Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[N:5]2.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:17])[CH:6]=[N:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cnc2cc(Br)ccc2n1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1cnc2cc(Br)ccc2n1
Yield: 92 %

Procedure:
6-Bromo-2-quinoxalinol (631 mg) in POCl3 (6.3 mL) was refluxed for 2 h, then poured onto ice. The solution was neutralized to pH 7 by addition of NH4OH, and the resulting solid collected by filtration. Washing with water and drying in vacuo gave 6-bromo-2-chloroquinoxaline (627 mg, 92%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.P([O-])(O)(O)=O.[K+].[O:15]=[CH:16][C@@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])O>>[CH:5]1[N:1]([C@@H:23]2[O:24][C@H:17]([CH2:16][OH:15])[C@@H:19]([OH:20])[C@H:21]2[OH:22])[N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Agent: [K+]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 20 h

Procedure:
To each suspension was added each 1 ml of an aqueous solution (pH 7.0) containing 20 mM 1,2,4-triazole-3-carboxamide, 20 ml of various ribose donors as shown in Table 10 and 25 mM monopotassium dihydrogen phosphate, and the reaction was carried out at 60° C. for 20 hours. After the reaction, the microbial cells were removed by centrifugation and the supernatant was analyzed to give the results of ribavirin yields as shown in Table 10.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:11][C:8]1[N:7]=[C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:5]([OH:4])=[CH:10][CH:9]=1
Reactant: COC(=O)COc1nc(Cl)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1nc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-acetoxy-6-chloro-2-(methoxycarbonyl)methoxypyridine, potassium carbonate and methanol is stirred for 3 hours at room temperature. The reaction solution is poured into water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 6-chloro-3-hydroxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[N+:22]([O-])=O)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:22][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]#[CH:21])=[CH:17][C:12]=1[C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)=[O:11]
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 10.59 g (30.7 mmol) (4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanone in 250 ml acetic acid are added 13.6 g (246 mmol) iron powder. After stirring for 20 h at rt the reaction mixture is basified by the addition of 2M sodium hydroxide solution, filtered and extracted with dichloromethane. After purification by chromatography using hexanes/ethyl acetate (7:3) as eluent (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester, MS: 450 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][CH:17]3[CH:12]([CH2:13][CH:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15](=[O:20])[NH:16]3)[CH2:11]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC2=C(CCC(Cc3ccc(OC)cc3)C2)NC1=O
Agent: CC[SiH](CC)CC
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC2CC(Cc3ccc(OC)cc3)CCC2NC1=O
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
Ethyl 3,4,5,6,7,8-hexahydro-6-((4-methoxyphenyl)methylquinolin-2[1H]-one-3-carboxylate (0.35 g) (prepared as in Example 5) was dissolved in CH2 Cl2 (1 ml) and triethylsilane (1.5 ml) was added. The solution was cooled with ice. TFA (1.5 ml) was added and the mixture was left to stir 1.5 hours. The reaction mixture was evaporated under reduced pressure and the residue dissolved in chloroform. The chloroform solution was washed with saturated sodium carbonate solution, dried (MgSO4) and evaporated. The residue was suspended in ether, filtered and the solid obtained was recrystallised from ethyl acetate to give the title compound (0.14 g) mp 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:13][CH2:14][NH2:15].C=O.[C:18](O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:13][CH2:14][NH:15][CH2:18]2
Reactant: O=C(O)C(F)(F)F
Reactant: NCCc1cccc(OCC2CC2)c1Br
Agent: C=O
Solvent: ClCCl
Product: Brc1c(OCC2CC2)ccc2c1CCNC2
Temperature: 25 °C

Procedure:
To 40 mg (0.15 mmol) 2-(2-bromo-3-cyclopropylmethoxy-phenyl)-ethylamine (example XXI) and 17 μL (0.22 mmol) formaldehyde (37% solution in water) in 2 mL DCM are added slowly 23 μL (0.30 mmol) TFA and the resulting mixture is stirred at r.t. over night. The reaction mixture is concentrated by evaporation
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl>Cl>[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][NH2:1])=[CH:10][N:11]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: NNc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 269.9 %

