Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH:18]=3)[N:13]=[C:12]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>C(Cl)Cl>[CH3:37][S:38]([O:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a suspension of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol (0.25 g, 0.61 mmol) and triethylamine (0.17 ml, 1.22 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (0.057 ml, 0.73 mmol). The mixture was stirred at room temperature for 1 h. Water (10 mL.) was added to the mixture and stirred for a while. The resultant precipitate was collected by filtration and washed with CH2Cl2 and dried to give 0.27 g of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate as pale yellow solid (91%), which was used without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1[NH:11][C:12](=O)C(Cl)Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:22].[K+]>C(O)C.O>[NH2:22][C:12]1[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([OH:8])[C:9]2[C:10](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=1
Reactant: O=C(c1ccccc1)c1ccccc1NC(=O)C(Cl)Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
2'-Benzoyl-2,2-dichloroacetanilide (50 g.) was suspended in 91% ethanol (750 ml) and treated with a solution of potassium cyanide (30 g) in water (50 ml). The reaction was stirred at room temperature for 40 hours. The crystalline precipitate was filtered off and the mother liquors diluted with water to provide further crops of 2-amino-3-phenyl-3H-indol-3-ol. Total 37 g. The product could be recrystallized from acetonitrile or aqueous dimethylformamide and had a m.p. of 204°-6°C (decomp).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% oil dispersion) (8.86 g) in tetrahydrofuran (170 mL) was added a solution of EXAMPLE 441B (30.52 g) in tetrahydrofuran (100 mL). The mixture was stirred for 30 minutes and benzyl bromide (24 mL) was added. After stirring for 72 hours, the reaction was quenched with saturated ammonium chloride solution (400 mL) and diluted with ether (500 mL). The layers were separated and the aqueous layer was extracted with ether (2×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel eluting with a 0, 10, 15, 75% ethyl acetate in hexanes step gradient to give the title compound.
Reaction SMILES: BrCC1C=CC(C(O)=O)=CC=1.Cl.CNOC.[CH:17]1([CH2:20][C:21]([OH:23])=O)[CH2:19][CH2:18]1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>>[CH:17]1([CH2:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:19]1
Reactant: O=C(O)CC1CC1
Reactant: OCC1CCNCC1
Agent: CNOC
Agent: Cl
Agent: O=C(O)c1ccc(CBr)cc1
Product: O=C(CC1CC1)N1CCC(CO)CC1
Yield: 73 %

Procedure:
Instead of 4-(bromomethyl)benzoic acid and N,O-dimethylhydroxylamine hydrochloride, cyclopropylacetic acid (869 mg) and 4-piperidinemethanol (1.00 g) were respectively used and treated by the same technique as in Reference Example 16-1(1) to give the titled compound as a colorless oil (1.25 g).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].C(Cl)(Cl)Cl>O>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH2:22][CH3:23]
Reactant: CCCNCCC
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)c1c(-c2c(F)cc(F)cc2F)c(Cl)nc2nccn12
Temperature: 80 °C
Yield: 83.1 %

Procedure:
A mixture of 0.095 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine and 0.12 g of di-n-propylamine was heated at 80° C. for one hour. The reaction mixture was allowed to cool, and chloroform and water were added thereto. The separated organic layer was dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.095 g of 5-(di-n-propylamino)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[Na][Na].[H-].[Na+].CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31])(=O)=O>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]([O:7][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]/[CH:23]=[CH:22]\[CH2:21][CH2:20][CH2:19][CH3:18])[CH2:5][O:6][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31])[CH3:8]
Reactant: CCCC/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Agent: [H-]
Agent: [Na+]
Agent: [Na][Na]
Solvent: C1CCOC1
Product: CCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCC

Procedure:
Racemic 1-dimethylamino-2,3-propanediol (0.96 g; Janssen Chimica) was converted to the disodium salt in situ by treatment with sodium hydride (60% in oil, 0.8 g) in tetrahydrofuran (70 mL). Condensation with myristoleyl methane sulfonate (5.3 g; NuChek Prep) afforded crude (±)-N,N-dimethyl-(2,3-bis(myristoleyloxy))propylamine (DMOP-DMA). This material was purified to homogeneity by silica gel chromatography employing a step gradient of ether in hexane (from 10% to 50%), and finally neat ether, as the eluents. DMOP-DMA (2.4 g) was then treated with N-(3-bromopropyl)phthalimide (2.5 g) in dimethylformamide (15 mL) at elevated temperature (85° C., overnight) to effect quaternization of the amine. Removal of the dimethylformamide in vacuo followed by silica gel chromatography using a step gradient of methanol/chloroform as the eluent afforded TLC homogenous material. Deprotection of the primary amine was accomplished by treatment of the phthalimide (2.1 g) with anhydrous hydrazine (1.7 mL) in anhydrous ethanol (40 mL) and propargyl alcohol (10 eq.). Filtration, evaporative removal of the solvent, basic extraction (0.1 M NaOH), alumina chromatography, and washing with 1 M NaBr afforded the pure product.
