Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:45](=[O:47])[CH3:46])=[CH:3][CH:4]=2)([C:26]2[CH:27]=[C:28]([CH3:35])[C:29]([O:33][CH3:34])=[C:30]([CH3:32])[CH:31]=2)[C:9]1=[O:25]
Reactant: COc1c(C)cc(C2(c3ccc(N)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C)cc(C2(c3ccc(NC(C)=O)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Yield: 94.5 %

Procedure:
Combine 3-(4-amino-phenyl)-1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (126 mg, 0.26 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol) and acetyl chloride (0.020 mL, 0.29 mmol) in CH2Cl2 (1 mL) and stirred at room temperature for 48 h. Dilute with CH2Cl2 and wash with water. Backwash water with CH2Cl2 and ethyl acetate. Combine all organics, dilute with more CH2Cl2 and wash with 1N HCl and brine. Dry (MgSO4), filter and concentrate in vacuo to give a residual foam. Purify by flash chromatography (gradient of 33% EtOAc/hexanes to 66% EtOAc/hexanes) to give 129 mg (67%) of the title compound as a white foam. MS (ES): m/z=525 (M+1), 523 (M−1); 1H NMR(DMSO-d6): δ9.99 (s, 1H), 7.53 (m, 3H), 7.41-7.26 (m, 4H), 7.12 (m, 3H), 6.98 (m, 2H), 6.82 (s, 2H), 5.08 (s, 2H), 3.64 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CO>C(Cl)(Cl)(Cl)Cl>[C:14]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)NCCNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A suspension of 2-(2-aminoethylamino)-5-nitropyridine (5.0 g, 27.47 mmol) in carbon tetrachloride (60 ml) was treated with acetic anhydride (5.6 g, 54.9 mmol) and methanol (0.5 ml) and the resulting mixture was refluxed for 2 h then allowed to cool to room temperature. The mixture was filtered and the residue partitioned between 1M sodium hydroxide and CH2Cl2. The organic phase was dried (MgSO4) and concentrated to afford the title compound (5.03 g) as a buff solid m.p. 177-180°. MS(ES+) 225 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CS(O[CH:12]1[CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)[CH2:13]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]2[CH2:13][C:14]3([CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[CH2:15]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(OS(C)(=O)=O)C2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC2(CC(n3cc(Br)cn3)C2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (210 mg, 1.428 mmol, 1.2 equiv) and tert-butyl 2-(methylsulfonyloxy)-6-azaspiro[3.5]nonane-6-carboxylate (380 mg, 1.19 mmol, 1.0 equiv) in DMF (2.5 mL) was added Cs2CO3 (465 mg, 1.428 mmol, 1.2 equiv). The mixture was stirred at 80° C. for 3 hrs. It was concentrated by rotary evaporator to give the residue which was purified by CombiFlash (25 g silica gel column, EtOAc/Hex: 0-40%) to afford 110 mg (yield 25%) of tert-butyl 2-(4-bromo-1H-pyrazol-1-yl)-6-azaspiro[3.5]nonane-6-carboxylate (cis and trans isomers) as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH2:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.O.O.[F:26][C:27]([F:35])([F:34])[C:28]([C:30]([F:33])([F:32])[F:31])=[O:29]>C(OCC)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([C:28]([OH:29])([C:30]([F:33])([F:32])[F:31])[C:27]([F:35])([F:34])[F:26])=[CH:10][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1ccccc1N
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N
Temperature: 130 °C
Yield: 42.8 %

Procedure:
2-Propylaniline (111 mmol, 15 g), p-toluenesulfonic acid monohydrate (11.09 mmol, 2.110 g) and hexafluoroacetone trihydrate (111 mmol, 24.41 g) were combined and heated to 130° C. for 3 hours. The mixture was allowed to cool and diluted with ethyl acetate (250 mL). The solution was washed with sodium bicarbonate solution (3×100 mL), the organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was allowed to crystallise overnight. The crystals were collected by filtration, washed with heptane (100 mL) and dried under vacuum to afford the title compound (14.3 g).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[OH:14][CH:15]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[Si:10]([O:14][CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CC(O)CC(=O)OCC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)CC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C

