Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].O.[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.ClC(OCC)=O.[C:20](=S)=[S:21]>>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1([CH2:12][N:13]=[C:20]=[S:21])[CH2:11][CH2:10]1
Reactant: S=C=S
Reactant: NCC1(c2cccs2)CC1
Agent: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: S=C=NCC1(c2cccs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 11 parts of potassium hydroxide in 200 parts of water is cooled to about 10° C. and there are added successively 22.8 parts of carbon disulfide and then dropwise 42 parts of 1-(2-thienyl)cyclopropylmethylamine (exothermic reaction). Upon completion, the whole is stirred for 30 minutes at room temperature. Then there are added at 30° C., 29.8 parts of ethyl chloroformate (exothermic reaction: cooling is necessary). The whole is stirred for 3 hours while heating at 50° C. The reaction mixture is cooled and the product is extracted with benzene. The extract is dried, filtered and evaporated. The oily residue is distilled twice, yielding 40 parts of [1-(2-thienyl)cyclopropylmethyl]isothiocyanate; bp. 140°-150° C. at 10 mm pressure; nD20 :1.6008; d2020 :1.1911.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)(O)=[O:6]>C1C=CC=CC=1>[Cl:3][C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C12CCCC(C1)C1CCC2C1
Solvent: c1ccccc1
Product: O=C(Cl)C12CCCC(C1)C1CCC2C1
Yield: 92 %

Procedure:
68 ml of thionyl chloride was added dropwise to 46.0 g (0.24 mole) of 1-carboxytricyclo[4.3.1.12,5 ]undecane dissolved in 200 ml of benzene at room temperature. The resulting mixture was refluxed for 1.5 hours, and excess thionyl chloride and benzene were distilled off under reduced pressure. The residue obtained was fractionally distilled under reduced pressure to afford 47.0 g (yield: 92%) of 1-chlorocarbonyltricyclo[4.3.1.12,5 ]undecane having a boiling point of 101° C. (1 mmHg).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: COCCN
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCOC)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 85.4 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.200 g, 0.833 mmol), 2-methoxyethanamine (0.065 mL, 0.757 mmol) in 80% aq. EtOH (5 mL) was heated at 90° C. overnight: After work-up, the crude product was purified by silica gel column chromatography (33% EtOAc/Hexanes to 50% EtOAc/Hexanes) to provide the title compound (0.191 g, 85%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.34 (s, 1H), 8.28 (d, J=2.8 Hz, 1H), 7.56 (dd, J=8.4 Hz, J=1.6 Hz, 1H), 6.91 (d, J=9.2 Hz, 1H), 3.69 (t, J=5.6 Hz, 2H), 3.53 (q, J=5.6 Hz, 2H), 3.44 (s overlapping with br s, 7H), 1.22 (t, J=6.4 Hz, 6H). MS (ESI) (M+H)+=296
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@@H:31]([OH:39])[CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:25][C:23]=2[N:24]=1.C(N(C(C)C)CC)(C)C>C(O)C>[OH:39][C@H:31]([CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH3:19])=[N:24][C:23]=2[CH:25]=1)[CH2:32][N:33]1[CH2:34][CH2:35][N:36]([CH2:2][C:3]([NH:5][C@@H:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4])[CH2:37][CH2:38]1
Reactant: CCOC(=O)[C@@H](NC(=O)CCl)c1ccc(F)cc1
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)[C@@H](NC(=O)CN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1)c1ccc(F)cc1

Procedure:
Ethyl (2S)-2-(2-chloroacetylamino)-2-(4-fluorophenyl)acetate (400 mg, 1.46 mmol), (2S)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol (560 mg, 1.46 mmol), and 1.26 ml diisopropylethylamine (7.3 mmol) was refluxed in ethanol for 24 hours. Solvent was removed under reduced pressure, and the residue purified by Prep TLC, to provide ethyl (2S)-2-(2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}acetylamino)-2-(4-fluorophenyl)acetate.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:21]1[O:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1)[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:26]([C:24]3[N:25]=[C:21]([CH2:19][CH3:20])[O:22][C:23]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-ethyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>C(OCC)(=O)C>[N:41]([C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[N+:33]([O-:35])=[O:34])[CH2:26][N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:13]3[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[NH:15][C:14]=3[CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:22]1)=[N+:42]=[N-:43]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(N=[N+]=[N-])c5)CC4)cccc3[nH]2)cc1
Yield: 93 %

