Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:53])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC>[NH2:1][C:2]1[C:3]([C:40]2[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=2)[C:37]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([OH:29])[CH:31]=2)=[O:53])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc(C(=O)Nc3cccc(O)c3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(C(=O)Nc4cccc(O)c4)c3)n(-c3ccccc3)c(=O)c12
Yield: 16 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (55 mg, 0.12 mmol) was treated with N-(3-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (106 mg, 0.31 mmol, prepared from 3-bromo-N-(3-hydroxyphenyl)benzamide and bis(pinacolato)diboron according to Preparation 119b), sodium carbonate (40 mg, 0.38 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (6 mg, 0.01 mmol) in water (1 ml) and dimethoxyethane (3 ml) according to the method described in Example 3 to give 11 mg (15% yield) of the title compound. Purity 100%.
Reaction SMILES: Cl.Cl[C:3]1C=CC=C[C:4]=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44](C)(C)[CH3:45])=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][CH2:44][CH2:45][CH2:3][CH3:4])=[O:42])[CH2:38]1)[C:27]1[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=1[Cl:25]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: [N-]=C=O
Product: CCCCNC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:20][CH:21]([CH3:26])[CH2:22][C:23](Cl)=[O:24]>CN(C)C=O>[CH3:1][C:2]1[N:3]([C:23](=[O:24])[CH2:22][CH:21]([CH3:26])[CH3:20])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1[nH]c2ccccc2c1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)CC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a solution of tert-butyl 2-methyl-1H-indole-3-carboxylate (300 mg, 1.30 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (103.76 mg, 2.59 mmol, 60%). The mixture was stirred at 0° C. for 30 minutes. Then 3-methylbutanoyl chloride (234.60 mg, 1.95 mmol) was added at 0° C. and the mixture was stirred at room temperature (25° C.) for 2 hours. The mixture was cooled with ice, quenched with water (5 mL), diluted with ethyl acetate (20 mL), washed with brine (20 mL), extracted with ethyl acetate three times (20 mL×3), then dried over sodium sulfate. After concentration, the residue was purified by column on silica gel (0%-5% PE/EA) to afford the title compound (200 mg, yield: 48.89%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16]O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CBr)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5.00 g (20.55 mM) of trans-4-[N-(tert-butoxycarbonyl)aminomethyl]cyclohexane-1-methanol and 6.42 g (24.48 mM) of triphenylphosphine in methylene chloride (30 ml) was added 13.63 g (41.1 mM) of carbon tetrabromide at 0° C. and the mixture was stirred at room temperature for 20 hours. This reaction mixture was purified by column chromatography (ethyl acetate-hexane: 10%) to provide the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]3[N:25]4[CH:26]=[CH:27][C:28](Br)=[CH:29][C:24]4=[N:23][C:22]=3[CH3:31])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:33]1([C:28]2[CH:27]=[CH:26][N:25]3[C:21]([CH2:20][C:18]4[CH:17]=[CH:16][C:10]5/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:32][C:6]=6[O:7][CH2:8][C:9]=5[CH:19]=4)=[C:22]([CH3:31])[N:23]=[C:24]3[CH:29]=2)[CH2:35][CH2:34]1
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C)nc4cc(Br)ccn34)cc2COc2cc(F)ccc21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C/C(C#N)=C1/c2ccc(Cc3c(C)nc4cc(C5CC5)ccn34)cc2COc2cc(F)ccc21
Temperature: 100 °C
Yield: 86.5 %

Procedure:
[step 5] (E)-2-{3-fluoro-8-[(7-bromo-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (350 mg, 0.72 mmol) obtained in step 4 was dissolved in toluene (4.0 mL), cyclopropylboronic acid (123 mg, 1.4 mmol), tricyclohexylphosphine (80 mg, 0.29 mmol), palladium acetate (32 mg, 0.14 mmol), potassium phosphate (532 mg, 2.5 mmol) and water (13 mg, 0.72 mmol) were added, and the mixture was stirred with heating at 100° C. for 3 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=19/1 v/v) to give the title compound (280 mg, 87%).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C[O:13][C:14](=O)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17].B(OB=O)=O>CO>[C:1]([NH:10][NH:11][C:14](=[O:13])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NNC(=O)c1ccccc1O
Reactant: COC(=O)c1ccccc1O
Agent: O=BOB=O
Solvent: CO
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1O
Reaction time: 3 h
Yield: 85 %