Procedure:
Imidazole and tert-butylchlorodimethylsilane are added to a solution of diethyl 3-hydroxyglutarate in methylene chloride, and the reaction is performed to give diethyl 3-[(tert-butydimethylsilyl)-oxy]pentanedioate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([OH:38])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].[CH3:39]OC>>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(O)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Reactant: COC
Product: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(OC)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Yield: 82 %

Procedure:
The product of step C was converted to the methyl ether derivative following the procedure of Example 54, step B. Purification by flash column chromatography (SiO2, 75:25 hexane/ethyl acetate) provided tert-butyl 8-((1-(ethoxycarbonyl)-1H-indol-5-yl)sulfonyl)-6-methoxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (25 mg, 82%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.30 (d, J=8.7 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.88 (dd, J=8.7, 1.8 Hz, 1H), 7.73 (d, J=3.6 Hz, 2H), 7.35 (s, 1H), 6.69 (d, J=3.6 Hz, 1H), 4.60-4.45 (m, 4H), 4.03 (s, 3H), 3.88-3.74 (m, 2H), 2.95-2.75 (m, 2H), 1.50 (s, 9H), 1.47 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[N:14]=[N:15][C:11]=2[C:10]=1[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1>CO.C(OCC)(=O)C>[CH:17]1([CH2:16][N:13]2[C:12]3[CH:20]=[CH:21][C:9]([OH:8])=[C:10]([C:22]([F:24])([F:25])[F:23])[C:11]=3[N:15]=[N:14]2)[CH2:19][CH2:18]1
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccc2c1nnn2CC1CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Reaction time: 1.5 h

Procedure:
5-Benzyloxy-1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole (5.04 g, 14.5 mmol) was dissolved in 1:1 mixture of methanol/ethyl acetate (40 mL), sparged under nitrogen, treated with Pearlman's catalyst (2 g, 0.2 wt equiv) and then sparged under hydrogen (1 atm). After stirring vigorously for 90 minutes, the mixture was filtered through a pad of Celite, which was washed with methanol (500 mL) and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.O.[OH-].[Li+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(C(C)(C)C(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Cc2ccc(C(C)(C)C(=O)O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 154.1 %

Procedure:
An 250-mL round bottom flask was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoate (0.472 g, 1.15 mmol), dioxane (24 ml) and water (12 ml). To this solution was then added lithium hydroxide monohydrate (0.242 g, 5.77 mmol). The resulting mixture was stirred at 50° C. for 7 h. After this time the reaction mixture was cooled and treated with 2M aqueous HCl until pH˜5. The volatile materials were removed under reduced pressure to afford the title compound (0.70 g, >100%) as a white solid. MW=394.89. 1H NMR (DMSO-d6, 500 MHz) δ 12.26 (br s, 1H), 8.38-8.34 (m, 2H), 7.61-7.53 (m, 2H), 7.35-7.27 (m, 5H), 4.09 (s, 2H), 2.78 (q, J=8.0 Hz, 2H), 1.44 (s, 6H), 1.27 (t, J=7.5 Hz, 3H). ESI MS m/z 395 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(C#N)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (65 mg, 81%), MS (ISP) m/z=320.6 [(M+H)+], mp 295° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[OH:19][C:20]1([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:26]=[C:25]([C:20]4([OH:19])[CH2:24][CH2:23][CH2:22][CH2:21]4)[O:29][N:28]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(C2(O)CCCC2)on1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C2(O)CCCC2)on1
Yield: 23.2 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxycyclopentyl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.69 mmol) and 5-(1-hydroxycyclopentyl)isoxazole-3-carboxylic acid (173 mg, 0.878 mmol). The product purified twice by Flash-chromatography (normal phase and reverse phase). Yield 23.2%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 1.75-2.12 (m, 8H), 4.28-4.44 (m, 2H), 4.52-4.64 (m, 1H), 6.51 (s, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.77 (dd, 1H), 7.88 (dd, 1H), 8.09 (dd, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][OH:4].[CH3:5][CH2:6][CH2:7][C:8](Cl)=[O:9]>C(N(CC)CC)C>[C:8]([O:1][CH2:2][CH2:3][OH:4])(=[O:9])[CH2:7][CH2:6][CH3:5]
Reactant: OCCO
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)OCCO

