Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]([CH3:22])[S:10]2(=O)=O)C=CC=CC=1.C(Cl)[Cl:26]>>[Cl:26][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([CH3:22])[S:10]1
Reactant: ClCCl
Reactant: CN1C(Cc2ccccc2)C(=O)N(CSc2ccccc2)S1(=O)=O
Product: CN1SN(CCl)C(=O)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92.4 %

Procedure:
To a solution of 2-phenylthiomethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (11.78 g, 33.05 mmol) in 200 ml of methylene chloride was added in one portion under nitrogen sulfuryl chloride (3.15 ml, 39.66 mmol) and the mixture was stirred for 3.5 hours at room temperature. The mixture was concentrated in vacuo and the residue was triturated in hexane and purified by flash chromatography (20% ethyl acetate in hexane) to afford 8.82 g (92.4%) of 2-chloromethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one (Formula II: R1 =H; R2 =CH2Ph; R3 =CH3 ; X'=Cl) as an oil.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].Cl[C:7]1[C:16]([C:17]#[N:18])=[C:15]([Cl:19])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1>C(O)(=O)C>[Cl:19][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:3])[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(Cl)nc2ncccc2c1Cl
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c(Cl)c2cccnc2[nH]c1=O
Temperature: 140 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Ammonium acetate (6.81 g, 88.37 mmol) was added to a suspension of 2,4-Dichloro-[1,8]-naphthyridine-3-carbonitrile (30) in acetic acid at room temperature and heated at 140° C. for 45 min. The solution was cooled and poured into ice water. The solids formed were filtered, washed with cold water and suspended in saturated sodium bicarbonate solution. After stirring overnight at room temperature, the solids were filtered, washed by cold water, and dried at room temperature under vacuum to yield 8.0 g (48%) of 4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (31) as white solids. MP: 310° C.; 1H-NMR (DMSO-d6): δ 7.58 (dd, J=4.4, 8.0 Hz, 1H), 8.50 (d, J=2.0, 8.0 Hz, 1H), 8.83 (dd, J=4.4, 1.6 Hz, 1H), 13.03 (S, 1H); EIMS: 206 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=[N:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:6](=[O:16])[CH:7](Br)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].C([O-])(=O)C.[Na+]>CO.C1CCCCC1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([OH:16])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:17]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(=NNc1ccccc1Cl)C(=O)C(Br)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CO
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo4-(4-chloro-phenyl)-2-[(2-chloro-phenyl)-hydrazono]-3-oxo-butyric acid ethyl ester (12.1 g, 26 mmol) and sodium acetate (10.8 g, 130 mmol) in methanol (100 ml) was heated at reflux for 4 hours, cooled, concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a solid. A slurry of this material in cyclohexane was heated to reflux and allowed to stir at ambient temperature for 2 hours, and filtered to afford the title compound (I-1d) as a yellow solid (I-1d), 6.5 g.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([O:9]C)[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.CCl>>[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1
Reactant: COc1cc(OC)nc(N)n1
Agent: CCl
Agent: Cl
Product: COc1cc(O)nc(N)n1

Procedure:
19.2 g of 2-amino-4,6-dimethoxy-pyrimidine hydrochloride are heated at 150° C. for 2 hours, during which methyl chloride is detached to give 2-amino-4-hydroxy-6-methoxy-pyrimidine. 80 ml of 40% sodium hydroxide solution and 100 ml of dioxane are added, and 22 g of difluorochloromethane are passed in at 70°-75° in the course of 3/4 of an hour. The organic phase is separated off and concentrated to about 1/5 of its volume, the residue is poured into water and the solid precipitate is separated off to give 2.4 g of 2-amino-4-difluoromethoxy-6-methoxy-pyrimidine of melting point 106°-107° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(F)ccn1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2ccc(F)cc2n1
Yield: 59 %

