Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]#N)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2(C=[O:27])CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:13]=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=CC1(c2ccccc2)CCCC1
Reactant: N#CC1(c2ccc(Cl)cc2)CCCC1
Product: O=CC1(c2ccc(Cl)cc2)CCCC1
Yield: 98.23 %

Procedure:
1-(4-chlorophenyl)-cyclopentanecarbaldehyde (22-02) (66 g, 98.23%) was synthesized from (4-chlorophenyl)-acetonitrile (21-02) (66 g, 321.95 mmol) as a white solid as a crude product following the procedure as described for 1-phenyl-cyclopentanecarbaldehyde (22-01).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:27])[C:5]=2[NH:4][N:3]=1.O.O.[OH-].[Li+]>O1CCCC1.CO>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:24])([F:25])[F:26])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:27])[C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
(S)-Methyl 2-(1,4-dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (230 mg, 0.542 mmol) was dissolved in a mixture of tetrahydrofuran (5.0 mL) and methanol (5.0 mL). Water (5.0 mL) was added to the mixture followed by lithium hydroxide hydrate (66 mg, 1.573 mmol). Reaction was warmed to 50° C. and held with stirring for 4.5 hours. Mixture was cooled to room temperature. Organic solvents were removed from the mixture by roto-vap. Residue was neutralized with 1.6 mL 1N hydrochloric acid. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 94% yield. MS (M−H)−=407.9, 409.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH:8]=[CH:9][Cl:10])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]([CH2:7][CH:8]=[CH:9][Cl:10])[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][Cl:19])[CH3:2]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)CNCC=CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CN(CC=CCl)C(=O)CCCCl
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Into a 100 ml four-necked flask there were placed 17.8 g of N-(3-chloroallyl)glycine ethyl ester, 15.2 g of triethylamine and 50 ml of benzene, and then 16.9 g of γ-chlorobutyryl chloride was gradually dropwise added thereto at room temperature with thorough stirring. Thereafter, the mixture was stirred for 1 hour at 60° C. After cooling, the reaction solution was washed with water, the benzene layer was dried over anhydrous sodium sulfate and the benzene was removed under reduced pressure. The residue obtained was distilled under reduced pressure to obtain 23.7 g of the objective N-(3-chloroallyl)-N-γ-chlorobutyryl glycine ethyl ester (b.p.2 167 - 170° C, nD23.0 1.4884).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH2:21])[CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH:21][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: O=C(Cl)CCCCCl
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CCCCCl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.6 %

Procedure:
5-Chlorovaleryl chloride (2.64 g, 17 mmol, 1.1 equiv) in CH2Cl2 (5 ml) was added over 2 min to a stirred solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (3 g, 15.3 mmol, 1 equiv) and NEt3 (2.6 ml, 18 mmol, 1.2 equiv) in CH2Cl2 (30 ml). The resulting mixture was stirred for 1 h at room temperature then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give 3-(5-Chloro-pentanoylamino)-5-nitro-benzoic acid methyl ester D3 (6 g, 112%) as a brown oil.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][C:35]1([CH3:42])[NH:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:34][C:35]1([CH3:42])[N:40]([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:39][CH2:38][NH:37][C:36]1=[O:41]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: CC1(C)NCCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1

Procedure:
Following the procedure reported for Example 179, the reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (102 mg, 0.193 mmol, Intermediate B), 3,3-dimethylpiperazin-2-one (26.0 mg, 0.203 mmol, ChemBridge, San Diego, Calif.), and potassium carbonate (80 mg, 0.579 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (1.286 mL). Purification by silica gel chromatography (1.5 to 7% MeOH in CH2Cl2 gradient) delivered the title compound as a mixture of two isomers.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO.O>[CH3:1][N:2]([CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: O=C1CCOCC1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CN(C1CCOCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 30 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (100 mg, 0.33 mmol, 1.00 equiv) in methanol (10 mL) was added oxan-4-one (66 mg, 0.66 mmol, 2.00 equiv), NaBH3CN (104 mg, 1.65 mmol, 5.0 equiv) and acetic acid (0.1 mL) at room temperature under nitrogen. The resulting solution was stirred for 16 h at 30° C. and diluted with water, extracted with EtOAc, washed with brine. The organic layer was concentrated in vacuo. The crude product (130 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 54.0% in 14 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 1-N-methyl-1-N-(oxan-4-yl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (16.2 mg) as a light yellow solid. MS (ES, m/z): 387 (M+H+); 1H NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 4.20-4.33 (m, 1H), 4.05-4.16 (m, 2H), 3.61-3.70 (m, 1H), 3.47-3.56 (m, 3H), 3.17 (t, 2H, J=6.8 Hz), 3.06 (t, 2H, J=6.8 Hz), 2.85 (s, 3H), 2.56-2.65 (m, 2H), 2.27-2.32 (m, 2H), 2.18-2.25 (m, 2H), 2.01-2.16 (m, 2H), 1.91-1.97 (m, 1H), 1.79-1.89 (m, 3H), 1.69-1.75 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[N:10][C:8](=[S:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)Nc1ccccc1

