Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[O:4]=[C:3]1[CH2:2][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][C:7]=2[NH:6]1
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2c(c1)NC(=O)CO2
Reaction time: 1 h
Yield: 90 %

Procedure:
Chloroacetyl chloride (1 equiv.) was added at room temperature to a mixture of methyl (3-amino-4-hydroxyphenyl)acetate (5.5 mmol) and sodium hydrogen carbonate (1.1 equiv.) in ethyl acetate (5 ml)/water (5 ml). The reaction mixture was stirred for 1 h, then the phases were separated and the organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in DMF (11 ml); activated potassium carbonate was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was again washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane). Yield: 90%
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH2:15])=[N:3]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15][C:23](=[O:25])[CH3:24])=[N:3]1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
To a solution of trans-1-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine (100 mg, 0.497 mmol) and triethylamine (104 μL, 0.746 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (70.5 μL, 0.746 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/hexane) to give the title compound (63.2 mg, yield 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17]N1C(=O)CCC1=O.C(O)(C)C>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:17])[C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(Oc2cc(Cl)c(N)c(Cl)c2)ccn1
Yield: 15 %

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (700 mg), N-chlorosuccinimide (0.44 g) and isopropanol (10 ml) were stirred at 80° C. for 1 hour. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (ethyl acetate), to obtain 120 mg of a brown oil.
Reaction SMILES: C(OC([N:11]([C:20]1[N:49]=[C:23]2[N:24]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=3)[C:25]([CH3:38])=[C:26]([C:36]#[N:37])[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[N:22]2[N:21]=1)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[C:36]([C:26]1[C@@H:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)[N:22]2[N:21]=[C:20]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:49]=[C:23]2[N:24]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=2)[C:25]=1[CH3:38])#[N:37]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(=O)OC(C)(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, tert-butyl N-[(benzyloxy)carbonyl]-N-{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}glycinate (23.0 mg, 34 mmol) was dissolved in degassed methanol (2.3 ml). After addition of palladium on activated carbon (10%-ig; 15.2 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.5 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (21.2 mg, quant.).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:29].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])[C:3]1=[O:29]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(=O)n(C)c(=O)c3c(-c4ccncc4)n(Cc4cccc5ccccc45)nc32)c1

Procedure:
This compound was synthesized by the reaction of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and methyl 3-(bromomethyl)benzoate using potassium carbonate as a base in DMF at 80° C.
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2].Cl.Cl[CH2:28][C:29]1[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:28][C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2]
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(O)ccc12
Reactant: Cc1ncccc1CCl
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCc3cccnc3C)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 16 and 3-chloromethyl-2 methylpyridine hydrochloride using a procedure analogous to that outlined for Example 2. Product was isolated by flash chromatography eluting with 30% methylene chloride in ethyl acetate. Mass spectrum: m/e 444 (M+1).
Reaction SMILES: C[NH:2][CH:3]1[CH2:21][CH2:20][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1>CO.CC(C)=O>[NH2:2][CH:3]1[CH2:21][CH2:20][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1
Reactant: CNC1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: CC(C)=O
Solvent: CO
Product: NC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
2-methylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine, oil; Rf in methanol:acetone (9:1) = 0.35 on SiO2.
Reaction SMILES: CN[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH3:19]NC(C1C=C(Cl)C=CN=1)=O>CCOC(C)=O>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3](=[O:4])[CH3:19])[CH:10]=2)=[CH:17][CH:16]=1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: CNC(=O)c1cc(Cl)ccn1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 1-(4-chloropyridin-2-yl)ethanone for 4-chloropyridine-2-carboxylic acid methylamide. 1H-NMR (Acetone-d6) δ 8.53 (d, J=5.4 Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 7.08 (dd, J=5.4, 2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H), 4.77 (br s, 2H), 2.59 (s, 3H); LC MS m/z 229 (M+H)+, RT=1.11 min; TLC (50% EtOAc/Hex), Rf=0.30.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(F)cnc1Cl
Temperature: 0 °C
Yield: 25 %