Procedure:
In a round bottom flask was combined 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (0.197 g, 0.40 mMol), dimethyl sulfoxide (3 mL), and sodium azide (0.029 g, 0.44 mMol) and the mixture stirred overnight. Upon arrival the mixture was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), washed with brine (50 mL), and the organics dried with magnesium sulfate and filtered. The organics were concentrated on a rotary evaporator to yield 190 mg (92% yield) of 4-[4-(3-Azido-4-nitro-benzyl)-piperazin-1-yl]-2-(4-tert-butyl-phenyl)-1H-benzoimidazole as a light yellow solid. 1H NMR (DMSO-d6): δ=12.69 (s, 1H), 8.04 (d, 2H, J=8.7 Hz), 8.01 (d, 1H, J=8.3 Hz), 7.57 (m, 1H), 7.54 (d, 2H, J=8.6 Hz), 7.39 (dd, 1H, J=8.5, 1.2 Hz), 7.03 (m, 2H), 6.50 (dd, 1H, J=5.5, 1.4 Hz), 3.70 (s, 2H), 3.60 (br s, 4H), 2.68 (br s, 4H), 1.33 (s, 9H). LC/MS (Method A), rt=1.41 mins., purity=89.8%, calculated mass=510, [M+H]+=511, [M−H]−=509.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH2:41][C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:47][C:48]([NH2:50])=[S:49].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:50][C:48]1[S:49][CH:2]=[C:3]([C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH2:41][C:42]([Cl:44])([Cl:45])[Cl:43])=[O:39])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:47]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Temperature: 35 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a solution of benzhydryl 7-[4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyramido]-3-vinyl-3-cephem-4-carboxylate (26.0 g) in tetrahydrofuran (100 ml) was added a solution of thiourea (3.1 g) and sodium acetate (3.3 g) in water (100 ml), and the mixture was stirred at 35° C. for 3 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, followed by drying over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (12.5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2cccnc2)c2ccc(OC(=O)NC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.5 mg, 42%) having the following characteristics.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Reactant: c1nc[nH]n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CCOC(C)=O.[CH3:7][C:8]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1)=[O:11].[H][H]>CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:8]([CH3:7])=[C:9]([CH:19]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][CH:16]=[N:15][CH:14]=1)=[O:11]
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cncnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(N)cc1C(=O)Nc1cncnc1

Procedure:
A 2 L high-pressure vessel was charged with Palladium 10% on carbon wet (50% water) and EtOAc (50 mL). 2-methyl-5-nitro-N-(pyrimidin-5-yl)benzamide 45 (18.79 g) was dissolved in methanol (400 mL) and added to the previous mixture. The reaction vessel was pressurized to 30 psi of H2 and mechanically stirred until the hydrogen intake stopped. The reduction of the nitro group was complete by LCMS and the mixture was filtered off through paper and glass paper. The crude 5-amino-2-methyl-N-(pyrimidin-5-yl)benzamide 46 was obtained as a yellow solid and used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[S:33]([O:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[S:8][C:4]=2[CH:3]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(O)cc2s1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a solution of 260 mg of 1-(6-hydroxy-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea in 19.4 cm3 of aqueous 0.1N sodium hydroxide solution are added 209 mg of finely ground 2,6-dichlorobenzenesulfonyl chloride. After stirring for about 5 hours at a temperature in the region of 20° C., a further 70 mg of 2,6-dichlorobenzenesulfonyl chloride are added. After stirring for about 18 hours at the same temperature, the reaction mixture is concentrated under reduced pressure (13 kPa) to a volume of about 5 cm3. The suspension obtained is cooled for about one hour at a temperature in the region of 5° C. The solid is filtered off by suction, washed with three times 2 cm3 of water precooled to about 5° C., and dried under reduced pressure (13 kPa) over phosphorus pentoxide. 216 mg of 2-{[(2-morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:58])([N:54]([CH2:56][CH3:57])[CH3:55])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:58])([N:54]([CH2:56][CH3:57])[CH3:55])=[O:53])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CCN(C)S(C)(=O)=Nc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: CCN(C)S(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(4-bromophenyl)-N-ethyl-N-methyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=714 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:31]=[N+:32]=[N-:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-benzyloxybenzyl alcohol (5.0 g, 23.3 mmol) and diphenylphosphoryl azide (7.7 g, 28.0 mmol) in dry toluene (40 mL) at 0° C., was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 g, 25.6 mmol). The resulting mixture was allowed to warm to ambient temperature, and stirred under argon for 18 hrs, then washed with water (2×15 mL), then 5% hydrochloric acid (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane −4% ethyl acetate to yield the product as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:33])=[C:29]([CH:32]=2)[CH:30]=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][C:2]([C:3]([NH2:5])=[O:4])=[CH:30][C:29]=3[CH:32]=2)[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC(=O)CCl
Reactant: O=Cc1cc(N2CCN(Cc3ccccc3)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: NC(=O)c1cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2o1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
10 ml of 1-methyl-2-pyrrolidone, 0.4 g of chloroacetamide and 0.8 g of potassium carbonate are added at 20° C. with stirring/under nitrogen to 1.0 g of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde. The mixture is stirred at 60° C. for 16 hours, cooled and then filtered, and the solvent is removed under reduced pressure. The residue is taken up in MTB ether, re-filtered and concentrated, and the residue is crystallized from toluene. The isolated yield is 0.73 g (65%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25](O)(=[O:29])[C:26]([CH3:28])=O>C(O)C>[CH2:1]([CH:3]([O:6][C:7]1[C:8]2[N:24]=[C:26]([CH3:28])[C:25](=[O:29])[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: CC(=O)C(=O)O
Solvent: CCO
Product: CCC(CC)Oc1nc(C)nc2c1nc(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
To a solution of 6-(1-ethyl-propoxy)-2-methyl-4-N-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine (100 mg, 0.305 mmol) in 2 ml of ethanol was added pyruvic acid (30 mg, 0.335 mmol) and the resulting mixture was heated at reflux for 1 hour. An additional 60 mg of pyruvic acid was added and the resulting mixture was heated at reflux overnight. The mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give an oil residue. The residue was purified through silica gel column chromatography using hexane to 15% ethyl acetate in hexane as eluent to give the title compound as a yellow solid. 1H NMR (CDCl3) δ 6.99 (s,2H), 5.39(m,1H), 2.61(s,3H), 2.40(s,3H), 2.35(s,3H), 1.88(s,6H), 1.7-1.9(m,4H), 0.99(t,6H)ppm.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([NH:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][CH:19]=[C:13]2[N:12]=1)[CH2:7][CH2:8][CH3:9].[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:20][C:19]1[CH:18]=[N:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][CH2:6][CH2:7][CH2:8][CH3:9])=[N:12][C:13]=12
Reactant: BrBr
Reactant: CCCCNc1ccn2nccc2n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C

