Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]=[C:60]2[CH2:66][CH2:67][NH:68][C:69]1[N:77]=[C:76]([C:78]2[C:79]3[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=3[S:81][CH:82]=2)[N:75]=[C:74]2[C:70]=1[N:71]=[CH:72][N:73]2[CH:87]([CH3:89])[CH3:88])=[O:55]>CN(C=O)C>[O:14]=[C:13]1[NH:12][C@H:11]2[CH2:10][S:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:2]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]3[CH:58]=[C:59]4[C:63](=[CH:64][CH:65]=3)[NH:62][CH:61]=[C:60]4[CH2:66][CH2:67][NH:68][C:69]3[N:77]=[C:76]([C:78]4[C:79]5[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=5[S:81][CH:82]=4)[N:75]=[C:74]4[C:70]=3[N:71]=[CH:72][N:73]4[CH:87]([CH3:89])[CH3:88])=[O:55])=[O:3])[C@H:16]2[NH:15]1
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCN)cc34)nc(-c3csc4ccccc34)nc21
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)CCCC[C@@H]5SC[C@@H]6NC(=O)N[C@@H]65)cc34)nc(-c3csc4ccccc34)nc21
Reaction time: 0.17 h

Procedure:
To a solution of (+)-biotin (35 mg, 0.14 mmol) and Et3N (36 mg, 0.35 mmol) in DMF (1 ml) was added HATU (90 mg, 0.24 mmol). The mixture was stirred for 10 min, and then was added to a solution of (3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-yl 6-aminohexanoate (b) (68 mg, 0.12 mmol) in DMF (1 ml). The reaction mixture was stirred for 16 hr at rt and then was concentrated. The residue was purified by reverse-phase HPLC (C18 column, eluting with MeOH—H2O 0.05% TFA) to afford the title compound as an off-white solid. Example 210 showed an EC50 value in the % CD34+ assay of 2.1 μM.
Reaction SMILES: N1CCCC1.[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[CH2:9][S:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[CH2:28][C:26](=[O:27])[O:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[C:28](=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([S:10][CH2:9][C:8]3[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=3[CH3:6])=[CH:12][CH:13]=2)[C:26](=[O:27])[O:25]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1ccccc1CSc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCNC1
Product: Cc1ccccc1CSc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1
Yield: 54 %

Procedure:
Pyrrolidine (0.45 mL, 5.27 mmol) was added to a solution of aldehyde 28.1 in diethyl ether (20 mL) and the mixture was sonicated for 5 minutes. The mixture was then added to a solution of Meldrum's acid (0.73 g, 5.08 mmol) in diethyl ether (20 mL) and the resultant mixture was sonciated for 5 minutes, forming a solid. The solid was filtered, rinsed with diethyl ether, and then suspended in DCM (10 mL). p-Toluenesulfonic acid (0.97 g, 5.10 mmol) was then added to the suspension and the suspension was sonicated until clear. The solvent was removed under reduced pressure, and the resulting residue was taken up in diethyl ether and partitioned between water and ethyl acetate. The aqueous layer was extracted 2 additional times with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4), and concentrated in vacuo to yield 1.05 g (54%) of 2,2-Dimethyl-5-[4-(2-methyl-benzylsulfanyl)-benzylidene]-[1,3]dioxane-4,6-dione (28.2) as a yellow oil The resulting yellow oil was used without further purification. LC/MSD m/e: 391.1 (M+Na).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24](=[O:26])[CH3:25])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1(C)C=CC=CC=1.O1CCCC1.O1CCCC1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([C:24]([OH:26])([CH3:1])[CH3:25])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(C(C)(C)O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a dry round bottom flask was added via syringe 16 ml methyl magnesium bromide in toluene/tetrahydrofuran (75:25, 1.4 M). The flask was cooled in an ice bath under a stream of nitrogen. A solution 4-acetyl-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (337 mg, 1.02 mmol) in 5 ml tetrahydrofuran was added dropwise to the flask over 20 minutes and the resulting mixture was stirred at 0° C. for 8 hours. The reaction mixture was warmed to room temperature and stirred for 5 days. The reaction was quenched by slow addition of 150 ml saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The yellow residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (7.5:2.5) to give the title compound (242 mg, 67%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH2:1]([NH:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 899.7 %