Procedure:
To a solution of 2-chloro-5-fluoronicotinic acid (5.2 g, 30 mmol) in methanol (20 ml) was added conc. sulfuric acid (0.5 ml) and the reaction mixture was stirred at reflux for 30 hours. The reaction mixture was cooled to 0° C. and 0.5 N sodium hydroxide solution was added to the mixture. The whole was extracted with diethylether. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 3.2 g (25%) of the title compound:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc(Cl)c(Cl)c2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (50 g) and triethylamine (63.1 ml) in tetrahydrofuran (250 ml) was dropwise added methanesulfonyl chloride (35.0 ml) with stirring at -5°-0° C. for 2 hours. After stirring for 1 hour, the mixture was poured into ice-water (500 ml) and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (250 ml). The organic layer was washed in turn with 1N hydrochloric acid (250 ml×2) and brine (250 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-methanesulfonyloxypyrrolidine (66.21 g).
Reaction SMILES: CC(C)(C)C([O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1
Reactant: CC(C)(C)C(=O)OCc1nc(C(=O)O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1csc(CO)n1

Procedure:
A solution of 2-{[(2,2-dimethylpropanoyl)oxy]methyl}-1,3-thiazole-4-carboxylic acid (3 g) and potassium carbonate (2.326 g) in methanol (100 ml) and water (30 ml) was heated to reflux for 4 h. The mixture was cooled and concentrated in vacuo to −30 ml. It was then acidified with 2 M HCl (aq) (50 ml) and concentrated in vacuo. The resulting solid was treated with hot MeOH/Ethyl acetate (2:1), washing well before filtering off the remaining solid. The filtrate was concentrated in vacuo to give a brown solid which was dissolved in MeOH and added to the top of 2×70 g aminopropyl cartridge that had been preconditioned with MeOH. The cartridges were both eluted with MeOH and then with 10% HCl in MeOH. The acidic fractions were combined and the solvent removed in vacuo to give the title compound as a brown oil, 550 mg.
Reaction SMILES: [CH:1]1[C:5]2[C:6](Cl)=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[NH2:11][C:12]1[CH:16]=[CH:15][O:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18].Cl>C(O)(C)(C)C.CO>[CH3:20][O:19][C:17]([C:13]1[O:14][CH:15]=[CH:16][C:12]=1[NH:11][C:6]1[C:5]2[CH:1]=[CH:2][NH:3][C:4]=2[N:9]=[CH:8][N:7]=1)=[O:18]
Reactant: COC(=O)c1occc1N
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CO
Solvent: CC(C)(C)O
Product: COC(=O)c1occc1Nc1ncnc2[nH]ccc12
Yield: 17.9 %

Procedure:
A suspension of 6-chloro-7-deazapurine (100.00 mg; 0.65 mmol), methyl 3-amino-2-furoate (138 mg; 0.98 mmol) and concentrated hydrochloric acid (55 μL; 0.65 mmol) in tert-butanol (2 mL) was microwaved at 75° C. for 3 h. The reaction mixture was diluted with methanol (2 mL) and purified by chromatography on a SP1 Biotage system, using dichloromethane and methanol as eluents to afford 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-furan-2-carboxylic acid methyl ester (30 mg, 18%) as a white solid. (HPLC: 99%, RT: 5.43 min). 1H NMR (DMSO-d6) 12.03 (br s, 1H), 8.99 (br s, 1H), 8.40 (s, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.38 (dd, J=3.3, 2.2 Hz, 1H), 6.60 (dd, J=3.3, 1.8 Hz, 1H), 3.90 (s, 3H); MS (m/z) 259 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51](Br)(Br)([Br:53])[Br:52]>O>[Br:52][C:51]([Br:53])=[CH:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:27])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCC(CC=C(Br)Br)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0° C., triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added. The reaction was stirred at 0° C. for 10 min, water was added and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water, NH4OH) to give 4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as an amorphous solid (50 mg, 10%). 1H NMR (400 MHz, CDCl3): δ 8.9 (s, 2H), 8.4 (s, 1H), 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS (M+H)+: m/z=556
Reaction SMILES: [NH3:1].[CH:2]([CH:20]1[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>C(#N)C>[CH:2]([CH:20]([CH2:25][C:24]([OH:23])=[O:26])[C:21]([NH2:1])=[O:22])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Agent: Cl
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCC=CC(CC(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
389 g of a 25% aqueous ammonia was mixed with 200 ml of acetonitrile and to the mixture was added 100 g of n-octadecenylsuccinic anhydride, followed by stirring for 2 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid. The crystals thus-deposited were collected by filtration, washed with water and then with acetonitrile, and dried to obtain 84.5 g of n-octadecenyl-succinic monoamide as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6]([NH:19][NH2:20])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoic acid (5 g) in THF (60 mL) was added N,N′-carbonyldiimidazole (6.98 g) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to −10° C., hydrazine monohydrate (10.44 mL) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and water was added. The precipitated solid was collected by filtration to give the title compound (0.70 g).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][C@@H:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]1[C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC2(CCOCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (3.54 g, 16.6 mmol) was dissolved in dry dichloromethane (80 mL), triethylamine (5.8 mL, 41.5 mmol) was added followed by benzylchloroformate (3.5 mL, 24.9 mmol) and the reaction is stirred at room temperature for 2 h under nitrogen. The reaction was diluted with dichloromethane, washed with 0.2 N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil. The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes to afford the title compound as a clear oil (1.66 g, 29% yield).
Reaction SMILES: CN(C)C=O.[C:6]([NH2:12])([NH2:11])=[N:7][C:8](N)=[NH:9].[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>O>[NH2:12][C:6]1[N:7]=[C:8]([NH2:9])[N:15]([CH2:13][CH3:14])[C:16](=[S:17])[N:11]=1
Reactant: N=C(N)N=C(N)N
Reactant: CCN=C=S
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(N)nc(N)nc1=S
Temperature: 100 °C
Yield: 104.9 %

