Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C#N)(CC)=O)C.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](=[O:26])[NH:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: CCP(=O)(C#N)CC
Product: COCCNC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Yield: 48.8 %

Procedure:
As described in example 1E, 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (80 mg, 0.22 mmol), diethylphosphoryl cyanide (54 mg, 0.33 mmol), and 2-methoxy ethylamine (25 mg, 0.33 mmol) were reacted to give [6,7-dimethoxy-4-(2-methoxy-ethylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (45 mg, 49%): 1H NMR (CDCl3) δ 1.50 (s, 9H), 3.41 (s, 3H), 3.62-3.64 (m, 2H), 3.72-3.76 (m, 2H), 4.03 (s, 6H), 4.89 (d, 2H), 6.19 (s, 1H), 6.47 (s, 1H), 7.34 (s, 1H), 7.85 (s, 1H), 8.47 (s, 1H); MS (APCI) m/z 419.9 [M+1]+.
Reaction SMILES: COCCN(S(F)(F)F)CCOC.[C:14]([N:17]1[CH2:21][CH2:20][CH:19](O)[CH:18]1[C:23]1[C:24]([O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)=[CH:25][C:26]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[NH:28][C:27]=2[CH:37]=1)(=[O:16])[CH3:15]>C(Cl)(Cl)Cl>[C:14]([N:17]1[CH2:21][CH2:20][CH:19]=[C:18]1[C:23]1[C:24]([O:38][C:39]2[CH:40]=[CH:41][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[CH:43][CH:44]=2)=[CH:25][C:26]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[NH:28][C:27]=2[CH:37]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCC(O)C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC=C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 mg of bis(2-methoxyethyl)aminosulfur trifluoride was added to a chloroform (1 ml) solution of 2 mg of 1-acetyl-2-(5-(4-(methanesulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-6-yl)pyrrolidin-3-ol diastereomer A obtained in Example 469, and the reaction liquid was stirred at room temperature for 15 minutes. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=15/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.[CH3:21]I>COCCOC>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH:16]([CH3:21])[C:17]#[N:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C#N)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (12.2 g. of 50% w/w Nah in mineral oil) in 1,2-dimethoxyethane is added 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile (62.6 g., 0.24 mole) in 1,2-dimethoxyethane over a period of 1/2 hr. at room temperature. After the addition is complete, the mixture is stirred for 1 hour and then 35 g. (0.25 mole) of methyl iodide is added. The reaction mixture is stirred for an additional 3 hrs., concentrated under reduced pressure, diluted with water and extracted with chloroform. After drying, the chloroform is removed leaving a brown solid residue which is triturated with cold methanol to give yellow crystals of 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetonitrile, m.p. 145°-148°C. Two recrystallizations from methanol raises the m.p. to 151.5°-152.5°C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[N:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[C:35]([C:40]4[CH:61]=[CH:60][C:43]6[NH:44][C:45]([C@@H:47]7[CH2:52][C@@H:51]8[C@@H:49]([CH2:50]8)[N:48]7C(OC(C)(C)C)=O)=[N:46][C:42]=6[CH:41]=4)[CH:34]=[CH:33]5)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[CH:61]=[CH:60][C:43]7[N:44]=[C:45]([C@@H:47]8[CH2:52][C@@H:51]9[C@@H:49]([CH2:50]9)[NH:48]8)[NH:46][C:42]=7[CH:41]=6)[N:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(-c3ccc4nc(-c5ccc6nc([C@@H]7C[C@H]8C[C@H]8N7C(=O)OC(C)(C)C)[nH]c6c5)ccc4n3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2cc1-c1ccc2nc(-c3ccc4nc([C@@H]5C[C@H]6C[C@H]6N5)[nH]c4c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
TFA (0.25 mL, 3.2 mmol) was added to a solution of tert-butyl (1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-b enzimidazol-6-yl)-1,5-naphthyridin-2-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (20 mg, 0.028 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatile were removed under vacuum and the residue was triturated with Et2O. The resulting solid was collected via filtration and rinsed with Et2O to yield a TFA salt of 2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridine (26 mg, 0.022 mmol, 78% yield) as a yellow solid. LC-MS retention time 1.41 min; m/z 525 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 8.61 (2H, d, J=8.8 Hz), 8.51 (2H, s), 8.40 (2H, d, J=9.0 Hz), 8.23 (2H, dd, J=8.5, 1.5 Hz), 7.81 (2H, d, J=8.5 Hz), 4.74-4.97 (2H, m), 3.47-3.57 (2H, m), 2.78-2.88 (2H, m), 2.52-2.65 (2H, m), 2.04-2.15 (2H, m), 1.22-1.33 (2H, m), 0.99-1.11 (2H, m).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:20])[C:14]=1[C:15](OCC)=[O:16])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:20])[C:14]=1[CH2:15][OH:16])[CH3:8]
Reactant: CCOC(=O)c1c(F)cncc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(F)c1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a 0° C. mixture of lithium aluminum hydride (760 mg, 10.1 mmol) in anhydrous THF (60 mL) was slowly added a solution of ethyl 3-ethyl-5-fluoropyridine-4-carboxylate (2.00 g, 10.1 mmol) in anhydrous THF (25 mL). The reaction mixture was stirred at 0° C. for 2 hours. The reaction was quenched with 5N NaOH. Water (100 mL) and EtOAc (100 mL) were added. The mixture was stirred for 30 minutes. The solid material was removed by filtration. The organic layer was recovered. The aqueous layer was extracted with EtOAc (1×100 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated and dried in vacuo, affording (3-ethyl-5-fluoropyridin-4-yl)methanol (1.5 g, 95% yield). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[C:25]=3[F:33])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:55][CH2:56][C:57]1([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH2:62][CH2:61][N:60]([CH2:63][CH2:64][OH:65])[CH2:59][CH2:58]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.O>[F:33][C:25]1[C:26]([C:30](=[O:31])[NH:55][CH2:56][C:57]2([C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH2:58][CH2:59][N:60]([CH2:63][CH2:64][OH:65])[CH2:61][CH2:62]2)=[N:27][CH:28]=[CH:29][C:24]=1[S:23][C:20]1[S:19][C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:12][CH:13]=2)=[N:22][CH:21]=1
Reactant: NCC1(c2ccccc2)CCN(CCO)CC1
Reactant: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(CCO)CC4)c3F)s2)nc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
4-(2-(5-((Tert-butoxycarbonyl(methyl)amino)methyl)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinic acid (0.120 g, 0.244 mmol) was diluted in NMP (4 mL) and treated with HOBT (0.043 g, 0.317 mmol), EDAC (0.094 g, 0.488 mmol) and 2-(4-(aminomethyl)-4-phenylpiperidin-1-yl)ethanol (0.074 g, 0.317 mmol) and diisopropylethylamine (0.213 mL, 1.22 mmol) at 23° C. The reaction was stirred overnight then water was added and this was extracted with ethyl acetate/THF (3×). The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give a residue which was purified on preparative HPLC (acetonitrile/water/TFA). The title material was obtained (0.140 g, ˜81%) as a solid which was used as such for the next step. LC/MS (M+H)+: 708. Ret. time: 1.612 min. (Condition F).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:26][OH:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
To a solution of 3.38 g of N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide and 0.934 g of hydroxylamine hydrochloride in 20 ml of ethanol, 1.10 g of sodium acetate was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 40 ml of water and extracted with ethyl acetate (20 ml×2), the resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 4:6) as the eluent to obtain 1.90 g of the desired product as white crystals.
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11](N3CCCC3)=[O:12])[CH2:10][C:5]=2[NH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]2[N:26]([CH:27]=1)[CH:25]=[CH:24][CH:23]=[CH:22]2.P(Cl)(Cl)(Cl)=O.O>ClCCCl>[CH3:18][C:19]1[CH:20]=[C:21]2[N:26]([C:27]=1[C:11]([CH:9]1[CH2:8][CH2:7][C:6]3[N:2]=[CH:3][NH:4][C:5]=3[CH2:10]1)=[O:12])[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: Cc1cc2ccccn2c1
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: Cc1cc2ccccn2c1C(=O)C1CCc2nc[nH]c2C1
Temperature: 85 °C
Yield: 38.5 %