Procedure:
152 parts by weight salicyclic acid hydrazide was heated with 152 parts by weight salicylic-acid methyl ester and 3 parts by weight boron trioxide in 230 parts by weight paraffin (viscosity at 60° C.: 100 m Pa s) to 140° to 150° C. while stirring vigorously. Methanol produced during the reaction was distilled off by a column. After about 3 hours, the reaction was completed. The now viscous reaction mixture was cooled down to 50° to 60° C., treated with alcohol (methanol or ethanol) and the mixture was stirred very vigorously at about 50° to 60° C. The yellow-colored alcohol phase was decanted from the viscous paste and the process was repeated until discoloration was complete. After separating the washing alcohol, drying in a vacuum at about 100° C. was performed. 460 parts by weight of a colorless viscous paste was obtained, consisting of 230 parts by weight N,N'-bis(salicyloyl)hydrazine (85% yield) and 230 parts by weight paraffin. By dissolving the paraffin with methylene chloride and boiling-out the solid matter with methanol, N,N'-bis(salicyloyl)hydrazine with a melting and decomposition range of 305° to 310° C. was obtained.
Reaction SMILES: C([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[O:23][C@@H:24]1[CH2:28][C@@H:27]([CH2:29][O:30][Si](C(C)(C)C)(C)C)[C@@H:26]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:25]1)C1C=CC=CC=1.C(O)=O.CO>[Pd]>[Si:39]([O:38][C@H:26]1[CH2:25][C@H:24]([O:23][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:8]3)[CH2:28][C@H:27]1[CH2:29][OH:30])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(-c2ccccc2)n3Cc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2ncnc3[nH]c(-c4ccccc4)nc23)C[C@H]1CO
Reaction time: 8 h

Procedure:
A suspension of 9-benzyl-6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-phenyl-9H-purine (0.161 g, 0.000249 mol), 10% Pd/C (0.04 g, 0.00004 mol) and formic acid (0.1 mL, 0.003 mol) in methanol (11.0 mL, 0.272 mol) was stirred under an atmosphere of nitrogen overnight. Added formic acid (0.2 mL, 0.005 mol) and 10% Pd/C (0.04 g, 0.00004 mol) to the reaction and stirred 24 h. Added 10% Pd/C (0.060 g, 0.000056 mol) and formic acid (0.2 mL, 0.005 mol) to the reaction and stirred an additional 24 h. The reaction was purged with nitrogen and filtered the mixture through celite with DCM. The filtrate was concentrated, purified by flash chromatography (30 to 50% ethyl acetate/hexane) to obtain 30 mg (27%). LC/MS: Rt=2.08 min, ES+ 441.18 (AA standard).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@H:23]3[N:27](C(OC(C)(C)C)=O)[C@@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:50])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@H:23]3[NH:27][C@@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CC[C@@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@]1(C)CC[C@@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.5 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5S)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-1,2-pyrrolidinedicarboxylate (Intermediate 19, 70 mg, 0.095 mmol) in dry Dichloromethane (DCM) (2 ml) was added TFA (0.5 ml, 6.49 mmol) and the reaction mixture was stirred for 2.5 hours at r.t. The solvent and the excess of TFA were evaporated and the residue was purified by SPE-SCX cartridge to afford the title compound (55 mg, 0.086 mmol, 91% yield) as a white solid. UPLC: Rt 0.76 min (broad peak), m/z 640 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](=S)[NH2:22])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.IC.CO[CH:28](OC)[CH2:29][NH2:30].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.CCOC(C)=O>[NH:30]1[CH:29]=[CH:28][N:22]=[C:21]1[C:12]1[S:11][C:10]([C:9]2[C:2]([CH3:1])=[N:3][N:4]3[CH:8]=[CH:7][S:6][C:5]=23)=[N:14][C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(CN)OC
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(-c2ncc[nH]2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carbothioamide (223 mg, 0.6 mmol) obtained in the similar manner described in Example 111-B(ii) in acetone (12 mL), was added iodomethane (75 μL, 1.2 mmol), and the mixture was stirred at rt for 2 h. The solvent was evaporated, and the residue was suspended in AcOH (12 mL). To the residue was added aminoacetaldehyde dimethylacetal (100 μL, 0.9 mmol), and the mixture was stirred at 90° C. for 16 h. The reaction mixture was allowed to cool to rt, then concentrated, and the residue was dissolved in THF (12 mL). To the solution was added 6N hydrochloric acid (400 μL, 2.4 mmol), and the mixture was stirred at 70° C. for 2 h. The reaction mixture was allowed to cool to rt, and then were added saturated aqueous solution of sodium bicarbonate (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL), and the organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=20/80→100/0) to give the title compound (133 mg, 61%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)(O)[NH:7][C:6]=2[C:5]([N+:19]([O-])=O)=[C:4]([F:22])[CH:3]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([NH2:19])=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[N:7]2
Reactant: O=[N+]([O-])c1c(F)cc(Br)c2c1NC(O)(c1cccnc1)CO2
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(F)cc(Br)c2c1N=C(c1cccnc1)CO2
Temperature: 60 °C

