Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([CH:76]=O)=[CH:74][CH:73]=2)[CH:71]=[CH:70][N:69]=[CH:68]1>C(O)C.CN(C=O)C>[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([C:76]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:74][CH:73]=2)[CH:71]=[CH:70][N:69]=[CH:68]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(-n4ccnc4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 26.6 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-imidazol-1-yl)benzaldehyde (1.1 eq, 0.056 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (7 mg, 27%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.64 (s, br, 4H, piperazine N(CH2)2), 3.63 (s, br, 2H, CH2), 3.70 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 7.16 (s, 1H, imidazole H-2), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.79 (td, J=7.8, 1.5 Hz, 1H, pyridine H-4), 7.85 (s, br, 1H, imidazole H-4 or H-5), 7.86 (d, J=8.7 Hz, 2H, phenyl H-2 & H-6), 8.26 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.30 (d, J=8.7 Hz, 2H, phenyl H-3 & H-5), 8.39 (s, br, 1H, imidazole H-4 or H-5), 8.50 (dd, J=4.7, 1.5 Hz, 1H, pyridine H-6), 8.57 (d, J=1.5 Hz, 1H, pyridine H-2), 13.59 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[CH:3]1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:25][C:22]1[S:23][CH:24]=[C:20]([C:19]#[C:18][C:15]2[CH:16]=[CH:17][C:12]([N:2]3[C:10]4=[CH:9][N:8]=[CH:7][CH:6]=[C:5]4[CH:4]=[CH:3]3)=[N:13][CH:14]=2)[N:21]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: c1cc2cc[nH]c2cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccc(-n3ccc4ccncc43)nc2)cs1
Temperature: 120 °C

Procedure:
6-azaindole hydrobromide (198 mg, 1.0 mmol), 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), and cesium carbonate (3.2 mmol, 1.04 g) were combined in DMF (15 mL) and heated at 120° C. for 18 hrs. The reaction was cooled to room temperature and partitioned in a separatory funnel with 1:1 hexanes:EtOAc (100 mL) and water (50 mL). The organic layer was washed with 5% NaCl (4×25 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on SiO2, elution with a 0% to 6% iPrOH gradient in DCM to afford the title compound as a white solid which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 10.1 (s, 1H), 8.83 (m, 2H), 8.43 (d, 1H), 8.27 (d, 1H), 8.22 (d, 1H), 7.99 (d, 1H), 7.92 (s, 1H), 7.26 (d, 1H), 2.79 (s, 3H). MS (ESI) 317.2 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[NH:4][C:5](=[O:20])[C:6](=[O:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].I[CH2:27][CH2:28][CH2:29][CH2:30]I>CC#N>[CH2:12]([N:7]1[CH:8]2[CH:3]([CH:2]([N:1]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:10][CH2:9]2)[NH:4][C:5](=[O:20])[C:6]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ICCCCI
Reactant: NC1CCCC2C1NC(=O)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1NC2C(N3CCCC3)CCCC2N(Cc2ccccc2)C1=O