Procedure:
[step 1] Using 2-amino-4-fluoropyridine (3.2 g, 28.5 mmol) and ethyl bromopyruvate (4.3 ml, 34.3 mmol), and in the same manner as in Reference Example 8A, step 1, ethyl 7-fluoroimidazo[1,2-a]pyridine-2-carboxylate (3.5 g, 59%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:17]=4[O:24][C:25]([C:28]([O:30][CH3:31])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:17]=4[O:24][C:25]([C:28]([O:30][CH3:31])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 62.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-4-fluoro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated and the residue was washed with DCM twice. The DCM solutions were combined and concentrated. The residue was purified by flash column to give the title compound as white solid (26 mg).
Reaction SMILES: [N:1]1(CCCC2N=[N+]([O-])C3C=C4C(CCC4)=CC=3[N+]=2[O-])[CH2:6]COC[CH2:2]1.N1(C[CH2:32][CH2:33][NH:34][C:35]2[N:36]=[N+:37]([O-:49])[C:38]3[CH:48]=[C:47]4[C:43]([CH2:44][CH2:45][CH2:46]4)=[CH:42][C:39]=3[N+:40]=2[O-:41])CCOCC1>>[CH2:33]([NH:34][C:35]1[N:36]=[N+:37]([O-:49])[C:38]2[CH:48]=[C:47]3[C:43]([CH2:44][CH:45]([N:1]([CH3:6])[CH3:2])[CH2:46]3)=[CH:42][C:39]=2[N+:40]=1[O-:41])[CH3:32]
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Reactant: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(N(C)C)C3

Procedure:
More preferably, the compound of Formula I is 3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-Dioxide or N-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1,4-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O.[C:29](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:29][N:12]([CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COc1ccc(CCN)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCCN)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 47 %