Reaction SMILES: [OH:1][C:2]1[C:20]([OH:21])=[CH:19][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:22]1[O:24][CH2:23]1.[ClH:25]>CC(C)=O.C(OCC)(=O)C.C(O)C>[ClH:25].[OH:1][C:2]1[C:20]([OH:21])=[CH:19][C:5]2[CH:6]([C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=3)[CH2:7][N:8]([CH2:22][CH2:23][OH:24])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CSc1ccc(C2CNCCc3cc(O)c(O)cc32)cc1
Reactant: C1CO1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CSc1ccc(C2CN(CCO)CCc3cc(O)c(O)cc32)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A 4 g sample of 7,8-dihydroxy-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine is slurred in 25 ml of acetone and 0.8 g ( ~ 10% excess) of ethylene oxide is added. The mixture is placed in a pressure bottle and stirred at ambient temperature for about 40 hours. The reaction mixture is then heated to 60°-80° for 30 minutes, cooled and filtered. Concentration of the filtrate gives a solid which is taken up in ethyl acetate and reprecipitated with ether. The solid thus obtained is dissolved in ethanol and treated with ethereal hydrogen chloride to give 7,8-dihydroxy-3-(2-hydroxyethyl)-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Si:15]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:38])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Si:45]([O:52][CH2:53][CH:54]=[O:55])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>O1CCCC1.CCCCCC>[Si:45]([O:52][CH2:53][CH:54]([OH:55])[CH:36]([C:37](=[O:38])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1)[CH2:35][CH2:34][CH2:33][O:32][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:48]([CH3:50])([CH3:51])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](OCCCCC(=O)c1cccnc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 0.93 ml (0.0044 mole) of hexamethyldisilazane in 14 ml of tetrahydrofuran, 2.15 ml (0.0044 mole) of 2.06 molar solution of n-butyllithium in hexane is added dropwise with stirring under argon at 0° C. The mixture is cooled to -20° C. and a solution of 1.68 g (0.004 mole) of 5-(t-butyldiphenylsilyloxy)-1-(3-pyridyl)pentan-1-one in 10 ml of tetrahydrofuran is added dropwise over a period of 15 min. The mixture is stirred at -20° C. for 15 min and a solution of 0.74 g (0.0042 mole) of t-butyldimethylsilyloxy acetaldehyde in 15 ml of tetrahydrofurane is added over a period of 1 min. The mixture is stirred at -20° C. for 15 min, quenched with 6 ml of concentrated aqueous ammonium chloride, diluted with ether and washed with water and brine, dried and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (1:1) as eluent to give 1-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-3-nicotinoylhexan-2-ol described in example 3.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:15])[NH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=1)[CH2:3][CH3:4].[C:16]([CH:20]1[CH2:25][CH2:24][CH:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([CH:20]1[CH2:21][CH2:22][CH:23]([C:26]([NH:1][CH:2]([C:5]2[C:6](=[O:15])[NH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:27])[CH2:24][CH2:25]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCC(N)c1nnc(C(C)(C)C)[nH]c1=O
Reactant: CC(C)(C)C1CCC(C(=O)Cl)CC1
Product: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C(C)(C)C)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 210 mg (1.00 mmol) 6-(1-aminopropyl)-3-tert-butyl-1,2,4-triazin-5(4H)-one, 200 mg (1.00 mmol) 4-tert-butylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH2:54][CH2:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N>CC(O)C.Cl.CO>[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=5[F:30])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:53][CH2:54][CH2:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCCOc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: CO
Product: CCCOc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 165 °C