Procedure:
To a solution of benzylamine (5 g, 4.67 mmol) in pyridine (25 ml) was added (cautiously) p-toluenesulphonyl chloride (10 g, 5.25 mmol). The deep red coloured solution was stirred at room temperature for 1 hour before being poured into water (80-100 ml). The oily precipitate which solidified on scratching was filtered and recrystallised from ethanol to give the title compound (10.98 g, 90% yield, m.p. 115°-116° C., (Lit.1 114° C.)). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(1H,t); 4.05(2H,d); 2.35(3H,s)ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]2[CH:16]=[CH:15][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]=1)[C:8]2=3)=[O:4].[H][H]>[Pd].O1CCCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8]3=[C:9]([CH:15]=[CH:16][N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1=Cc2cccc3ccn(c23)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C1Cc2cccc3ccn(c23)C1

Procedure:
4H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (10.9 g, 51.1 mmol) and palladium on carbon (5%, 1.1 g) were taken into tetrahydrofuran (300 mL), and the mixture was stirred under 60 psi of hydrogen at room temperature for 8 hours. Additional palladium on carbon (5%, 0.6 g) was added, and the mixture stirred under 60 psi of hydrogen for another 15 hours. Filtration and concentration of filtrate gave the desired compound.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[CH:14]1([N:20]=[C:21]=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:20][C:21](=[S:22])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[C:6]([O:12][CH3:13])[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: S=C=NC1CCCCC1
Reactant: COc1cc(N)ccc1NNC=O
Product: COc1cc(NC(=S)NC2CCCCC2)ccc1NNC=O

Procedure:
Procedure (11.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.2 g, 0.0066 mole) and cyclohexyl isothiocyanate (0.93 g, 0.0066 mole). Yield 0.50 g (24%), m.p. 131°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]2([C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH2:38]2)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]2([C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:8]([C:6](=[O:7])[C:5]4[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]([CH3:19])[CH2:10]3)[CH2:38]2)[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: c1ccc(CN2CCC3(CC2)CNc2ccccc23)cc1
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CC4(CCN(Cc5ccccc5)CC4)c4ccccc43)CC2C)cc1OC
Yield: 52.4 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 1′-benzylspiro[indoline-3,4′-piperidine] (849 mg, 3.05 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (376 mg, yield: 44%) as a colorless oil. (cis:trans=1:1.5)
Reaction SMILES: [Cu][C:2]#[N:3].[NH2:4][C:5]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CN1CCCC1=O.C(N)CN>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([C:2]#[N:3])[CH:13]=[CH:14][C:5]=1[NH2:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)ccc1N
Temperature: 180 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
Copper(I) cyanide (available from Alfa Aesar; 10.71 g, 0.12 mol) was added to a stirred solution of methyl 2-amino-5-bromobenzoate (available from Aldrich Chemical Company, Inc.; 25.0 g, 0.11 mol) in N-methyl-2-pyrrolidone (50 mL) and the mixture was stirred at 180° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with aqueous ethylenediamine (water:ethylenediamine=1:1; 250 mL), and filtered through pad of Celite. The filtrate was extracted with EtOAc (3×100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, evaporated under reduced pressure, and purified by silica gel chromatography (100-200 mesh), using 5-10% ethyl acetate/hexanes as eluent, to give 2-amino-5-cyanobenzoic acid methyl ester (14.0 g, 73%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=1.9 Hz, 1H), 7.57 (dd, J=1.9, 8.8 Hz, 1H), 7.44 (br s, 2H), 6.88 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[NH2:11]O.C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]#[N:11])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cnccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
The compound (19) (27.0 g, 0.19 mol), hydroxylamine hydrochloride (13.01 g, 0.19 mol) and sodium acetate (15.6 g, 0.19 mol) were suspended in methanol (100 ml) and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated and the residue was dissolved in chloroform (100 ml). Phosphorus oxychloride (125 g) was added and the mixture was heated under ref lux for 3 hrs. The solvent was evaporated and the residue was added to water (200 ml), which was adjusted to pH=7 with sodium carbonate. The mixture was extracted with ethyl acetate (200 ml×2) and the organic layer was dried (MgSO4). The solvent was evaporated under reduced pressure to give the title compound (18 g, 68%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)=[CH:17][CH:16]=[C:15]([CH:26]3[CH2:28][CH2:27]3)[N:14]=2)=[O:12])=[CH:8][N:7]([CH3:29])[N:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH:26]1([C:15]2[N:14]=[C:13]([C:11]([NH:10][C:9]3[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([CH3:29])[CH:8]=3)=[O:12])[C:18]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[N:22][CH:21]=3)=[CH:17][CH:16]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
To a stirred solution of 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (example 27, step 4; 300 mg, 0.76 mmol) in MeOH (7 ml) was added a solution of NaOH (49 mg, 1.2 mmol) in water (2 ml) while keeping the internal bath temperature below 5° C. The reaction mixture was stirred for 12 h at rt, then concentrated. The residue was dissolved in water (10 ml), and the aqueous layer was washed with EtOAc. The aqueous phase was acidified with aqueous 1N HCl solution (pH˜4-5), then saturated with sodium chloride, and extracted with EtOAc. Combined organic layers were washed with brine, dried (Na2SO4), and filtered. The organic layer was concentrated to give the title compound (142 mg, 45%) as yellowish sticky solid, which was directly used for next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>C1C=CC=CC=1.[Ag]=O>[CH3:23][O:22][C:20]([CH2:19][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:21]
Reactant: O=C(OCc1ccccc1)C1CCCCNC1
Reactant: COC(=O)CBr
Agent: O=[Ag]
Solvent: c1ccccc1
Product: COC(=O)CN1CCCCC(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of 1.46 g 3-benzyloxycarbonylperhydroazepine and 1.06 g methvl bromoacetate in 30 ml benzene add 1.06 g silver oxide. Stir the reaction in the dark for 24 hr., filter and concentrate the filtrate in vacuo. Dissolve the residue in HCl (pH 1.5) and wash the solution with ether. Make the aqueous phase to pH 12 and extract with ethyl acetate. Dry and concentrate the extracts to obtain 1-methoxycarbonylmethyl-3-benzyloxycarbonylperhydroazepine. NMR (CDCl3, TMS)-δ 1.8 ;(m, 6H); δ 2.8 (m, 2H); δ 3.1 (d, 2H); δ 3.45 (s, 2H); δ 3.65 (s, 3H); δ 5.15 (s, 2H); δ 7.3 (s, 5H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][S:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>>[C:13]1([S:11]([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(CCCl)c1ccccc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCS(=O)c2ccccc2)CC1