Procedure:
A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:45]([Cl:47])[Cl:46]>C(O)(=O)C>[NH3:1].[CH2:45]([Cl:47])[Cl:46].[CH3:19][N:20]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: CNCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCc1ccccc1)Cc1ccc(OCCCN2CCCCC2)cc1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (208 mg), methyl-phenethyl-amine (113 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (300 mg). 1H NMR (400 MHz, CDCl3): 7.30–7.25 (m, 2H), 7.21–7.16 (m, 5H), 6.83 (d, J=8.6 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.49 (s, 2H),2.84–2.79 (m, 2H), 2.65–2.62 (m, 2H), 2.51–2.37 (m, 6H), 2.26 (s, 3H), 1.98 (m, 2H), 1.63–1.56 (m, 4H), 1.47–1.40 (m, 2H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:25][O-:26].[Na+].CO.Cl.[OH2:31]>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:6][CH2:5][C@@H:14]([CH3:13])[C:25]([OH:31])=[O:26])=[O:4])[N:6]=1)#[N:24]
Reactant: C[O-]
Reactant: O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H](CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 14 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-2-(R)-methyl-propionic acid, trifluoroacetic acid salt (32 mg, 0.32 mmol) was added 0.5 M NaOMe/MeOH solution (1.52 mL) (to bring the pH of the mixture to 8). The resultant mixture was microwaved at 130° C. for 1 h. Reaction mixture was diluted with water (80 mL) and acidified by 1 N HCl to pH=3-4. It was extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with 5-100% EtOAc/CH2Cl2, to provide the title compound 8.6 mg (0.022 mmol) in 14% yield. LC-MS ESI−: 390.12 (M−1)−.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:14][O:15][C@H:16]([CH3:29])[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6].Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]2[N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[Cl:46])[N:38]=[CH:39][C:32]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[N:37]1[C:33]2=[N:34][CH:35]=[N:36][C:31]([O:3][C@@H:4]([CH2:14][O:15][C@H:16]([CH3:29])[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:20]([CH3:21])[CH3:22])[CH:23]([CH3:25])[CH3:24])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[O:6])=[C:32]2[CH:39]=[N:38]1
Reactant: CC(C)[Si](OC[C@@H](C)OC[C@H](O)C(=O)Nc1ccccn1)(C(C)C)C(C)C
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccccn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
Sodium hydride (78 mg, 1.95 mmol) was added to (S)-2-hydroxy-N-(pyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AQ4) (387 mg, 0.98 mmol) in anhydrous THF (20 mL). The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (250 mg, 0.89 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane to afford the product (329 mg, 59.4%). 1H NMR (400 MHz, CDCl3) δ 1.01-1.15 (24H, m), 3.55-3.78 (3H, m), 4.19-4.35 (2H, m), 6.03 (1H, t), 7.05 (1H, t) 7.40-7.65 (4H, m), 7.7 (1H, t), 8.2-8.3 (2H, m), 8.43 (1H, s), 8.58 (1H, s), 8.75 (1H, s); m/z (ES+) M+=625.44; HPLC tR=4.02 min.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:24]1[C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1.ClC1C=C(O)C=NC=1>>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C@@H:11]1[CH2:21][O:22][C:24]1[C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1ncccc1O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using (2R,4S)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (PCT Int. Appl., WO2009026197) and ethyl 3-hydroxypicolinate instead of (R)-pyrrolidin-2-ylmethanol and 5-chloropyridin-3-ol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:33][C:32](=[O:34])[NH:31][N:30]=2)=[CH:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[O:24]1[CH:28]=[CH:27][C:26]([C:29]2[NH:30][N:31]=[C:32]([O:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:33]=2)=[CH:25]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1CC(c2ccoc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4ccoc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 0.44 mol), (prepared as described for the starting material in Example 2), and 3-(3-furyl)-4,5-dihydro-1H-pyrazol-5-one (80 mg, 0.53 mol) in DMF (2 ml) containing potassium carbonate (92 mg, 0.67 mol) was heated at 100° C. for 2.5 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5), followed by methanol/methylene chloride (1/9) to give 4-(5-(3-furyl)pyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (155 mg, 77%).
Reaction SMILES: [CH:1]1([C:4]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1C1CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N)cc1C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a solution of tert-butyl 2-cyclopropyl-4-nitrobenzoate (500 mg) obtained in Step B of Example 301 in ethanol (5.0 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature for 3 hr under hydrogen atmosphere (at normal pressures). The palladium-carbon was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (300 mg).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH3:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)=[O:12]>ClCCl>[CH:16]1[C:7]2[CH2:23][CH2:24][C:25]3[CH:26]=[CH:9][CH:10]=[CH:11][C:5]=3[CH2:4][N:3]([C:18]([C:17]3[CH:21]=[CH:22][C:14]([NH:13][C:11](=[O:12])[C:10]4[CH:23]=[CH:24][CH:25]=[CH:26][C:9]=4[CH3:8])=[CH:15][CH:16]=3)=[O:19])[C:6]=2[CH:22]=[CH:14][CH:15]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a mixture of 0.245 g (1 mmol) of 5,6,-12-tetrahydrodibenz[b,f]azocine hydrochloride and 30 μl (2.2 mmol) of triethylamine in 2 ml of dichloromethane is added a solution of 0.281 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 4 ml of dichloromethane. The mixture is stirred overnight at room temperature, washed with water 2N HCl (3×2 ml) and 1N sodium bicarbonate (3×2 ml). The organic layer is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with 3 volumes of CH2Cl2). The filtrate is concentrated to give 200 mg of a foam; Mass Spec.-FAB 447 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](Br)[C:25]#[CH:26]>CN(C=O)C>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:2][CH2:3]1)[C:25]#[CH:24]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1CCN(c2cccc3c2CCC(=O)N3)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 9 %