Procedure:
6.1 g. phenylthiourea and 4.3 g. dimethyl formamide dimethylacetal were suspended in 100 ml. of benzene with ~ 100 mg of p-toluene sulfuric acid and the mixture distilled through a 6 plate distilling column. The methanol-benzene azeotrope, bp 57° C, came off rapidly. After the bp rose to 80° C, the mixture was cooled and the product crystallized from the benzene. The yield was 6.3 g of solid m.p. 131°-138° C which was triturated with ether to give 6 g m.p. 139°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.ClC(OCC)=O.C(N(CC)CC)C.[N:27]1([CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:42][CH:41]=1)=[O:7]
Reactant: NCc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCc2ccc(OCCN3CCCC3)cc2)c(OC)c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a cooled suspension of 1.82 g of 2,4-dimethoxybenzoic acid in 10 ml of tetrahydrofuran was added 1.09 g of ethyl chloroformate and 1.01 g of triethylamine. After stirring for 15 minutes, to the mixture was added a solution of 2.00 g of 4-[2-(1-pyrrolidinyl)ethoxy]benzylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 15 minutes and the solvent was evaporated. To the residue was added 10% hydrochloric acid, and the solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give 3.31 g of the title compound as a colorless oil.
Reaction SMILES: C([S:11][CH:12]1[N:15]([C:16](=[C:30]([OH:33])[CH2:31][Br:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:34])[CH:13]1[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(OCC1C=CC=CC=1)=O.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[SH:11][CH:12]1[N:15]([C:16](=[C:30]([OH:33])[CH2:31][Br:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:34])[CH:13]1[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1SC(=O)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of p-nitrobenzyl α-[4-carbobenzoxythio -3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyehtylidene)acetate (480 mg) in methylene chloride (5ml) containing 20% of nitromethane is added a solution of aluminum chloride (270 mg) in methylene chloride containing 20% of nitromethane (4ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into diluted hydrochloric acid, and is extracted with methylene chloride. The extract solution is washed water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (376 mg). Yield: 99.5%.
Reaction SMILES: [CH:1]1[NH:8][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]=1C(O)=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH:35]([C:38]1[C:46]2[C:41](=[N:42][CH:43]=[CH:44][C:45]=2[C:47]2[CH:48]=[N:49][C:50]3[C:55]([CH:56]=2)=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:40]([C:57]2[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[C:59]([NH:65][CH:66]3[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH:58]=2)[N:39]=1)([CH3:37])[CH3:36].CN([CH:75]=[O:76])C>O.C(OCC)(=O)C>[OH:7][C:6]1[N:8]=[C:1]([C:75]([N:69]2[CH2:68][CH2:67][CH:66]([NH:65][C:59]3[CH:58]=[C:57]([N:40]4[C:41]5=[N:42][CH:43]=[CH:44][C:45]([C:47]6[CH:48]=[N:49][C:50]7[C:55]([CH:56]=6)=[CH:54][CH:53]=[CH:52][CH:51]=7)=[C:46]5[C:38]([CH:35]([CH3:37])[CH3:36])=[N:39]4)[CH:64]=[CH:63][C:60]=3[C:61]#[N:62])[CH2:71][CH2:70]2)=[O:76])[CH:2]=[C:3]([OH:4])[N:5]=1
Reactant: O=C(O)c1c[nH]c(=O)[nH]c1=O
Reactant: CN(C)C=O
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C#N)c(NC3CCN(C(=O)c4cc(O)nc(O)n4)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 39 %

Procedure:
Isoorotic acid (0.021 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.029 g), and 1-hydroxybenzotriazole monohydrate (0.016 g) were added to a solution of compound (77a) (0.050 g) in DMF (1.0 mL), followed by stirring under argon flow at room temperature for 15 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away to obtain 2-{1-(2,6-dihydroxypyrimidine-4-carbonyl)piperidin-4-ylamino}-4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. According to Example 1(7), compound (78) (0.026 g, the second stage yield: 39%) was prepared as a white solid using 2-{1-(2,6-dihydroxypyrimidine-4-carbonyl)piperidin-4-ylamino}-4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:27][B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[CH:50]1[CH2:55][CH:54]([F:56])[CH2:53][CH2:52][NH:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:51]3[CH2:52][CH2:53][C:54]([F:56])([F:27])[CH2:55][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: F[B-](F)(F)F
Reactant: FC1CCNC(F)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,4-difluoro piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(NCc2nnn(C)n2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(C)cc2)[C@H]1O
Yield: 75 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.1 mmol) obtained in step 1 of example 2 and N-(4-methylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (388 mg, yield: 75%).
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH2:6]=[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)[CH3:8].ClC(Cl)C.ICI>[Cl-].[NH4+]>[CH3:6][C:7]1([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]3)[CH2:1][CH2:8]1
Reactant: CC[Zn]CC
Reactant: C=C(C)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc2cc(C3(C)CC3)ccc2c1
Temperature: 25 °C
Yield: 151.5 %