Procedure:
As a nonlimiting example using method B in FIG. 2 to obtain the (5-oxo-1,3-oxathiolan-2-yl) methyl butanoate or its 5-acetyloxy derivative is to react 1,2-dihydroxy ethane with n-butyryl chloride in triethylamine. This reaction produces 2-hydroxyethyl butanoate, which is further reacted P2O5 in dry DCM, followed by DMSO and triethylamine to produce 2-oxyethyl butanoate. The 2-oxyethyl butanoate can be converted to the 5-acetyloxy derivative of (5-oxo-1,3-oxathiolan-2-yl) methyl butanoate by the process described above, or it can be converted into (5-oxo-1,3-oxathiolan-2-yl) methyl butanoate by reacting with mercaptoacetic acid and CSA in dry DCM.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[OH:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[O:11][CH2:14][CH:16]1[O:18][CH2:17]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: BrCC1CO1
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1[nH]c(C)c(C)c1OCC1CO1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
100 g of 2-carboethoxy-3-hydroxy-4,5-dimethylpyrrole, 150 g of epibromohydrin and 152 g of dry potassium carbonate in 500 ml of acetone are refluxed for 16 hours. When it has cooled, the entire reaction mixture is poured into 3 liters of ice water, the batch is extracted with ether and the combined extracts are washed with 2 N sodium hydroxide solution and water and dried over sodium sulfate. The evaporation residue which remains after distilling off the ether and the excess epibromohydrin is extracted with heptane. 122 g of 1-(2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy)-2,3-epoxypropane, of melting point 70°-71° C., are obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, benzoyl chloride (0.31 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2C12 (70 mL). The CH2Cl2 solution was washed with H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAC 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}benzamide (0.55 g, 76%) as a white solid: mp 227–229° C.; 1H NMR (DMSO-d6) δ 11.16 (s, 1H), 9.16 (t, J=5.7 Hz, 1H), 7.95–7.72 (m, 5H), 7.60–7.46 (m, 3H), 5.22–5.12 (dd, J=5.4 and 12.8 Hz, 1H), 4.96 (d, J=5.7 Hz, 2H), 2.98–2.85 (m, 1H), 2.65–2.50 (m, 2H), 2.11–2.06 (m, 1H); 13C NMR (DMSO-d6) δ 172.72, 169.80, 167.54, 166.96, 166.60, 139.34, 134.77, 133.92, 133.02, 131.52, 131.42, 128.34, 127.28, 127.12, 121.83, 48.88, 38.32, 30.93, 21.98; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.47; H, 4.50; N, 10.34.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1.[BH4-].[Li+].O>C1COCC1>[C:21]([O:20][C:18](=[O:19])[N:5]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:10]=1)[CH2:4][CH2:3][OH:2])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1nc(-c2ccc(F)cc2)cs1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCO)c1nc(-c2ccc(F)cc2)cs1

Procedure:
Under argon, 435 mg (1.18 mmol) of (tert-butoxycarbonyl-(4-(4-fluorophenyl)thiazol-2-yl)-amino)acetic acid methyl ester and 51.7 mg (2.37 mmol) of lithium borohydride were stirred in 20 ml of THF at 60° C. for 1 h. After cooling, the mixture was cautiously hydrolyzed with water, the precipitate was filtered off with suction, and water and ethyl acetate were added to the filtrate. The organic phase was separated, washed with water and concentrated. Yield: 273 mg (68%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)[CH:3]=1.[C@@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:28].CN1CCCC1=O>CO>[NH2:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:29][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: CO
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
A mixture of 6-chloro-4-(5-(methylsulfonyl)pyridin-2-ylamino)pyridazine-3-carboxamide (60 mg, 0.183 mmol), cis-cyclohexane-1,2-diamine (125 mg, 1.1 mmol) and N-methyl-2-pyrrolidinone (2 mL) was heated to 150° C. After 18 h, the reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (spherical silica 20-45 uM, 23 g, Versaflash Supelco, 0 to 5% MeOH containing 10% NH4OH in CH2Cl2, 20 min) gave a solid residue. This residue was dissolved in MeOH and CH2Cl2, then precipitated by addition of cyclohexane. The solid formed was obtained by decantation of the mother liquor, then dried to give 6-(cis-2-aminocyclohexylamino)-4-(5-(methylsulfonyl)pyridin-2-ylamino)pyridazine-3-carboxamide (19 mg, 45.6 μmol, 25%) as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.21 (s, 1H) 8.73 (d, J=2.27 Hz, 1H) 8.48 (br. s., 1H) 8.16 (s, 1H) 8.12 (dd, J=8.69, 2.64 Hz, 1H) 7.75 (br. s., 1H) 7.14 (d, J=8.69 Hz, 1H) 7.03 (d, J=7.93 Hz, 1H) 4.06 (br. s., 1H) 3.26 (s, 3H) 3.09 (br. s., 1H) 1.24-1.78 (m, 10H). LCMS (EI/CI) m/z: 406 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C@@H:9]([C:14]([OH:16])=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[OH:20].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[OH:20][C@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][NH:17][C:14]([C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[O:10]1)=[O:16]
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C(O)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Reaction time: 18 h