Procedure:
To a mixture of 1 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 30 ml of DMF and 900 mg of sodium carbonate was added 491 mg of propargyl bromide and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Then, chloroform was distilled off and the residue was purified through silica gel column chromatography and recrystallized from chloroform to give 0.1 g of 5-[4-(2-propynyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 225°-226° C., pale yellow powders.
Reaction SMILES: COC(C1C=CN2C=CN=C2C=1)=N.O.NN.N.C[C:19]([CH:21]=[O:22])=[O:20].C[C:24]1[CH:29]=[CH:28][N:27]=[N:26][N:25]=1>>[CH:19]([CH:21]=[O:22])=[O:20].[N:25]1[CH:24]=[CH:29][CH:28]=[N:27][N:26]=1
Reactant: CC(=O)C=O
Reactant: Cc1ccnnn1
Agent: COC(=N)c1ccn2ccnc2c1
Agent: N
Agent: NN
Solvent: O
Product: O=CC=O
Product: c1cnnnc1

Procedure:
In particular, heterocyclic halide or pseudo-halide precursors are commercially available or can be prepared from an appropriately functionalised heterocyclic compound. Alternatively the R2 rings can be formed on the imidazopyridine scaffold using intramolecular or radical cyclisation reactions under standard conditions. For example the imidazo[1,2-a]pyridine-7-carboximidic acid methyl ester or imidazo[1,2-a]pyridine-7-methyl ester are reacted with hydrazine hydrate to generate the hydrazide. Triazines can then be synthesized by reacting the hydrazide with the appropriate aldehyde in the presence or absence of ammonia (e.g. the carboxylic acid hydrazide, pyruvic aldehyde and ammonia to create methyltriazine or the carboximidic acid hydrazide and glyoxal to give triazine) or with the appropriate ketone (e.g. diacetyl to create dimethyltriazine). Alternatively the carboxylic acid hydrazide is reacted with triethyl orthoacetate to give methyloxadiazole, or an isothiocyanato group to give substituted thiadizole (e.g. isothiocyanatocyclopropane to give cyclopropyl-thiadiazol-2-yl-amine).
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1[Cl:30])C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][C:54]([C:56]3[CH:61]=[CH:60][C:59]([C:62]([CH3:65])([CH3:64])[CH3:63])=[CH:58][CH:57]=3)=[O:55])[CH2:47][CH2:46]2)=[CH:41][C:40]=1[F:66])C1C=CC=CC=1>>[ClH:30].[C:62]([C:59]1[CH:58]=[CH:57][C:56]([C:54](=[O:55])[CH2:53][CH2:52][CH2:51][N:48]2[CH2:47][CH2:46][N:45]([C:42]3[CH:43]=[CH:44][C:39]([OH:38])=[C:40]([F:66])[CH:41]=3)[CH2:50][CH2:49]2)=[CH:61][CH:60]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCN(c3ccc(OCc4ccccc4)c(F)c3)CC2)cc1
Reactant: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCN(c3ccc(O)c(F)c3)CC2)cc1
Product: Cl

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 4-[4-(4-benzyloxy-3-fluorophenyl)piperazin-1-yl]-1-(4-tert-butylphenyl)-1-butanone (274 mg), to provide 1-(4-tert-butylphenyl)-4-[4-(3-fluoro-4-hydroxyphenyl)piperazin-1-yl]-1-butanone hydrochloride (191 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[H-].[Na+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CN(C=O)C>[C:17]([O:20][CH2:21][CH2:22][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)(=[O:19])[CH3:18]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 20 mL pressure vial was charged pyrazole-4-boronic acid pinacol ester (5.15 mmol, 1.00 g) and DMF (10 mL). NaH (60% w/w in mineral oil, 5.67 mmol, 227 mg) was then added portion-wise. The resulting solution was stirred at room temperature for 10 minutes. 2-bromoethyl acetate (5.67 mmol, 623 μL) was then added dropwise. The vial was flushed with argon, sealed, and the reaction was stirred at 60° C. for 18 hours. At 18 hours, the DMF was removed in vacuo, and the residue taken up in DCM. This suspension was filtered through celite and then purified via flash chromatography to yield the title compound.