Procedure:
1-(2-Phenylsulfinylethyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-2-phenylsulfinylethane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][N:20](C(OCC4C=CC=CC=4)=O)[C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[ClH:31]>[Pd].C(O)C.CO>[ClH:1].[ClH:31].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][NH:20][C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]2[C@H](c3ccc(Cl)cc3)Nc3ccccc3[C@@H]21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Clc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of benzyl (3aR*,4R*,9bR*)-4-(4-chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (730 mg, 1.75 mmol) and 10% palladium on carbon (50% aqueous, 0.3 g) in ethanol (10 ml) was added a hydrogen chloride in methanol solution (1 ml) and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hrs. The reaction mixture was filtered, washed with aqueous methanol, and the filtrate was concentrated. The residue was dried under reduced pressure to give the crude title compound as an oil. (350 mg, ca. 100%)
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][N:25]1[CH2:30][CH2:29][CH2:28][NH:27][S:26]1(=[O:32])=[O:31]>N1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:27]3[CH2:28][CH2:29][CH2:30][N:25]([CH3:24])[S:26]3(=[O:32])=[O:31])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CN1CCCNS1(=O)=O
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: c1ccncc1
Product: CN1CCCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S1(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.300 g, 0.80 mmol), 2-methyl-1,2,6-thiadiazinane 1,1-dioxide (0.144 g, 0.96 mmol) and Cu2O (0.086 g, 0.60 mmol) in pyridine (6.0 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.5 g) in water (25 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.50 g in water 50 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6].[N:11]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:6][NH2:11])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: NNc1ccc(F)c(Cl)c1
Reaction time: 8 h
Yield: 69 %