Procedure:
Diethylzinc (1.0 M in Hexane)(6.30 ml, 6.30 mmol) was added to a solution of methyl 6-(prop-1-en-2-yl)-2-naphthoate (0.57 g, 2.5 mmol).in dichloroethane at 0° C. Diiodomethane (1.01 ml, 12.6 mmol) was then added dropwise to the mixture solution and the resultant mixture was stirred at 60° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (30 mL), and the mixture was extracted with CH2Cl2 (30 ml×3). The combined organic layer was washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), and the organic layer was dried over Na2SO4. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with ethyl acetate-hexane (1:20) to give 0.91 g of the title compound as white solid. 1H NMR (270 MHz, CDCl3) ppm 0.75-0.95 (2H, m), 0.95-1.13 (2H, m), 1.52 (3H, s), 3.97 (3H, s), 7.41 (1H, d, J=9.9 Hz), 7.74 (1H, s), 7.82 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=8.6 Hz), 8.04 (1H, d, J=8.6 Hz), 8.56 (1H, s). MS (ESI) m/z: not observed M+ peak.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][CH:9]2[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:16]=[C:17](Cl)[C:18]2[N:19]([C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([F:33])[CH:28]=3)=[O:25])=[CH:22][N:23]=2)[N:20]=1.BrC1C2N(C(C(NC3C=CN=C(F)C=3)=O)=CN=2)N=C(Cl)C=1.BrC1C2N(C(C(NC3C=CN=C(F)C=3)=O)=CN=2)N=C(Cl)C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:14][C:15]1[CH:16]=[C:17]([N:8]([CH:9]2[CH2:11][CH2:10]2)[CH2:7][C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:18]2[N:19]([C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([F:33])[CH:28]=3)=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: COc1ccc(CNC2CC2)cc1
Reactant: O=C(Nc1ccnc(F)c1)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(Nc1ccnc(F)c1)c1cnc2c(Br)cc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 78 %

Procedure:
N-(4-methoxybenzyl)cyclopropanamine (381 mg, 2.148 mmol) was added to ˜1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (467 mg, 1.432 mmol, example 13A) and DIEA (0.500 mL, 2.86 mmol) in DMF (10 mL). The reaction mixture was heated at 80° C. for 1.5 hrs. Water (20 mL) was added, and the solid was collected via Buchner filtration and dried under reduced pressure overnight to afford 6-Chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as a yellow solid (519 mg, 78%). The crude material was taken into the next step without further purification. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=2.22 minutes. [M+H]=467.21.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].CN1CCOCC1.ClC(OCC)=O.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:32][CH:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: NC1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NC1CCOCC1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Under nitrogen atmosphere, 3-nitrobenzoic acid (1.00 g, 5.98 mmol) was taken in THF (20 ml) and the mixture was cooled to 0° C. followed by addition of N-methylmorpholine (0.85 ml, 7.78 mmol) and ethyl chloroformate (6.58 mmol). The reaction mixture was stirred for 30 min at 0° C. and tetrahydro-2H-pyran-4-amine (0.6 ml, 5.98 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under vacuum and the residue was taken in ethyl acetate (20 ml), washed with water and brine, dried over sodium sulfate and concentrated under vacuum to afford the solid product (1.2 gm).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1.[BrH:12].N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:12][C:2]1[S:3][C:4]2[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: CN1CCc2nc(N)sc2C1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2nc(Br)sc2C1
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
2-Amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (600.0 g) was suspended in water (6.0 L), and 48% hydrobromic acid (4.2 L) was added dropwise thereto at 5 to 15° C. A solution of sodium nitrite (367.2 g) in water (1.8 L) was added dropwise thereto at 0 to 5° C. over 1.5 hours, and the reaction mixture was heated to 30° C., followed by stirring for 24 hours. The resultant mixture was made strongly basic (pH 12.5) with 5N aqueous sodium hydroxide (6.0 L). The aqueous layer was extracted with toluene twice (12.0 L, 6.0 L), and the toluene layers were combined. The combined toluene layer was dried over sodium sulfate anhydrate (1202.0 g), and after any insoluble material was filtered off, the mother liquor was concentrated at 40° C. under reduced pressure, to thereby give 557.6 g of the title compound.
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][C:7]#[N:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.[CH3:15][C:16](O)([CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:17].S(=O)(=O)(O)[OH:26].O>C(O)(=O)C>[C:4]1(=[O:9])[N:5]([CH2:6][C:7]([NH:8][C:16]([CH3:17])([CH3:15])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:26])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)CCCC(C)(C)O
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCCC(C)(C)NC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
A suspension of phthalimidoacetonitrile (6.01 g, 0.03 mole) in glacial acetic acid (16 ml) was heated to 60° C. with stirring; 2,6-dimethylheptan-2-ol (4.64 g, 0.03 mole) was then added followed dropwise by concentrated sulphuric acid (4.4 ml, 0.08 mole). The temperature rapidly rose to 20° and was controlled at this temperature during the addition. When the addition was complete the solution was stirred for 5 minutes and then added slowly to a mixture of ice and water (350 g). The precipitated solid was filtered off, washed thoroughly with water and dried in vacuo. The product was recrystallised from benzene with filtering to afford 2-phthalimido-N-(1,1,5-trimethylhexyl)acetamide, m.p. 162°-163°.