Procedure:
(2R)-6-Nitro-3,4-dihydro-2H-chromene-2-carboxylic acid (4.1 g, 18 mmol) and (1R)-2-amino-1-(3-pyridinyl)ethanol (5.0 g, 24 mmol) (both described in U.S. Pat. No. 6,051,586) were suspended in CH2Cl2 and stirred vigorously. Triethylamine (9.2 mL, 66 mmol) was added followed by hydroxybenzotriazole (4.9 g, 36 mmol) and EDCl (6.9 g, 36 mmol), and the reaction was stirred overnight. After 18 hours, TLC showed no remaining acid starting material, so the reaction was partitioned between water and CH2Cl2 and the organic layer was washed 3×100 mL of water. The organic layer was washed with 1N HCl, which removed the product into the aqueous layer. This aqueous layer was washed with CH2Cl2 and the organic was discarded. The aqueous solution was then basified and became cloudy with a white precipitate. The basified mixture was extracted with 3×100 mL of CH2Cl2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=O.CC(O)=O.C[N:34](C)C=O>>[O:25]1[C:22]2[CH:23]=[CH:24][C:19]([C:10]3[CH:11]=[C:12]([C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[N:34]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH:9]=3)=[CH:20][C:21]=2[O:27][CH2:26]1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccsc2)n1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-benzo[1,3]dioxol-5-yl-6-thiophen-3-yl-pyridin-2-yl)-phenol; mp 120-121° C.; 1H NMR (DMSO-d6) d 6.15 (s, 2 H), 6.97 (m, 2 H), 7.13 (d, j=8.2 Hz, 1 H), 7.35 (m, 1 H), 7.66 (dd, J=8.2, 1.9 Hz, 1 H), 7.80 (m, 3 H), 8.16 (d, J=1.1 Hz, 1 H), 8.31 (m, 2 H), 8.37 (dd, J=2.9, 1.4 Hz, 1 H), 14.58 (s, 1 H); IR (KBr) 1602 cm−1; MS [M+H]+m/z=374. Anal. calcd for C22H15NO3S: C, 70.76; H, 4.05; N, 3.75; Found: C, 70.66; H, 4.02; N, 3.59.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow solid (155 mg).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](Cl)=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:18]C(=O)C)(=O)C.O.[SH2:23].[Na]>CO>[OH:18][C:6]1[CH:7]=[C:8]([C:11]2[C:12](=[S:23])[NH:13][CH:14]=[N:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccc(-c2cncnc2Cl)cc1OC(C)=O
Reactant: S
Agent: [Na]
Solvent: CO
Solvent: O
Product: Oc1ccc(-c2cnc[nH]c2=S)cc1O
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 97.1 %

Procedure:
4-(4-Chloro-5-pyrimidinyl)-o-phenylene diacetate (1.1 g) (3.6 mmol) are dissolved in 30 ml of methanol. 1.56 g of sodium hydrogen sulphide hydrate are added thereto and the mixture is stirred at 60° C. for 4.5 hours. The solvent is distilled off in a vacuum and the residue is dissolved in 20 ml of water. The solution is acidified with dilute aqueous hydrochloric acid to pH 5, the precipitated product is filtered off under suction and washed with water and diethyl ether. After drying in a high vacuum there are obtained 770 mg of 5-(3,4-dihydroxyphenyl)-4(3H)-pyrimidinethione as yellow crystals of m.p. 235° C. (dec.).