Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.Cl.N1C=CC=CC=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>>[Br:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH:37][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Nc1cccc(Br)c1
Yield: 61.9 %

Procedure:
A solution of 400 mg (1.38 mmol) of 4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 8 mL of 2-ethoxyethanol containing 160 mg (1.38 mmol) of pyridine hydrochloride and 0.180 mL (1.65 mmol) of 3-bromoaniline is heated at reflux for 4 hours. The reaction mixture is filtered hot and the solid is stirred with methanol and ammonium hydroxide. The mixture is poured into water and the solid is collected, washing with ethyl acetate to give 363 mg (62%) of 4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile as a brown solid, mp>300° C.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.C1COCC1.[OH-].[Na+].Cl>CO>[F:1][C:2]1([F:17])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC[C@H]2CC2(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OC[C@H]2CC2(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of methyl 4-(((1R)-2,2-difluorocyclopropyl)methoxy)benzoate (637 mg), THF (10 mL), methanol (10 mL) and 1M aqueous sodium hydroxide solution (10 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (559 mg).
Reaction SMILES: [O:1]([CH:8]=[CH:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[N:15][N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:12]2[CH2:13][CH2:14][N:10]([CH:9]=[CH:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:22][N:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(C=COc2ccccc2)CCN1Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A mixture comprising 2.8 g of 1-(2-phenoxyvinyl)2-nitroiminoimidazolidine, 3.6 g of 2-chloro-5chloromethylpyridine, 3.2 g of potassium carbonate and 15 ml of dimethylsulfoxide was stirred at 70° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluet: ethyl acetate) to give 3.0 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-phenoxyvinyl)-imidazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:10][O:11][CH3:12])[C:8]=1[OH:9])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[C:7]([CH2:10][O:11][CH3:12])[C:8]=1[OH:9]
Reactant: COCc1cc(N)cc(Cl)c1O
Reactant: CC(C)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
3-Chloro-4-hydroxy-5-methoxymethylaniline (52.8 g) and N,N-diethylaniline (42.0 g) were dissolved in ethyl acetate (300 ml). To the resultant solution was dropwise added isopropyl chloroformate (34.6 g) in 15 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water. The organic layer was washed with dilute aqueous hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using tolouene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g). Sodium hydride (9.60 g, 60% dispersion in mineral oil) was added to dimethylformamide (240 ml). To the resultant mixture was added isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g) under 5° C. The resulting solution was stirred for 30 minutes at a temperature of 20° C. and, to this solution was added chloroacetonitrile (19.0 g) in 5 minutes. The mixture was heated at 90° C. for 10 minutes and poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-cyanomethoxy- 5-methoxymethylphenyl)carbamate (67.5 g) in a yield of 76.8%. M.P., 58.5°-60.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>N1C=CC=CC=1>[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:1]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([CH3:22])[CH:24]=1)[C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:27]
Reactant: N#Cc1c(N)nc2ccccc2c1NCc1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)N(C(=O)c2cccc(C)c2)c2nc3ccccc3c(NCc3ccccc3)c2C#N)c1
Temperature: 0 °C

Procedure:
To the solution of 5 g of 2-amino-3-cyano-4-benzylaminoquinoline in 30 ml of pyridine 6 ml of 3-methylbenzoyl chloride are dropped, under stirring at 0° C. The reaction mixture is stirred at 80° C. for 8 hour, then it is poured onto 150 ml of ice-water. The precipitate is filtered off, washed twice with 40 ml of water. The resulting white crystalline material is recrystallized from 200 ml of ethanol to give 9.2 g of the title compound, mp.: 234° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]3[C:22]([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:41])NC(C)(C)CO)[CH:31]=[CH:30][C:29]=4[F:42])=[O:26])=[CH:23][N:24]=[C:18]3[CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12].[OH-:43].[Na+].Cl>COCCOC.O>[F:42][C:29]1[CH:30]=[CH:31][C:32]([C:34]([OH:43])=[O:41])=[CH:33][C:28]=1[NH:27][C:25]([C:22]1[N:19]2[CH:20]=[CH:21][C:16]([C:4]3[CH:5]=[CH:6][C:7]([C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[C:2]([F:1])[CH:3]=3)=[CH:17][C:18]2=[N:24][CH:23]=1)=[O:26]
Reactant: [OH-]
Reactant: CC(C)(CO)NC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)NC(C)(C)CO)c(F)c4)ccn23)c1
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(CO)NC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)O)ccc4F)cnc3c2)cc1F
Temperature: 60 °C