Procedure:
To 8-bromo-6-fluoro-5-nitro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-3-ol (690 mg, 1.9 mmol) in acetic acid (20 mL), iron (520 mg, 9.4 mmol) was added and heated at 60° C. overnight. The reaction was extracted with ethyl acetate to give the crude product, 0.60 g, 100%. 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.68 (m, 1H), 8.51 (m, 1H), 7.52 (m, 1H), 6.89 (m, 1H), 5.80 (s, 2H), 5.13 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H). LCMS calculated for C13H10BrFN3O (M+H)+: m/z=322.0, 324.0. found: 321.8, 323.8.
Reaction SMILES: [C:1]([OH:12])(=O)[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10].CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[C:1]([Cl:20])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10]
Reactant: CC=CC=CCCC=CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC=CC=CCCC=CC(=O)Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, a toluene solution of the above-mentioned 2,6,8-decatrienoic acid (7) and DMF (3.7 g, 0.05 mol) were added to a 100 ml capacity flask, followed by cooling to 5° C. Thionyl chloride (11.9 g, 0.10 mol) was added dropwise to this, followed by stirring at 5° C. for 0.5 hour to obtain a toluene solution of 2,6,8-decatrienoic acid chloride (8).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:28](=[O:29])[CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(Cl)c1
Temperature: 0 °C

Procedure:
Triethylamine (18 mL, 130 mmol) was added to methyl 2-amino-5-bromobenzoate (25 g, 110 mmol) in DCM (150 mL). The mixture was cooled to 0° C. and 2-(3-chlorophenyl)acetyl chloride (24.3 g, 130 mmol) in DCM (100 mL) was added. The mixture was allowed to warm to room temperature overnight with stirring. Aqueous K2CO3 (10 wt. %) was added and the mixture was extracted with DCM. The organic phase was dried (MgSO4), filtered, and concentrated to yield the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:14][CH2:13][CH2:12][Br:11])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1ccc2c(c1)NCCO2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: BrCCCN1CCOc2ccccc21
Temperature: 70 °C

