mixture was stirred at 50° C. under hydrogen for 1 day. The insoluble material was removed by filtration, silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and crystallized from THF/IPE to give the title compound (35.4 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.[O-]CC.[Na+]>C(O)C>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)=[O:3])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(=O)C=Cc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
4-Cyanoacetophenone (0.01 mol) in ethanol (100 ml) is added dropwise to a 0° C. mixture of 3-(2-quinolinylmethyl-oxy)benzaldehyde (0.01 mol) and sodium ethoxide (0.001 mol) in ethanol (200 ml). The reaction mixture is allowed to.thaw to ambient temperature and after several hours it is evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)benzonitrile.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2ncc(Br)nc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Brc1cnc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A mixture of dimethyl 6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (300 mg, 0.895 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (210 mg, 0.895 mmol) and cesium carbonate (600 mg, 1.79 mmol) in acetonitrile (25 mL) was heated on a 100° C. oil bath for 2 hours in an open flask, with nitrogen bubbling through the solution the entire time to help in the removal of methanethiol. After 2 hours, TLC showed the reaction to be complete, so the mixture was cooled to ambient temperature, diluted with water and concentrated in vacuo. The mixture was extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (200 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.39 (br. s., 1 H) 8.48 (s, 1 H) 4.05 (d, J=9.79 Hz, 1 H) 3.72 (d, J=9.79 Hz, 1 H) 3.42 (dd, J=15.06, 1.76 Hz, 1 H) 2.73-3.08 (m, 5 H) 2.10-2.22 (m, 2 H) 1.73-1.84 (m, J=14.09, 9.94, 4.17, 4.17 Hz, 1 H) 1.52-1.65 (m, 2 H). MS (LC/MS) R.T.=1.29; [M+H]+=394.99.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[N:16]([CH3:27])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=4)=[N:18][C:14]=3[CH:13]=2)[CH:10]=1)=[O:4].[CH3:30][NH2:31]>>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17]2[N:16]([CH3:27])[C:15]3[CH:28]=[CH:29][C:12]([O:11][C:9]4[CH:10]=[C:5]([C:3]([NH:31][CH3:30])=[O:4])[CH:6]=[N:7][CH:8]=4)=[CH:13][C:14]=3[N:18]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1
Reactant: CN
Product: CNC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1

Procedure:
To a solution of methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate in added methylamine and the resulting mixture was stirred at ambient temperature for 16 h. It was then concentrated and purified by preparative chromatography to yield (5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide. MS: MH+=452.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.S([CH2:22][N:23]=C=O)(C1C=CC(C)=CC=1)(=O)=O.C(O[K])(C)(C)C>CN(C)C=O.O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:22]#[N:23])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 1,4-Dioxa-spiro[4,5]decan-8-one (2.0 grams, 12.8 mmole) and tosyl-methyl isocyanate (5.0 grams, 25.6 mmole) in dimethylformamide (25 ml) at 0° C. was added 1.0 M tBuOK in tButanol (25.6 ml) and stirred at 0° C. for 1 hour and room temperature over night. The mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid (1.45 g). MW 167.209; MS (m/e) 168 (M++1).
Reaction SMILES: Cl.Cl.[O:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][NH:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[N:4]1.C(N(CC)CC)C.Cl[C:28]1[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[C:30]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[N:29]=1>O1CCCC1>[O:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[NH:15][CH2:16][CH2:17][N:18]([C:28]4[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[C:30]([C:36]5[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=5)[N:29]=4)[CH2:19]3)=[CH:10][CH:9]=2)=[N:4]1
Reactant: c1nc(-c2ccc(C3CNCCN3)cc2)no1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(-c4ncon4)cc3)C2)nc(-c2ccncc2)cc1=O
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a suspension of 2-(4-(1,2,4-oxadiazol-3-yl)phenyl)piperazine dihydrochloride (102 mg, 0.34 mmol) in tetrahydrofuran (6 mL) was added triethylamine (0.23 mL, 1.65 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (73 mg, 0.33 mmol) at room temperature. After stirring for 24 h, the resulting mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and saturated sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated in vacuo to yield crystals, which were washed with diisopropyl ether and ethanol to afford (S)-2-(3-(4-(1,2,4-oxadiazol-3-yl)phenyl) piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (102 mg 74%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:23])[C:17]1=[O:26])[CH2:27][C:28](=[O:31])[CH2:29][CH3:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCOCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid (0.035 g) in DCM (2 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.044 g), HOBT (0.031 g) and triethylamine (0.064 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.02 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>CS(C)=O>[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:27][CH2:26]1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Br)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Br)c(Cl)cn2)CC1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To a solution of 3-bromo-5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (100 mg, 0.250 mmol) in DMSO (1 mL) was added trans-1,4-diaminocyclohexane (114 mg, 0.998 mmol). The mixture was stirred at 110° C. for 19 hr. The crude reaction mixture was purified by reverse phase HPLC and lyophilized to give 51 mg of N2′-(trans-4-aminocyclohexyl)-3-bromo-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 494.2/496.1 (MH+), retention time=0.61 min; 1H NMR (400 MHz, DMSO-d6) d ppm 1.06-1.31 (m, 4 H) 1.31-1.49 (m, 2 H) 1.49-1.64 (m, 2 H) 1.64-1.82 (m, 1 H) 1.85-2.11 (m, 4 H) 2.93-3.12 (m, 3 H) 3.22 (t, J=10.96 Hz, 2 H) 3.61 (t, J=10.76 Hz, 1H) 3.81 (dd, J=11.35, 2.74 Hz, 2 H) 6.39 (s, 1 H) 6.48 (d, 1 H) 6.82 (br. s., 1 H) 6.94 (br. s., 1 H) 7.59 (d, J=9.00 Hz, 1 H) 7.78 (d, J=3.91 Hz, 2 H) 8.02 (s, 1H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:11]([C:4]1[CH:3]=[C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([O-:13])=[O:12]
Reactant: OCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CO)cc2)cc1[N+](=O)[O-]
Reaction time: 22 h
Yield: 45.2 %