Procedure:
To 15 ml of dry dimethylformamide were dissolved 1.52 g of diguanide and 1.31 g of ethylisothiocyanate, and the solution was heated at 100° C. for 4 hours. After cooling, the solution was added to 60 ml of water to produce white precipitates, which subsequently was dried to obtain 2.7 g of the title compound having the characteristics of:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C@@H:10]1[NH:11][CH2:12][CH2:13][N:8]([C:5]2[N:6]=[N:7][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=3)=[C:3]3[CH:18]=[CH:17][N:16]=[CH:15][C:4]=23)[CH2:9]1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a round bottomed flask was added (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (155 mg, 588 μmol), 4-trifluoromethylphenylboronic acid (167 mg, 882 μmol), tetrakis(triphenylphosphine)palladium (34 mg, 29 μmol), and 2 M aqueous sodium carbonate (588 μl, 1.18 mmol). Toluene (5.9 mL) was added and the reaction was heated to 100° C. After 16 h, the reaction was cooled to RT and diluted with ethyl acetate (70 mL). The organic layer was washed with 1×10 mL of sat. NaHCO3, 1×10 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (10:0.5:0.1) (CH2Cl2:MeOH:Et3N) afforded (S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 47 (154 mg, 70% yield). 1H-NMR (400 MHz, CDCl3): δ 9.55 (d, J=0.8 Hz, 1H), 8.90 (d, J=5.5 Hz, 1H), 7.86 (m, 4H), 7.73 (dd, J=5.5, 0.8 Hz, 1H), 4.09 (m, 2H), 3.37 (ddd, J=12.5, 11.0, 3.5 Hz, 1H), 2.23 (m, 3H), 2.99 (dd, J=12.5, 10.2 Hz, 1H), 2.85 (br s, 1H), 1.17 (d, J=6.3 Hz, 1H). MS 373.1 (calc'd) 374.0 (M+H, found).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH2:24])[CH2:12][CH2:11]2)=[N:2]1.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](Cl)=[O:29]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:28](=[O:29])[CH:27]=[C:26]([CH3:31])[CH3:25])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(C)=CC(=O)Cl
Product: CC(C)=CC(=O)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 105.4 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (1 g, 2.82 mmol) and 3,3 dimethyl acryloyl chloride (0.33 mL, 2.97 mmol) and following the procedure as outlined in Example 1, 1.25 g of 3-methyl-but-2-enoic acid {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated as a white foam in 93% purity @ 214 nm; LCMS (APCI): 421 [M+H]+; mp 52° C.