Procedure:
An aqueous sodium nitrite solution (3.49 g of sodium nitrite in 12.5 mL of water) was dropwise added to a solution of 6-chloropyridine-3-amine (5.00 g) in hydrochloric acid (77.8 mL) over 10 minutes (such that the temperature does not exceed −20° C.) under dry ice-acetone cooling (−20 to −40° C.), followed by stirring under the same conditions for 1 hour. A solution of tin chloride (14.8 g) in hydrochloric acid (25 mL) was dropwise added thereto over 15 minutes, followed by stirring at approximately 0° C. for 2 hours. The precipitated solid was collected by filtration (washed with water and n-hexane) and was vacuum dried at 40° C. to yield the title compound (9.45 g, brown solid).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([C:19]1([OH:27])[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)#[CH:18].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][C:19]3([OH:27])[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A stirred mixture of 4-bromo-4'-ethoxybiphenyl (1.1 g), 3-ethynyl-3-hydroxyquinuclidine (600 mg), bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and dry triethylamine (5.0 ml) in dry dimethylformamide (20 ml) was stirred at 90° C. under an atmosphere of argon for 4 hours. The dimethylformamide and triethylamine were removed by evaporation and the residue was treated with saturated sodium carbomate solution (20 ml). The solid obtained was collected by filtration and crystallised from dimethylformamide to give 3-[2-(4'-ethoxybiphenyl-4-yl)ethynyl]quinuclidin-3-ol (300 mg) as a soild, m.p. 255°-256° C.; microanalysis, found C, 79.1; H, 7.3; N, 3.9; C23H25NO2 requires C, 79.5; H, 7.3; N, 4.03%; NMR (DMSO-d6): 1.2-1.4(3H, t), 1.52-1.71(1H, m), 1.8-2.0(3H, m), 2.6-2.98(5H, m), 3.05-3.2(1H, m), 4.0-4.16(2H, q), 5.51-5.62(1H, br), 6.95-7.05(2H, d), 7.4-7.5(2H, d) and 7.57-7.68(4H, m); m/z 348 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[C:31]([O:33][CH3:34])=[N:32][C:27]([NH:26][CH2:24][CH3:25])=[N:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCNc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c(OC)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-[4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (Stage 235.1.1) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.16-8.06 (m, 3H), 8.01-7.97 (m, 1H), 7.74-7.69 (m, 1H), 7.61-7.58 (m, 1H), 3.88 (s, 3H), 3.84 (s, br, 3H), 3.56 (s, 3H), 3.36-3.28 (m, 2H), 1.93 (s, 3H), 1.13 (t, 3H))
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=[O:19])[C@@H:7]([NH:11]C(=O)OC(C)(C)C)[CH2:8][CH2:9][CH3:10])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C:6]([N:4]1[CH2:3][CH:2]([OH:1])[CH2:5]1)=[O:19]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](N)C(=O)N1CC(O)C1
Reaction time: 2 h
Yield: 176 %

Procedure:
To a solution of (S)-tert-butyl 1-(3-hydroxyazetidin-1-yl)-1-oxopentan-2-ylcarbamate (Compound A2) (3.5 g, 12.8 mmol) in anhydrous DCM (50 mL) was added TFA (18 mL, 242 mmol) dropwise at 0° C. under N2(g). The reaction mixture was stirred at r.t for 2 h and then concentrated under reduced pressure. The residue was dissolved in DCM and concentrated under reduced pressure to remove the residue of TFA. This procedure was repeated twice with DCM and twice with MeOH. To the residue was added diethyl ether and decanted (×2). The crude product was dried in vacuo give the title compound (3.88 g) used in the next step without further purification. LCMS (M+H)+: 173.1
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:45])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41](=[O:44])[O:42][CH3:43])=[N:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>>[C:1]1([C@H:7]([NH:9][C:10](=[O:45])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41](=[O:44])[O:42][CH3:43])=[N:19][NH:20][C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]
Reactant: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-methyl (6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (0.622 mmol) was taken up in TFA (5 ml) and the reaction mixture stirred at room temperature for 1 h. Triethylsilane (0.113 ml, 0.705 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered preparative HPLC to afford (R)-methyl (6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, TFA (190 mg, 0.406 mmol, 57.5% yield) as a white solid. MS ESI calc'd. For C17H19N6O3 [M+H]+ 355. found 355. 1H NMR (600 MHz, DMSO): 12.69 (br s, 1H); 10.39 (br s, 1H); 9.27 (br s, 1H); 8.95 (s, 1H); 7.76 (br s, 1H); 7.43 (s, 1H); 7.31 (d, J=4.5 Hz, 4H); 7.21 (m, 1H); 4.85 (t, J=7.3 Hz, 1H); 3.68 (s, 3H); 1.39 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:44]([OH:47])(=[S:46])[CH3:45]>O1CCCC1.ClCCl>[CH3:1][N:2]1[CH2:6][C@@H:5]([S:46][C:44](=[O:47])[CH3:45])[CH2:4][C@H:3]1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9]
Reactant: CC(O)=S
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N(C)C)N(C)C1
Reaction time: 0.5 h

Procedure:
(2S,4R)-1-Methyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (970 mg) was dissolved in dry tetrahydrofuran (11.1 ml), and triphenylphosphine (2.66 g) was added thereto. To the resultant mixture, diethyl azodicarboxylate (1.60 ml) was added under nitrogen steam while ice-cooling, and the mixture was stirred for 30 minutes. Thioacetic acid (1.45 ml) was added to the mixture under ice-cooling, and stirring was continued for 40 minutes under ice-cooling, followed by allowing to stand overnight. The reaction mixture was diluted with dichloromethane, washed with aqueous potassium carbonate solution and dried over magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give (2S,4S)-1-methyl-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:29][CH2:28][CH2:27][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25])[C:22]2=[O:23]
Reactant: ClCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCCl)cc2c1=O