Procedure:
4-fluoro-1,2-dinitrobenzene (20.0 g, 107.5 mmol), 4-(hydroxymethyl)phenol (14.7 g, 118.2 mmol) and potassium carbonate (17.8 g, 129.0 mmol) were stirred in 250 ml of dimethylformamide at room temperature for approximately 17 hours. The reaction was heated at 35 degree Centigrade for 1.5 hours. Cesium carbonate (2 g, 6.14 mmol) was added and the reaction was heated at 45 deg. C. for approximately 22 hours. The solids were filtered away and washed with ethyl acetate. The filtrate was diluted with water and extracted 4 times with ethyl acetate. The ethyl acetate layers were washed with a water/brine mixture 5 times. The aqueous wash layers were back extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexane) to give 14.1 g of {4-[(3,4-dinitrophenyl)oxy]phenyl}methanol.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]([CH3:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([CH:38]([CH3:40])[CH3:39])[N:25](/[CH:34]=[CH:35]/[CH:36]=[O:37])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([CH:38]([CH3:40])[CH3:39])[N:25](/[CH:34]=[CH:35]/[CH:36]([OH:37])[CH2:11][C:12](=[O:13])[CH3:14])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1
Reactant: CC(C)=O
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)CC(O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (4.1 ml, IM solution in THF) in dry THF (20 ml) at -78° under nitrogen was added dry acetone (275 μl). After 25 min, a solution of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (881 mg) in dry THF (15 ml) was added dropwise over 10 min. Stirring was continued for 25 min at -78° then the reaction was quenched with saturated aqueous ammonium chloride solution (25 ml) and allowed to warm to room temperature. The layers were separated and the aqueous phase extracted with ethyl acetate (2×50 ml). The combined extracts were dried and evaporated to a white solid (1.09 g). FCC eluting with System A (1:1) gave the title compounds as a white solid (709.6 mg). (CDCl3) 7.35-7.45 and 7.20-7.29(2m,4H,C-2 and C-6 protons of 4-fluorophenyl), 7.10 and 6.90(2t,4H,C-3 and C-5 protons of 4-fluorophenyl,J=9 Hz), 6.70(d,1H,NCH=CHCH,J=13.7 Hz), 5.26(dd,1H,NCH=CHCH,J=13.7 Hz,6.3 Hz), 4.58(m,1H,NCH=CHCH), 3.15(m,2H,CH(CH3)2 and OH), 2.50(m,2H,CH(OH)CH2C(O)), 2.15(s,3H,CH2C(O)CH3), 1.40(d,6H,CH(CH3)2,J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)Cc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(F)cc1F
Reaction time: 1.5 h

Procedure:
A solution of 2,4-difluorophenylacetyl chloride (10 mmol) in dry DCM (15 ml) was added over 10 min. to a mixture of t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (20 ml). After stirring for 1.5 h the mixture was washed with 1M HCl then with aqueous NaHCO3. The organic phase was evaporated to afford 1,1-dimethylethyl 2-[(2,4-difluorophenyl)acetyl]hydrazinecarboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=[O:14])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OCCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1OCCCO2
Yield: 84 %