Procedure:
7-(3-Fluoro-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)phenyl)-N-(2-fluoro-5-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (step 1) (590 mg, 1.129 mmol) in 1,2-dimethoxyethane (10 ml) and water (10.00 ml) was treated with sodium hydroxide (181 mg, 4.52 mmol) and warmed to 60° C. for 1 hr. After cooling to RT, the pH of the mixture was adjusted to pH5 using 2M HCl (2.2 ml). The solvent was removed in vacuo and the resulting crude product was triturated with water to afford the title compound;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:3]1.O.NN.C(N(CC)CC)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[S:42](Cl)(=[O:44])=[O:43]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][NH:11][S:42]([C:33]2[CH:34]=[CH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:32]=2)(=[O:44])=[O:43])[CH2:3]1
Reactant: CN1CCCC(CCCN2C(=O)c3ccccc3C2=O)C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CN1CCCC(CCCNS(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a stirred solution of the product of step c (437 mg, 1.53 mmol) in ethanol (10 ml) was added hydrazine hydrate (0.37 ml) and the reaction heated at reflux for 1.5 h. The resultant suspension was filtered, the filter-cake was washed with further ethanol (20 ml) and the filtrate was evaporated. The residue was suspended in DCM (20 ml) and the solid was removed by filtration. The filtrate was evaporated at reduced pressure and the residue was dissolved in DCM (5 ml). The solution was treated sequentially, with ice-cooling, with triethylamine (0.290 ml, 2.08 mmol) and 2-naphthalenesulfonyl chloride (217 mg, 1.39 mmol). The coolant was removed and the reaction mixture stirred at ambient temperature for 2 h. The reaction was diluted with DCM (20 ml), washed with water (20 ml) and brine (20 ml), and dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure and the residue was purified by flash column chromatography (90:10:1 DCM:methanol:ammonia) to afford the title compound (240 mg, 45%). 1H NMR 8.44 (1H, d, 1.2), 7.99-7.59 (6H, m), 2.98 (2H, t, 6.9), 2.76-2.69 (2H, m), 2.24 (3H, s), 1.87-1.84 (3H, m), 1.64-1.46 (5H, m), 1.21-1.13 (2H, m), 0.75 (1H, m). Microanalysis found C 64.32 H 7.75 N 7.59. C19H26N2O2S-0.5H2O requires C 64.19 H 7.76 N 7.88.
Reaction SMILES: [CH3:1][O:2][P:3]([CH:7]([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)([O:5][CH3:6])=[O:4].C(OC(=O)[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][C:26]=1[NH2:36])(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:6][O:5][P:3]([CH:7]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:14])[NH:36][C:26]2[CH:27]=[C:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH:29]=[CH:30][C:25]=2[NH2:24])=[CH:15][CH:16]=1)[F:17])(=[O:4])[O:2][CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COP(=O)(OC)C(F)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(F)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[(Dimethoxy-phosphoryl)-fluoro-methyl]-benzoic acid (52 mg, 0.198 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (69 mg, 0.238 mmol), EDC (57 mg, 0.298 mmol), HOBT (36 mg, 0.238 mmol), and DIPEA (77 mg, 0.595 mmol) were combined and diluted with DMF (0.79 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were combined and concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature. After 2 hours the deprotection was complete and the mixture was concentrated in vacuo to give the title compound: 1H NMR (DMSO-d6, 600 MHz) δ 9.87 (br-s, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.48 (s, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.24-7.27 (m, 1H), 7.04 (dd, J=3.6 Hz, J=5.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.33 (dd, J=8.4 Hz, J=43.8 Hz, 1H), 3.64-3.71 (m, 6H). MS: cal'd 435 (MH+), exp 435 (MH+)
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:10][N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>O1CCCC1>[CH3:10][N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:8](=[O:9])[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CN(C)CCCCCCO
Reactant: CCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCNC(=O)OCCCCCCN(C)C

Procedure:
0.65 ml (5 meq) of hexyl isocyanate and 726 mg (5 meq) 6-(dimethylamino)hexanol are combined in 5 ml of tetrahydrofuran and reacted over a weekend at room temperature. The reaction mixture is evaporated under reduced pressure (<30° C.), dried in vacuo and the product purified by silica gel chromatography in the system CH2Cl2 :CH3OH:NH3 (65:25:4). Fractions 50-64 are combined, evaporated under reduced pressure <30° C. and dried in vacuo to yield 460 mg of title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].Cl[C:23]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][N:24]=1>C1COCC1>[Cl:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21])[N:28]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.5M (in cyclohexane) lithium diisopropylamide (mono THF) (9.06 mmol, 6.04 mL) in THF (15 mL) at 0° C. was added tri-n-butyltin hydride (2.34 g, 8.05 mmol) in THF (2 mL) dropwise. The reaction mixture was stirred at 0° C. for 15 minutes, then cooled to −78° C. To this solution was added 2,4-dichloropyrimidine (1 g, 6.71 mmol) in THF (7 mL) dropwise. The reaction mixture was stirred at −78° C. for 3 h, then warmed to 0° C. over 30 min. The reaction was quenched with saturated aqueous ammonium chloride (12 mL) at 0° C., then warmed to room temperature and extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (hexanes/DCM eluent) provided the product. LCMS-ESI+ calc'd for C16H30ClN2Sn (M+H+): 405.1; Found: 405.1 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=5.4, 1.3 Hz, 1H), 7.16 (dd, J=5.4, 1.2 Hz, 1H), 1.67-1.49 (m, 6H), 1.38-1.27 (m, 6H), 1.26-1.10 (m, 6H), 0.88 (td, J=7.5, 1.3 Hz, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15].CN(C)[CH:22]=[O:23]>>[CH:17]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH:22]=[O:23])[CH:3]=1)[N:10]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])([CH3:19])[CH3:18]
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Reactant: CN(C)C=O
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21