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2 mmol), 1,3-dibromopropane (22.5 ml, 10 eq, 222 mmol) and anhydrous sodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to yield the title compounds as liquid mass (2.6 g, 47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15](O)[CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:25])CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([F:25])[CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: CC(F)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
To a cold solution of [1-(2-hydroxy-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.70 g, 2.7 mmol) in DCM (30 mL) was added DAST (1.1 mL, 8.1 mmol) and the mixture was stirred at 25° C. for 20 h. The reaction mixture was washed with saturated sodium bicarbonate solution, water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford [1-(2-fluoro-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.5 g, 70%). LCMS (Method G; ESI): RT=0.53 min; m+1=261.3. This was used without further purification below.
Reaction SMILES: [Na].C(=O)(O)O.[NH2:6][C:7]([NH2:9])=[NH:8].[CH2:10]([O:12][C:13](=[O:37])[NH:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][C:24]([C:33]#N)=[CH:25][NH:26]C2C=CC=CC=2)=[CH:17][C:16]=1[O:35][CH3:36])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:37])[NH:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][C:24]2[C:25]([NH2:26])=[N:8][C:7]([NH2:9])=[N:6][CH:33]=2)=[CH:17][C:16]=1[O:35][CH3:36])[CH3:11]
Reactant: CCOC(=O)Nc1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reaction time: 1 h

Procedure:
A solution of 360 mg. of sodium in 100 ml. of absolute ethanol was treated with 2.8 g. of guanidine carbonate and 2.0 g. of 4-(3-anilino-2-cyano-allyl)-2,6-dimethoxy carbanilic acid ethyl ester and boiled under reflux for 20 hours. The solution was diluted with 100 ml. of water and the alcohol removed under vacuum. After standing at room temperature for 1 hour, the precipitate was removed by filtration with suction, washed with water and dissolved in about 200 ml. of boiling ethanol. The solution was chromatographed on 100 g. of silica gel using ethanol/ethyl acetate (1:1) and there was obtained 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester which, after recrystallization from ethanol, had a melting point of 228° C. (decomposition).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[CH:48][C:49]4[N:54]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[C:53](=[O:60])[CH2:52][O:51][C:50]=4[N:61]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:47]([C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[CH:48][C:49]4[N:54]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[C:53](=[O:60])[CH2:52][O:51][C:50]=4[N:61]=3)=[CH:44][CH:45]=2)[CH2:37][CH2:38][CH2:39]1
Reactant: CN(C)CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: CN(C)CCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 158.2 %

Procedure:
Following the procedure 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(1-(2-(dimethylamino)ethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (7 mg, 0.01 mmol) was reacted to afford the title compound (7 mg, quantitative). LCMS (Method A): RT=2.92 min, M+H+=443. 1H NMR (500 MHz, MeOD): 7.63 (1H, S), 7.41 (2H, d), 7.38 (2H, d), 7.31-7.29 (3H, m), 7.25-7.23 (m, 2H), 5.00 (2H, s), 4.45 (2H, t), 3.48 (2H, t), 3.02 (6H, s), 2.77-2.72 (m, 2H), 2.59-2.53 (m, 2H), 2.25-2.19 (m, 1H), 1.99-1.92 (m, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][CH3:43]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:44])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[S:42][CH3:43])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccccc1SC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1SC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (8.26 g, 16.6 mmol) in anhydrous THF (50 mL) was added 2 M isopropylmagnesiumchloride in THF (18.4 mL, 36.8 mmol) at −40° C. It was then warmed to 0° C. and stirred at the same temperature for 30 minutes and then N-Methoxy-N-methyl-2-methylsulfanyl-benzamide (10.5 g, 49.8 mmol) was added in and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography to provide 4-chloro-N-[5-chloro-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. Mass spectrum m/z: 486.9 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:26]([NH2:27])=[CH:25][NH:24][N:23]=2)=[O:21])=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]2[C:26]([NH:27][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])=[CH:25][NH:24][N:23]=2)=[O:21])=[CH:17][CH:18]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: COc1ccccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
2-Methoxy-benzoic acid (38 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol), and HOBt (37 mg, 0.27 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The residue was purified by preparative LC/MS and, after evaporation of product-containing fractions, yielded the product as a pinkish solid (12 mg, 15%). (LC/MS: Rt 4.00, [M+H]+ 354.67).