Yield: 57.2 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-(1,4′-bipiperidin-1′-yl)-2-(propyloxy)aniline (0.137 g, 0.433 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (3 drops) was added. The vial was sealed and heated in the microwave at 165° C. for 30 min. The reaction was cooled to rt, neutralized with 7N ammonia in MeOH, adsorbed onto silica gel, and flash chromatographed. Product was then triturated with diethyl ether to give the title compound (0.184 g, 58%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 9.18-9.41 (m, 1H), 8.24-8.47 (m, 2H), 8.18 (d, J=4.9 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.26-7.48 (m, 3H), 7.17 (t, J=8.1 Hz, 2H), 6.83-7.01 (m, 1H), 6.63 (br. s., 1H), 6.43 (d, J=5.1 Hz, 2H), 3.91 (t, J=6.0 Hz, 2H), 3.69 (d, J=11.4 Hz, 2H), 2.60 (t, J=11.6 Hz, 2H), 2.36-2.52 (m, 4H), 2.22-2.36 (m, 1H), 1.75 (d, J=11.0 Hz, 2H), 1.14-1.66 (m, 10H), 0.66-0.88 (m, 3H). MS (M+H) 743.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C)C=O>[C:21]([O:20][C:18]([CH2:17][N:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1)=[O:19])([CH3:24])([CH3:23])[CH3:22].[C:21]([O:20][C:18]([CH2:17][N:2]1[CH:3]=[C:4]2[C:5]([N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9]2=[O:10])=[N:1]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1c2cn[nH]c2nc2n1CCS2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc2c(=O)n3c(nc2n1)SCC3
Product: CC(C)(C)OC(=O)Cn1ncc2c(=O)n3c(nc21)SCC3
Temperature: 50 °C
Reaction time: 12 h
Yield: 33 %
Yield: 20 %

Procedure:
In 120 ml of dimethylformamide was dissolved 3.00 g (15.4 mmol) of Compound 1 prepared in Example 1, and 1.86 g (46.3 mmol) of sodium hydride (60%) and 7.48 ml (46.3 mmol) of tert-butyl bromoacetate were added to the solution, followed by stirring at 50° C. for 12 hours. After addition of water and evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1). The first and second main fractions gave 1.59 g (33%) of Compound 34 and 0.97 g (20%) of Compound 35, respectively. Each compound was recrystallized from ethanol for purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]([CH2:25][CH2:26][OH:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]([CH2:25][CH:26]=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N(CCO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCOC(=O)N(CC=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
To a solution of oxalyl chloride (13.8 ml) in dichloromethane (270 ml) was added dropwise a solution of dimethyl sulfoxide (19.7 ml) in dichloromethane (30 ml) below -60° C. under atmosphere of nitrogen. After stirring the mixture at the same condition for 30 minutes, a solution of 2-(N-allyloxycarbonyl-N-benzylamino)ethanol (32.6 g) in dichloromethane (30 ml) was added to the mixture below -60° C. with stirring. After 30 minutes, triethylamine (58 ml) was added to the mixture at the same condition. The mixture was stirred below -60° C. for 30 minutes and the reaction temperature was allowed to rise to ambient temperature. The mixture was washed with water (300 ml), 1N hydrochloric acid (300 ml×2), saturated aqueous sodium hydrogen carbonate (300 ml), and brine (300 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-(N-allyloxycarbonyl-N-benzylamino)acetaldehyde (32.9 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([O:24][CH3:25])=[O:23].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:11]([C:20]2[CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[NH:17][CH:21]=2)(=[O:13])=[O:12])=[O:16])[N:3]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1cc(S(=O)(=O)NC(=O)Nc2nc(C)cc(C)n2)c[nH]1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2.58 g (0.021 mol) of 2-amino-4,6-dimethylpyrimidine in 75 ml dry nitromethane at -10° was added dropwise, via syringe, under nitrogen, 2.0 ml (0.023 mol) of chlorosulfonyl isocyanate at such a rate to maintain the temperature below 0°. The resulting clear solution was stirred 0.5 hour at -5° to -10°, then treated dropwise with a solution of 2.29 g (0.021 mole) of methyl pyrrole-2-carboxylate in 25 ml dry nitromethane. Upon completion of the addition, 2.95 gm (0.022 mole) of aluminum (III) chloride was added in one portion. The reaction mixture was heated at reflux for 2 hours, then allowed to stand overnight at ambient temperatures. The mixture was poured into 300 ml H2O and the two phase system extracted with three portions of CH2Cl2. The organic solutions were washed with water, dried over MgSO4 and evaporated to a tan foam which was triturated with minimal CH2Cl2 to afford the product as a white solid, m.p. 202°-204°.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].C[O:27][C:28]1[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]2[C:29]=1[CH2:30][CH2:31][CH:32]([C:40]([O:42][CH3:43])=[O:41])[CH2:33]2>O.C(#N)C>[O:27]=[C:28]1[CH:37]=[CH:36][C:35](=[O:38])[C:34]2[CH2:33][CH:32]([C:40]([O:42][CH3:43])=[O:41])[CH2:31][CH2:30][C:29]1=2
Reactant: COC(=O)C1CCc2c(OC)ccc(OC)c2C1
Agent: [Ce]
Solvent: CC#N
Solvent: O=[N+]([O-])O
Solvent: O
Product: COC(=O)C1CCC2=C(C1)C(=O)C=CC2=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98.4 %

Procedure:
A solution of 19.74 g (0.036 mol) of ammonium ceric nitrate in 120 ml of water was added to a stirred solution of 3.00 g (0.012 mol) of methyl rac-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate in 54 ml of acetonitrile. The mixture was stirred at room temperature for 25 minutes and then diluted with 150 ml of water. The solution was extracted with three 150 ml portions of diethyl ether and the combined diethyl ether extracts were washed with 150 ml of water, dried and evaporated to yield 2.60 g (98.5%) of methyl rac-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene-2-carboxylate in the form of a bright yellow solid of melting point 41°-42° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].C[C:16](O)=[O:17]>CCO.[Cl-].[Na+].O>[CH3:16][O:17][C:11]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)=[O:13]
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: CC(=O)O
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of -(4-bromo-phenyl)-cyclopropanecarbonitrile from Step 1 in EtOH (0.2M) was added NaOH 25% (10 eq.). The mixture was stirred for 6 h at 100° C., quenched with AcOH (20 eq.), poured in brine, extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was dissolved in CH2Cl2 and diazomethane was added portionwise until the esterification was completed by TLC. Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12]C)=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.[Na].[CH3:15][OH:16]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:2]([O:16][CH3:15])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: CO
Reactant: CCOC(=O)Cc1cncnc1Cl
Agent: [Na]
Product: COC(=O)Cc1cncnc1OC
Temperature: 120 °C
Yield: 93 %

Procedure:
To a solution of 0.250 g (1.25 mmol) of ethyl (4-chloro-5-pyrimidinyl)acetate (see i-48, Step A) in 10 mL of absolute methanol was dissolved 0.060 g (2.50 mmol) of sodium metal. The resulting solution was heated under microwave conditions at 120° C. for 10 min. All volatiles were removed in vacuo and the residue was diluted with saturated sodium bicarbonate and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to afford the title compound as a clear gum (0.21 g, 93%). 1H-NMR (500 MHz, CD3OD) δ: 8.72 (s, 1H), 8.35 (s, 1H), 3.96 (s, 2H), 4.01 (s, 3H), 3.70 (s, 3H), 3.57 (s, 2H). LC-MS: m/z (E/S) 183 (MH)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH3:42])=[O:40]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH3:42])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccn1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethylamide hydrochloride and methyl chloroformate. Yield: 62% of theory, C28H29N7O5 (543.6); Rf value: 0.19 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=544; (M+H+Na)++=283.8; (M+Na)+=566.