Procedure:
To a solution of 0.50 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride and 0.39 g of 2-methylindolizine in 5 ml of 1,2-dichloroethane was added dropwise 0.90 g of phosphorus oxychloride. The reaction mixture was refluxed at 85° C. for one night. After cooling to room temperature, 5 ml of water was added thereto. The organic layer was removed, and 10 ml of chloroform was added to the aqueous layer. The solution was adjusted to a pH of 9 with a 20% aqueous solution of sodium hydroxide and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography using chloroform/methanol as an eluent, followed by recrystallization from ethanol to obtain 0.21 g of 5-[(2-methylindolizin-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)[CH3:3].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.C(Cl)(Cl)Cl.O>[F:10][C:7]1[N:8]=[CH:9][C:4]([CH:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH3:3])=[CH:5][CH:6]=1
Reactant: CC(Br)c1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of 5-(1-bromoethyl)-2-fluoropyridine (17.65 g, 87 mmol) and tert-butyl piperazine-1-carboxylate (16.92 g, 91 mmol) in acetonitrile (300 mL). was treated with potassium carbonate (14.35 g, 104 mmol) and potassium iodide (2.87 g, 17.30 mmol). The mixture was placed into a pre-heated (70° C.) bath and allowed to stir under inert atmosphere overnight. The reaction mixture was diluted with chloroform (200 mL) and water (100 mL). The organic layer was extracted with chloroform (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (330 g) eluting with 50% ethyl acetate/hexanes to give tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (17.27 g, 55.8 mmol, 64.5% yield) as a yellow oil. m/z (ESI, +ve ion) 310.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.C[O:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)=[O:11].[NH2:21][C:22]1[CH:23]=[C:24]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1)=[O:26]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:21][C:22]2[CH:23]=[C:24]([CH:37]=[CH:38][C:39]=2[CH3:40])[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=2)=[O:26])=[O:17])=[CH:14][CH:13]=1)([OH:9])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(C(=O)O)cc1