Procedure:
(4aRS,5SR,8aRS)-5-Amino-1-benzylperhydroquinoxaline-2,3-dione (3.06 g, 11.2 mmol) was dissolved in CH3CN (300 ml). NaHCO3 (6.4 g, 76.2 mmol) and 1,4-diiodobutane (13.9 g, 44.8 mmol, 5.9 ml) were added and the mixture was heated under reflux for 18 hours. NaHCO3 was separated off with a blue-band filter (Schleicher&Schuell) and the yellow solution was concentrated in vacuo. The solid was taken up in CH2Cl2 and the mixture was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. A pale yellow solid was obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([NH:34][C:35](=[O:60])[C@H:36]([CH:45]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[NH:37][C:38]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:39])[C:8]=1[CH2:9][CH2:10][C@H:11]1[O:16][CH2:15][C@@H:14]([CH2:17][O:18][C:19](=[O:26])[NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:13](C(OC(C)(C)C)=O)[CH2:12]1>O1CCOCC1>[F:59][C:56]1[CH:57]=[CH:58][C:53]([CH:45]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C@@H:36]([C:35]([NH:34][C:7]2[CH:6]=[N:5][CH:4]=[C:3]([F:2])[C:8]=2[CH2:9][CH2:10][C@H:11]2[O:16][CH2:15][C@@H:14]([CH2:17][O:18][C:19](=[O:26])[NH:20][CH2:21][C:22]([F:24])([F:23])[F:25])[NH:13][CH2:12]2)=[O:60])[NH:37][C:38]([O:40][CH2:41][CH:42]([CH3:43])[CH3:44])=[O:39])=[CH:54][CH:55]=1
Reactant: CC(C)COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
4M HCl in Dioxane (0.2 mL) was added directly to the product from step 2 (14 mg, 0.016 mmol) and the reaction stirred at RT for 1 hour. The solvent was removed in vacuo and the residue was dissolved in MeOH and loaded onto a 400 mg Porapak cartridge (preconditioned with 5 mL of MeOH). The cartridge was washed with 100 mL of MeOH, then the desired product was eluted with 10 mL of 2M NH3 in MeOH. The solvent was removed in vacuo to afford 4-fluoro-β-(4-fluorophenyl)-N-(5-fluoro-4-{2-[(2R,5S)-5-({[(2,2,2-trifluoroethyl)carbamoyl]oxy}methyl)morpholin-2-yl]ethyl}pyridin-3-yl)-Nα-[(2-methylpropoxy)carbonyl]-L-phenylalaninamide (10 mg, 0.014 mmol) as a tan solid, LC MS: RT=1.94 min, M+H=740.4 (4 min gradient).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)=O.CC(C)=O.CS(C)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:35]=[C:34]([NH:36][CH:37]([CH:42]([OH:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])[CH2:33][N:32]=[C:31]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:30]=2[CH:52]=1>ClCCl.C(N(CC)CC)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:35]=[C:34]([NH:36][CH:37]([C:42](=[O:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])[CH2:33][N:32]=[C:31]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:30]=2[CH:52]=1
Reactant: COC(=O)C(NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)C(C)O
Agent: O=C=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)C(C)=O
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of 3.8 ml of trifluoroacetic acid anhydride in 7.3 ml of dichloromethane was added dropwise to a solution, cooled with dry ice/acetone, of 2.7 ml of dimethyl sulphoxide in 18 ml of dichloromethane was added in such a manner that the temperature did not exceed −55° C. After stirring in the cold for 30 min. a solution of 7.54 g of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-hydroxybutyrate in 15 ml of dichloromethane was added dropwise in a manner such that the temperature did not exceed −60° C. The mixture was stirred in a dry ice bath for 2 h., then brought to −30° C. for 5 min. and subsequently again cooled in a dry ice bath. After the slow addition of 7.5 ml of triethylamine the mixture was stirred, firstly in the cold for a further 30 min., then at room temperature for 30 min. For the working up the mixture was extracted with 30 ml of water. The organic phase was dried over magnesium sulphate, concentrated in a vacuum and purified by chromatography on 350 g of silica gel. Byproducts were eluted with dichloromethane containing 1% methanol. With dichloromethane containing 3% methanol there were isolated 5.56 g (74%) of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-oxo-butyrate which was used without further purification for the step described below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1.Br>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: COc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Yield: 98.1 %

Procedure:
A mixture of 4-(3,5-difluorophenoxy)anisole (22.0 g, 0.093 mol), acetic acid (200 ml) and a 47% aqueous hydrogen bromide solution (200 ml) was heated with stirring under reflux for 8 hours. After allowed to cool, the reaction mixture was poured into ice-water and extracted with a mixture of ether and n-hexane (1:2). The organic layer was washed with water three times and dried over anhydrous magnesium sulfate. Removal of the solvent gave 4-(3,5-difluorophenoxy)phenol (20.27 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:6]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(CO)C(=O)O
Product: COc1ccc(CNC(=O)C(C)(C)CO)cc1
Yield: 97 %

Procedure:
Prepared as in Example 4c from 3-hydroxy-2,2-dimethylpropanoic acid and 4-methoxybenzylamine in 97% yield as a white solid. MS 238 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C(=O)C)=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1)(=O)C.C(O)(=O)C1C=CC=C(C(O)=O)C=1.ClCC(Cl)(Cl)Cl.C1(O)C=CC=CC=1.CC1C=CC=C(C)C=1O.C(Cl)(Cl)Cl.C(O)C.[OH-].[K+]>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(C(C)(C)c2ccc(OC(C)=O)cc2)cc1
Agent: Cc1cccc(C)c1O
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(O)c1cccc(C(=O)O)c1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 290 °C