Procedure:
Following General Procedure B, 8-bromo-6-isopropyl-4,4-dimethyl-1-n-propyl-1,2,3,4-tetrahydro-quinoline (Intermediate 6, 5.64 g, 19.6 mmol) and N,N-dimethylformamide (6.0 g, 78.5 mmol) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1)#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:60]2[CH:59]=[CH:58][C:57]([C:55]#[N:56])=[CH:62][CH:61]=2)(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 22 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-cyanobenzenesulfonyl chloride as starting materials in 22% yield. LCMS for C31H30ClN8O3S (M+H)+: m/z=629.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][C:4]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2cc(C3CNC(=O)C3)ccc2OC)c1
Temperature: 90 °C
Yield: 62.9 %

Procedure:
A solution is prepared from 339 mg of 4-(4-methoxy-3-trifluoromethanesulfonyloxyphenyl)-pyrrolidin-2-one in 9 ml of toluene and 4 ml of ethanol and stirred for 5 minutes under argon at room temperature with 38 mg of tetrakis(triphenylphosphine) palladium(0). After addition of 172 mg of m-methoxyphenylboronic acid and 1.3 ml of 2-molar sodium carbonate solution, the mixture is heated to 90° C. for 4 hours. After adding ethyl acetate and water, the organic phase is separated, washed neutral with saturated sodium chloride solution, dried over sodium sulfate, and concentrated. Recrystallization from alcohol/ethyl acetate/petroleum ether (40°-60° C.) yields 187 mg of compound having a melting point of 137°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][CH:10]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].[I:16]I>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[I:16])[CH:7]=1
Reactant: Clc1ccc2cncn2c1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(I)ncn2c1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of 6-chloroimidazo[1,5-a]pyridine (417 mg, 2.73 mmol) in EtOH (5 mL) and water (2.4 mL) was added sodium bicarbonate (861 mg, 10.2 mmol) and iodine (832 mg, 3.28 mmol) and the mixture stirred at room temperature under N2. After 16 h the reaction mixture was quenched with sodium thiosulfate, then extracted into ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated. Purification of the filtrate by chromatography (silica, 20-60% ethyl acetate/hexanes) gave 6-chloro-1-iodoimidazo[1,5-a]pyridine (271 mg, 973 μmol, 36%) as a brown solid. MS (M+H)+=278.8; 1H NMR (CDCl3) δ: 8.10 (s, 1H), 8.0 (m, 1H), 7.30 (d, J=9.5 Hz, 1H), 6.76 (9.5 m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
To a solution of 5-fluoro-2-nitrophenol (8.05 g, 51.2 mmol) in acetone (100 mL) were added benzyl bromide (8.90 g, 52.0 mmol), potassium carbonate (11.0 g, 79.3 mmol) and sodium iodide (1.51 g, 10.1 mmol) at room temperature, and the mixture was heated under reflux for 2.5 hr. The reaction mixture was cooled to room temperature, the inorganic salt was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate (150 mL), and the mixture was washed with water (150 mL×2) and saturated brine (100 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (13.2 g) as a brown oil.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](C3CCNCC3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrCCCO.C(#N)C>O>[O:8]1[C:4]2[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=2[CH:6]=[N:7]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: c1ccc2oncc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140-142° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[C:10]1([CH2:16][CH2:17][CH2:18]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCCCc1ccccc1)OCC
Yield: 27.3 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 3-phenylpropyl bromide (3.02 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform only) to obtain the title compound (1.37 g, 27%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:30][CH2:28][CH3:29])=[O:24])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Reactant: CCN
Product: CCNC(=O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Yield: 3 %

Procedure:
3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (35 mg) was coupled with ethylamine as in General Procedure 8 to give the title compound as a yellow solid (3% yield). LCMS: m/z=387.26 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.27 (3H, t, J=7.2 Hz), 3.47 (2H, quartet, J=7.2 Hz), 4.50 (2H, s), 5.28 (2H, s), 7.36 (8H, m), 7.48 (1H, t, J=7.6 Hz), 7.79 (2H, m), 7.84 (1H, s).