Procedure:
Triethylamine (0.26 ml) was added to a stirred mixture of 4-methoxycarbonylbenzoyl chloride (0.221 g), 4-dimethylaminopyridine (0.01 g), 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.2 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with methylene chloride and washed with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulphate and evaporated. The residue was triturated under isohexane. The resultant solid was isolated and dried under vacuum at 55° C. to give the required starting material as a solid (0.286 g); NMR Spectrum: (CDCl3) 2.4 (s, 3H), 2.98 (s, 6H), 3.98 (s, 3H), 6.54 (m, 1H), 6.92 (d, 1H), 7.2 (m, 3H), 7.35 (d, 1H), 7.71 (d, 1H), 7.92 (s, 1H), 7.98 (d, 2H), 8.18 (d, 2H), 8.35 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[CH3:34])[CH3:6])=[O:4].[CH3:35][O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48](O)=[O:49])=[CH:42][CH:41]=1)=[O:38]>>[CH3:26][O:25][C:22]1[N:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:14][C:9]3[C:8]([CH3:34])=[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:48](=[O:49])[CH2:47][CH2:46][C:43]4[CH:42]=[CH:41][C:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])=[N:45][CH:44]=4)[CH:12]=[CH:11][C:10]=3[CH3:13])[C:24]=2[N:23]=1
Reactant: COc1nc2c(OCc3c(C)ccc(N(C)C(=O)CN)c3C)cccc2n1Cc1ccccn1
Reactant: COC(=O)Nc1ccc(CCC(=O)O)cn1
Product: COC(=O)Nc1ccc(CCC(=O)NCC(=O)N(C)c2ccc(C)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2C)cn1

Procedure:
2-amino-N-(3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)-2,4-dimethylphenyl)-N-methylacetamide and 3-(6-((methoxycarbonyl)amino)pyridin-3-yl)propanoic acid were used to prepare 4 using the method described for 1. LCMS (+APCI) 666 (M+). 1H-NMR (CDCl3, δ ppm): 1H-NMR (CDCl3, δ ppm): 8.58 (m, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.55 (m, 3H), 7.20 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.03 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.81 (m, 2H), 6.43 (bt, J=4.0 Hz, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 4.20 (s, 3H), 3.79 (s, 3H), 3.69 (dd, J=4.4, 18.0 Hz, 1H), 3.47 (dd, J=4.0, 18.0 Hz, 1H), 3.21 (s, 3H), 2.88 (t, J=7.6 Hz, 2H), 2.49 (s, 3H), 2.47 (m, 2H), 2.31 (s, 3H). Calcd. for C36H39N7O6+0.8H2O: C, 63.57; H, 6.02; N, 14.42. Found: C, 63.64; H, 5.93; N, 14.53.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([CH2:26][N:27]3[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][N:29]=[CH:28]3)=[CH:24][C:23]=2[O:38][CH3:39])=[C:4]([CH3:40])[N:3]=1.[NH2:41][C@@H:42]([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][OH:45]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:41][C@@H:42]([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][OH:45])[C:5]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([CH2:26][N:27]3[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][N:29]=[CH:28]3)=[CH:24][C:23]=2[O:38][CH3:39])=[C:4]([CH3:40])[N:3]=1
Reactant: CCC[C@H](N)CCO
Reactant: COC(=O)c1cncn1Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(Cn2cncc2C(=O)OC)cc1OC
Yield: 69 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (i) (90 mg) and (s)-3-aminohexan-1-ol (56 mg). The sub-title compound (53 mg) was obtained as a colourless oil; LC-MS: m/z 483.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:20]1CCOC[CH2:21]1.O=C(Cl)OC(Cl)(Cl)Cl>O>[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:21](=[O:20])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:16][CH2:15]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCN(c2ccc(N)c(C(=O)O)c2)CC1
Reactant: C1COCCO1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)N1CCN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC1