Procedure:
A mixture of intermediate (5) (0.25 mol) and KOH (1 mol) in water (650 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled, acidified with HCl and the resulting precipitate was filtered off, washed with water, and dried, yielding 48 g of 8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid (intermediate 6).
Reaction SMILES: [OH:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl>[CH3:29][O:28][C:26]([O:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:27]
Reactant: O=C1CCCCCCCCCCC(O)CCCO1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OC1CCCCCCCCCCC(=O)OCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
480 g (1.89 mol) of 12-hydroxy-15-pentadecanolide (VII) are dissolved in 900 ml of methylene chloride with 205.5 g of pyridine. 213 g (2.2 mol) of methyl chloroformate in 900 ml of methylene chloride are added dropwise to this mixture at 0° to 5° C. in the course of 1 hour. The reaction mixture is stirred at room temperature for a further 5 hours. The organic phase is washed neutral and dried over Na sulphate. The organic phase is freed from methylene chloride and subjected to fractional distillation. 540 g of 12-methoxycarbonyloxy-15-pentadecanolide are obtained; yield: 91% of theory.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)[CH:34]=1
Reactant: CC1(C)OB(c2cnc(N)c(Cl)c2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)c(Cl)c4)nc3s2)CC1
Yield: 89.8 %

Procedure:
4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine (0.8 g, 1.7 mmol) was reacted with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.6 g) according to General Procedure Suzuki to provide 376 (0.8 g) following silica gel purification (0-15% MeOH in CH2Cl2) MS (Q1) 524 (M)+.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CCN(CC)CC>C1(C)C=CC=CC=1>[CH:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCO
Agent: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCC=O
Temperature: -25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of N-chlorosuccinimide (0.1 g, 0.8 mmol) in toluene (2 mL) was added flurous sulfide 1 (0.4 g, 1 mmol) at 0° C. resulting in the immediate formation of a white cloudy precipitate. The reaction mixture was cooled to −25° C., and a solution of octanol (0.07 g, 0.5 mmol) in toluene (2 mL) was added. After stirring at −25° C. for 2 hours, a solution of Et3N (0.08 g, 0.8 mmol) was added. The cold bath was removed after 5 minutes, and the reaction mixture washed with saturated aqueous NH4Cl, then water. The organic layer was extracted continuously with FC72 solvent (15 mL) in a cooled continuous extractor for a period of 4 hours. Concentration of the toluene layer and chromatography on silica gel (eluent: EtOAc/hexanes 3:1) yielded octanal (0.06 g, 88%). The FC72 layer was carefully concentrated under aspirator vacuum to give recovered fluorous sulfide 1 (0.3 g, 75%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH2:27]([NH2:30])[C:28]#[CH:29]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:27][C:28]#[CH:29])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: C#CCN
Solvent: ClCCl
Product: C#CCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (2S,3R,4R,5R,6R)-6-(acetoxymethyl)-3-isothiocyanatotetrahydro-2H-pyran-2,4,5-triyl triacetate (1.4 g, 3.6 mmol) in DCM (15 mL) at 0° C., was added propargyl amine (0.345 mL, 5.4 mmol) dropwise. After the addition, reaction mixture was stirred at RT for 1 h. DCM layer was washed with satd. NaHCO3, dried over anhydrous Na2SO4 and concentrated. The crude product (2S,3R,4R,5R,6R)-6-(acetoxymethyl)-3-(3-(prop-2-yn-1-yl)thioureido)tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.59 g, 98%) thus obtained was carried forward without further purification.
Reaction SMILES: C[Al](C)C.[C:5]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C[O:31][C:32]([C:34]1[N:35]=[CH:36][CH:37]=[C:38]2[CH:42]=[CH:41][NH:40][C:39]=12)=O>ClCCl>[C:5]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:26])([F:27])[F:25])[CH:18]=2)[C:32]([C:34]2[N:35]=[CH:36][CH:37]=[C:38]3[CH:42]=[CH:41][NH:40][C:39]=23)=[O:31])=[CH:11][CH:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)c1nccc2cc[nH]c12
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2nccc3cc[nH]c23)cc1
Yield: 100.5 %

Procedure:
Trimethylaluminum solution (2 M in heptane, 0.14 mL, 0.28 mmol) was added at RT to a solution of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine (100 mg, 0.28 mmol) in dichloromethane (0.7 mL), then after 15 min a solution of 1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid methyl ester (50 mg, 0.14 mmol) in dichloromethane was added. After 2 h the reaction mixture was partitioned between ethyl acetate and 2 M aq. hydrochloric acid solution. The organic layer was washed with brine, dried (MgSO4), evaporated, and chromatographed (SiO2, heptane/ethyl acetate gradient), to afford the title compound (70 mg, 50%). White foam, MS (ISP) 498.3 (M+H)+.