Procedure:
An equimolar mixture of 2,2-bis(4-acetoxyphenyl)propane (Bisphenol A diacetate) and isophthalic acid is heated gradualy to 290° C. in a stirred vessel under gradually increasing vacuum to remove the acetic acid which is liberated. When the melt viscosity of the condensate reaches a level such that stirring becomes difficult the melt is drained from the reaction vessel and crystallized. The crystallized polymer is subjected to solid state polymerization under vacuum at 280° C. until the inherent viscosity reaches 0.65 dl/g (in 40/60 by weight tetrachloroethane/phenol solution at 25° C.). The polymer is then extruded at 350° C. and pelletized. The polymer has an inherent viscosity of 0.62 and a carboxylic acid content of 40 microequivalents per gram (μeq./g), determined by potentiometric titration of a solution of the polymer in a 2,6-dimethylphenol/chloroform/ethanol mixture with an ethanolic solution of potassium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18].[OH-:19].[Na+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:11][C:10]([OH:18])=[O:19]
Reactant: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a stirred solution of 1-(2,6-Dichloro-phenyl)-1,3-dihydro-indol-2-one 1 (10 g, 0.03 mol) in toluene (340 mL) was added aq. NaOH (2N, 34 mL)) at rt. The resulting mixture was stirred at 90° C. for 16 h. After completion, clear solution was cooled in an ice bath and acidified with con. HCl. The precipitated solid was filtered, washed with ethanol and dried under reduced pressure to get 9.0 g (84.4% yield) of Compound 2 as an off white solid. Used in the next step without any further purification; Mass: 294.1 (M−H); 1H-NMR (400 MHz, DMSO): 12.70 (s, 1H), 7.53-7.51 (d, J=8.0 Hz, 2H), 7.24-7.16 (m, 3H), 7.08-7.03 (m, 1H), 6.87-6.83 (m, 1H), 6.28-6.26 (d, J=7.8 Hz, 1H), 3.69 (s, 2H); 13C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76, 115.95, 37.74.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:40](=[O:39])[CH2:41][OH:42])[CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f25) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:5]1[CH2:29][CH2:28][CH2:27][CH2:26][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:30])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C.O>[C:1]([N:5]1[CH2:29][CH2:28][CH2:27][CH2:26][C:8]2[C:9]([Br:38])=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCS(=O)c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCCC2
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
A solution of 350 mg of 23c in 4 ml of DMF was treated with 155 mg of NBS. After stirring for 10 min. the reaction was diluted with 25 ml of water and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the residue was treated with diisopropyl ether, to give 360 mg of 23d, Mp: 140-145° C. Rf 0.18 (heptane/ethyl acetate 1/1). LC-MS-ESI: [M+1] 506.97 and 524.99. NMR (CDCl3) δ 1.24 (t, 3, ethyl), 2.82 and 3.08 (2×m, 2, ethyl), 3.88 (s, 3, OCH3), 6.77, 8.78 (2×s, 2, Ar—H).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[N:15]=[C:16]=[S:17])([CH2:3][CH3:4])[CH3:2].Cl.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]=1[NH:15][C:16]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[S:17])([CH2:13][CH3:14])[CH3:12]
Reactant: CC(C)(C)N
Reactant: CCC(C)c1cccc(C(C)CC)c1N=C=S
Agent: Cl
Product: CCC(C)c1cccc(C(C)CC)c1NC(=S)NC(C)(C)C
Reaction time: 12 h