Procedure:
To the mixture of 18 g 2-amino-5-(4-acetylpiperazin-1-yl)benzoic acid and 60 ml dioxane, 10 ml diphosgene is added dropwise under stirring and cold water cooling. The mixture is then heated at reflux temperature for 2 hours. After cooling the solid material is filtered off, washed with 50 ml ether and dried. 24 g of the title compound is obtained (MH+: 290).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][C:14]([CH3:16])=O.N1CCCC1.C1(C)C=CC=CC=1>O>[CH3:13][C:14]1([CH3:16])[CH2:2][C:1](=[O:3])[C:4]2[C:11](=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=2)[O:12]1
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: CC(C)=O
Solvent: O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(C#N)ccc2O1
Reaction time: 1 h

Procedure:
A mixture of 81 g of 3-acetyl-4-hydroxybenzonitrile, 48 ml of acetone, 11.8 ml of pyrrolidine and 300 ml of toluene is allowed to stand at 200 for 1 hour, then boiled for 2 hours in a water separator and cooled. After customary working up, 2,2-dimethyl-6-cyano-4-chromanone is obtained, m.p. 119-120°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:2].[H][H]>[Pd].C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)C(C)Oc1cccc(C=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1cccc(CO)c1
Yield: 62.3 %

Procedure:
Into 100 ml of ethyl acetate was dissolved 5.09 g of methyl 2-(3-formylphenoxy)propionate; 0.57 g of 10% palladium on carbon was added; the mixture was stirred for 30 minutes in a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered; the filtrate was concentrated and the residue was subjected to silica gel column chromatography to give 3.20 g of methyl 2-[3-(hydroxymethyl)phenoxy]propionate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16]>>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]([NH:13][C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)C(C)C
Product: COC(=O)[C@H](NC(=O)c1ccc2c(c1)OCO2)C(C)C
Yield: 50 %

Procedure:
Prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and (R)-methyl 2-amino-3-methylbutanoate. Yield: 50%. MS (M+H, 280.1).
Reaction SMILES: [CH2:1](N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1.ClC(OC)=O>ClCCl>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:1])=[O:14])=[CH:11][N:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (28.4 g) was added to a solution of 6-chloronicotinic acid (40 g) in dry dichloromethane (900 ml). The mixture was cooled in an ice bath and methyl chloroformate (26.8 g) was added dropwise. The mixture was stirred at room temperature overnight, washed in turn with water, aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give methyl 6-chloronicotinate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([S:15][C:2]2[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Sc1ccccc1
Product: Brc1cnc(Sc2ccccc2)nc1

Procedure:
The title compound was prepared from 2-chloro-5-bromo-pyrimidine and thiophenol as described in Example 1; yield: 90% of a non-crystalline product which was pure enough for the successive oxidation. MS m/e: 267 (M, 100%). 1H NMR (CDCl3): δ7.4 (Ph), 8.50 (H-4, H-6).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O.C(OCC)C>CC(C)=O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:7]=[C:2]3[N:1]([CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:13][CH:14]=1
Reactant: Cc1ccccn1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1ccc(-c2cc3ccccn3c2)cc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 74.2 %

Procedure:
To a stirred solution of 2-picoline (5.12 g) in acetone (10 ml) was added 2-bromo-4'-methylacetophenone (10.4 g) in one portion and the mixture was heated at 80° C. for one hour. After addition of diethyl ether, the crystalline product was collected and washed with diethyl ether. After drying in air for several hours, this product was suspended in water (100 ml) and a solution of sodium bicarbonate (21 g) in water (100 ml) was added dropwise to the suspension. The mixture was stirred at ambient temperature for 45 minutes and refluxed for half an hour. The mixture was diluted with methylene chloride and washed with aqueous saturated sodium chloride. The organic layer was separated, dried over potassium carbonate and filtered. The solvent was removed in vacuo and the resulting solid was recrystallized from benzene to give 2-(4-methylphenyl)indolizine (7.51 g).