Procedure:
Sodium acetate [127-09-3] (0.7 g, 8.9 mmol) was added to a solution of butyl-pyrazolo[1,5-a]pyrimidin-5-yl-amine (1.1 g, 5.9 mmol) in glacial acetic acid (100 mL) and allowed to stir at ambient temperature until all of the solid had dissolved. Bromine [7726-95-6] (0.3 mL, 6.4 mmol) was added drop by drop into the ambient temperature, buffered, acetic acid reaction solution over 5 minutes. Upon completion of the bromine addition, the suspension was allowed to stir for a further 15 minutes then was slowly poured into 500 mL of stirred water. Saturated aqueous sodium bicarbonate was added to the stirred suspension until pH of the supernatant was determined to be approximately 8 by pH paper, then the suspension was extracted with ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel eluted with 60% (v/v) ethyl acetate/heptane) to provide 1.2 g of off white solid, mp. 94-95° C. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H) 1.31-1.44 (m, 2 H) 1.56 (quin, J=7.20 Hz, 2 H) 3.31-3.38 (m, 2 H) 6.28 (d, J=7.58 Hz, 1 H) 7.61 (t, J=5.05 Hz, 1 H) 7.85 (s, 1 H) 8.42 (d, J=7.58 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.67, 19.64, 30.53, 76.99, 100.87, 135.14, 143.03, 145.13, 156.09. LRMS (ESI) m/z 269.0/271.0 [(M+H)]+, calc'd for C10H13BrN4: 269.15.
Reaction SMILES: B.CSC.[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2[C:19]([C:24]#[N:25])=[C:20]([Cl:23])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1>[NH2:25][CH2:24][C:19]1[C:16]2[CH2:17][CH2:18][N:12]([C:10]([O:9][C:5]([CH3:7])([CH3:6])[CH3:8])=[O:11])[CH2:13][CH2:14][C:15]=2[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#N)c2CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CN)c2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Add borane-methyl sulfide complex (40 mL, 80 mmol, 2M solution in THF) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-cyano-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.79 g, 10.2 mmol) in anhydrous THF (120 mL). Reflux the mixture overnight under nitrogen. Cool the mixture to room temperature and quench with methanol. Add KHSO4 (20 g in water) and stir for 1 h. Remove the organic solvent in vacuo and basify by addition of solid K2CO3. Extract with DCM and wash with brine. Collect the organic layer, dry over anhydrous Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1), DCM and DCM/(chloroform:methanol:concentrated ammonium hydroxide 88:18: 2) (20:1, 10:1 and 5:1) to give the title compound (2.56 g, 81% over 2 steps). MS (ES+) m/z: 311 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].[C:34](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:11]([CH3:34])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1COCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1COCCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 40 °C
Yield: 68.4 %

Procedure:
To a slurry of 0.3 g (0.634 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid methyl ester (Example 24, Step 1) and potassium carbonate (0.176 g, 1.27 mmol) in DMF (10 mL) was added iodomethane (0.109 g, 0.765 mmol). The reaction was heated at 40° C. for 2 h and then the reaction was allowed to cool to 25° C. over 19 h. The DMF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL) and then washed with water (2×30 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude oil (0.170 g,). The crude product was purified by Biotage Flash 40S chromatography, eluting with 1:1 ethyl acetate:hexanes, to afford 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid methyl ester as an amorphous white solid (0.210 g, 68%). MS: 485 (M+H)+.