Procedure:
N-Cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (0.621 g), 1-bromo-2-chloroethane (0.772 ml) and potassium carbonate (2.56 g) were stirred in DMF (25 ml) at 50° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 70-80% ethyl acetate/hexane gave 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.46 g) as a white solid; NMR Spectrum: DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.12 (s, 3H), 2.35 (m, 1H), 3.98 (t, 2H), 4.41 (t, 2H), 7.52 (d, 1H), 7.55 (d, 1H), 7.61 (s, 1H), 7.75 (d, 1H), 7.85 (s, 1H), 7.91 (d, 1H), 8.20 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH2:21][CH3:22])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC)n1
Yield: 55.8 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 6.6 ml (0.1 mol) of ethylamine were stirred in 15 ml of ethanol in an autoclave at 130° C. for 3 hours. The reaction mixture was freed from solvent, the residue was suspended in 8 ml of ethanol and treated in an ultra-sound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 01N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.18 g (56%) of 4-amino-N-(6-ethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 252° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 74.5 %

Procedure:
A solution of 56 g of 4-nitrophenol, 90 g of methyl bromoacetate and 100 g of potassium carbonate in 500 ml of dimethylformamide was stirred at room temperature for 2 days. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was crystallized by trituration with hexane, to give 63.3 g of the title compound, melting at 98°-99° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:13]([CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:14]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.2 g, 0.49 mmol) in 1,4-dioxane:H2O (2:1) was added 1N aqueous lithium hydroxide (10 eq), and the reaction was stirred overnight at room temperature. The pH was adjusted to pH 6 with 10% aqueous HCl, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product (0.2 g)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C(N(CC)C(C)C)(C)C.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[NH2:1][C:2]1[C:3]([C:7](=[N:17][O:18][C:36]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nonc1C(=NOC(=O)NCc1ccccc1)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 24.7 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (50 mg, 0.18 mmol) and N,N-diisopropylethylamine (64 μL, 0.37 mmol) in dichloromethane (2 mL) was treated with benzyl isocyanate (29 mg, 0.22 mmol) and stirred for 3 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (18 mg, 24%). LCMS for C17H15ClFN6O3 (M+H)+: m/z=405.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)O)=O)=[CH:4][CH:3]=1.[CH:19]([NH:22][C:23]([NH2:25])=[S:24])([CH3:21])[CH3:20]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:25]=[C:23]([SH:24])[N:22]([CH:19]([CH3:21])[CH3:20])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(N)=S
Reactant: O=C(c1ccc(F)cc1)C(O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC(C)n1c(S)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A mixture of 30 g (0.121 mole) of 4,4'-difluorobenzoin, 14.3 g (0.121 mole) of N-isopropylthiourea and 100 ml DMF was heated at reflux through molecular sieves for five hours. The mixture was cooled to room temperature and the crystalline product was collected, washed with DMF/water, then water, then dried to give 22.7 g of 4,5-bis(4-fluorophenyl)-1-isopropylimidazole-2-thiol as a pale yellow solid, mp 308°-312°.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([Cl:23])[C:16]([Cl:24])=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[C:25](OCC)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].[CH3:33][S:34]([OH:37])(=[O:36])=[O:35]>>[S:34]([OH:37])(=[O:36])(=[O:35])[CH3:33].[Cl:23][C:17]1[C:16]([Cl:24])=[C:15]2[C:14]3=[C:19]([C:20]4[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=4[N:13]3[CH:27]([CH3:28])[CH2:26][C:25]2=[O:29])[CH:18]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Reactant: C/C=C/C(=O)OCC
Agent: CS(=O)(=O)O
Product: CC1CC(=O)c2c(Cl)c(Cl)cc3c4c(n1c23)CCNCC4

Procedure:
Following the general procedure of Example 41, making non-critical variations but starting with 3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, using ethyl crotonate in step 7, and using methanesulfonic acid for the salt formation, the title compound was obtained (mp 225-230° C. [dec.]). 1H NMR (d-DMSO) δ 8.94, 8.12, 4.97, 3.48-3.20, 3.13, 2.77, 2.30, 1.20; IR (drift) 3029, 2979, 2849, 2792, 1683, 1481, 1410, 1312, 1214, 1196, 1184, 1161, 1145, 1040, 775 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]([OH:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.CC(C)=O.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([O:18][C:3]1[CH:4]=[C:5]([OH:17])[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:2]=1[Cl:1])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Nc1cc(Cl)c(O)cc1O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1O)c1ccccc1
Yield: 41.6 %

Procedure:
To crude N-(5-chloro-2,4-dihydroxyphenyl)benzamide (1 mmol) in acetone (10 mL) potassium carbonate (280 mg, 2 mmol) and benzoylchloride (140 mg, 1 mmol) was added. The mixture was stirred at ambient tempearature over night. The solvent was removed in vacuo and the residue purified by flash chromatography on silica using DCM and methanol in gradient. The pure compound was obtained as a white solid (153 mg, 42%).