Procedure:
In a 500 ml round bottom flask provided with efficient stirring and external cooling arrangement, 51 ml (, 0.5 mole) of conc. HCl was cooled to below 5 deg C and 25 gms (0.13 mole) 3-chloro-4-fluoroaniline was added. The hydrochloride thus precipitated was then diazotised below 0 deg C with 12 gms (0.17 mole)sodium nitrite and the resulting diazonium salt was decomposed with 100 gms (0.79 mole)sodium sulphite and 12 ml caustic lye. The reaction mixture was filtered to remove impurities.225 ml conc. HCl was added and stirred well and allowed to stand overnight. The 3-chloro-4-fluorophenylhydrazine hydrochloride thus precipitated was filtered and recrystallized from water. The dried product was 18 gms (yield 69%) M.pt: decomposed at 193 deg C. IR (KBr) cm−1 2939 and 2690(NH), 1506 (C═C), 1114 (C—F), 744(C—Cl)
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:17])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:17][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([C:3]#[N:4])[CH3:18])[C:14]=2[O:15][CH3:16]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2ccc(Cl)cc2nn1CC(C)(N)C#N
Product: COc1c2ccc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (40 mg, described in Example 116) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (65 mg, 91%). MS (ES): M/Z [M+H]=469. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 4.20 (s, 3H), 4.76 (d, 1H), 4.89 (d, 1H), 6.87 (dd, J=9.0, 1.7 Hz, 1H), 7.51 (s, 1H), 7.86-7.91 (m, 3H), 7.97 (d, 2H) and 9.01 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]2=[CH:12][C:11]=1[C:19]([OH:21])=O.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:11]1[CH:12]=[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:23]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (67 mg, 0.18 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (18 mg, 0.18 mmol), HOBt (26 mg, 0.19 mmol), EDCI hydrochloride (37 mg, 0.19 mmol) and DIPEA (31 μL, 0.18 mmol) were suspended in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 hours, during which time the reagents dissolved. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a yellow solid (54 mg, 65%). LCMS (Method B): RT=3.38 min, M+H+=483.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[CH2:8][CH2:7]1)=[O:4].[C:9]([OH:14])(=[S:13])[CH:10](C)O.O.Cl>ClCCl>[CH:6]1([NH:5][C:3]([CH2:2][S:13][C:9](=[O:14])[CH3:10])=[O:4])[CH2:8][CH2:7]1
Reactant: CC(O)C(O)=S
Reactant: O=C(CCl)NC1CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)SCC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a solution of 2-chloro-N-cyclopropyl-acetamide (58.1 g, 0.435 mol) in dichloromethane (700 ml) at 0° C. is added thiolactic acid (49.65 g, 0.652 mol). The mixture is stirred at 0° C. for 5 minutes, then TEA (88.0 g, 0.870 mol) is added very slowly (exothermic reaction). The mixture is stirred at 0° C. for 2 hours, then poured over 700 ml of water with stirring. The aqueous layer is acidified to pH2 with 5 N HCl, and the layers are shaken and separated. The aqueous layer is extracted with dichloromethane (2×400 ml). The combined organic layers are washed with brine, then dried (anhydrous magnesium sulfate), filtered, and concentrated to give the title compound as a yellow-orange solid (74.5 g, 99%). Mass (m/z): 174.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].F[C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a 5-liter, 4-necked flask fitted with a stirrer, thermometer, addition funnel, reflux condenser and drying tube is added dimethyl sulfoxide (200 ml), 2-chloro-4-trifluoromethylphenol) (715 g, 3.64 mole), and anhydrous potassium carbonate (520 g, 3.72 moles). The reaction mixture is stirred at room temperature overnight under a nitrogen atmosphere. Then methyl 5-fluoro-2-nitrobenzoate (724 g, 3.64 moles) is added over a 1 hour period (slight exotherm to 31° C.). After stirring overnight at room temperature, the inorganic solids are removed by filtration and 1700 ml of dimethyl sulfoxide removed under vacuum (1 mm, pot temp. of 85° C., vapor temp. of -40° C.). The residue is diluted with a large volume of carbon tetrachloride and water washed. The organic layer is dried with anhydrous magnesium sulfate and the solvent removed under vacuum to afford 1142 g of methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (84% yield). Anal. Calcd. for C15H9ClF3NO5 : C, 47.90; H, 2.42; Cl, 9.45; F, 15.20; N, 3.73. Found: C, 47.83; H, 2.47; Cl, 9.15; F, 14.84; N, 3.69.