Procedure:
20.6 g of 2,6-di-sec.-butyl-phenyl isothiocyanate are dissolved in 20.0 g of tert.-butylamine and the batch is kept for 12 hours at 20° C. It is then poured into dilute hydrochloric acid and the reaction product is filtered off, washed until neutral and dried.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O-])([O-])=O.[K+].[K+].C(O[CH:13]=[C:14]([C:20]([CH:22]([F:24])[F:23])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>O.C1(C)C=CC=CC=1>[F:23][CH:22]([F:24])[C:20]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
40% Methylhydrazine (565 g, 4.91 moles) in aqueous solution and K2CO3 (237 g, 1.72 moles) are dissolved in water (2134 g) and mixed to make a clear solution. Toluene (2292 g) is added to make a two phase system, and then cooled to −10-0° C. Crude ethyl 2-ethoxymethylenedifluoroacetoacetate (Formula VI) (˜1010 g, ˜4.91 moles) in toluene (1500 g) is then added dropwise with effective agitation while maintaining at the same temperature. The agitation is kept constant for 1-2 hours until GC shows the content of ethyl 2-ethoxymethylenedifluoroacetoacetate <0.2%. Two phases are separated and the organic phase is concentrated until GC shows toluene content <5%. A mixture of toluene (757 g) and petroleum ether (3028 g) (bp. 60-90° C.) is added in and then heated up to 50-60° C. to make a solution. The yellowish solid precipitated after the solution is slowly cooled down to 10-15° C. The solid is collected by filtration and dried in a vacuum oven to give a yellowish solid (828 g, Yield=82.5%). The product only contains 0.01% of the positional isomer of formula XI and 0.01% of the des-difluoro-impurity of Formula XII.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(NC(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
Into a suspension of methyl 4-{[(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]carbonyl)benzoate (546 mg, 0.96 mmol) in THF/H2O (2/1) (20 mL) was added NaOH (1.0 N, 4.8 mL). The resulting solution was stirred at rt for 2 hr and quenched with HCl (5 N, 4 mL). A yellow solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (451 mg, 86%) in 97.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Yield: 61 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (1 g, 3.87 mmol) in 1,2-dimethoxyethane (20 ml) was degassed by N2 bubbling for 5 min. Phenyl-boronic acid (0.61 g, 5.04 mmol, 1.3 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.63 g, 0.77 mmol, 0.2 eq.) and aqueous sodium carbonate (1.23 g, 11.6 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 61% yield (0.6 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:25])C(=O)C1>CC#N>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:25])[NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1c(=O)n(CC)c(=O)c2[nH]cnc21
Solvent: CC#N
Product: CCCCn1c(=O)n(CC)c(=O)c2[nH]c(Cl)nc21
Temperature: 120 °C

Procedure:
3-Butyl-1-ethyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) and NCS (56 mg, 0.42 mmol) were suspended in MeCN (5 mL) and heated at 120° C. under microwave irradiation. The reaction mixture was concentrated under reduced pressure and the title compound isolated using HPLC. [HPLC conditions used for the purification: 23 minute run time. Solvents: 0.1% TFA in MeCN and 0.1% TFA in water. MeCN increased from 5% to 95% linearly over 15 minutes. Held at 95% for 2 min. Then decreased to 5% linearly over 1 min., equilibrated at 5% for 5 minutes before next injection.]; 1H NMR (400 MHz; CDCl3) δ: 0.97 (3H, t), 1.31 (3H, t), 1.38-1.45 (2H, m), 1.72-1.80 (2H, m), 4.09-4.20 (4H, m), 13.40 (1H, br.s); m/z 271[MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=3)[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.51 g of 3-dimethylaminobenzoyl chloride in 130 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 7.97 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 3.6 g of triethylamine in 150 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with methylene chloride, rendered alkaline with 2N NaOH and washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(3-dimethylaminobenzoyl)-piperazine having a melting point of 110°-112° is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO.C(OCC)C>[NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: Nc1cnccc1C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccncc1N

Procedure:
A suspension of 3-aminoisonicotinic acid (13.81 g, 100 mmol, prepared using the procedure described in Crum J. D.; Fuchsman, C. H. J. Heterocyclic Chem., 1966, 3, 252) in methanol (250 mL) was treated with thionyl chloride (14.7 mL, 200 mmol) and heated to reflux for 3 days. The yellow solution was concentrated to dryness to provide a yellow solid. This solid was suspended in 200 mL of ethyl ether and treated with 400 mL of saturated, aqueous NaHCO3 and the biphasic solution was stirred until all of the solids were dissolved. The layers were separated and the aqueous phase was extracted with 2 additional portions of ethyl ether. The combined organic phases were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the title compound as a light yellow solid. MS (DCI/NH3) m/z 153 (M+H)+.