Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccc(F)cc2Cl)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 110.6 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.34 g of potassium carbonate, and 0.24 g of 2-chloro-4-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.53 g of 4-(2-chloro-4-fluorophenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (16)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[CH3:10].C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27].Cl>C(OCC)(=O)C.C(OCC)C.C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:27])[CH2:25][Cl:24])=[C:3]([C:9]([OH:11])([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:4]=1
Reactant: CC(O)(c1cccs1)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(O)(c1cccs1)c1cc(Br)ccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of 1-(2-amino-5-bromo-phenyl)-1-thiophen-2-yl-ethanol (3.9 g, 13 mmol) in a mixture of anhydrous THF and diethyl ether (20 mL/20 mL) at 0° C. under nitrogen was added triethyl amine (4 mL, 28.7 mmol) and chloroacetyl chloride (1.6 mL, 20 mmol). After addition, the reaction mixture was slowly warmed to room temperature (rt), stirred for 3 h, and treated with a cold 1N hydrogen chloride aqueous solution (70 mL). Ethyl acetate (100 mL) was added and organic layer separated, dried (Mg2SO4), concentrated to yield the title compound as a white solid (4.7 g, 94%). 1H-NMR (DMSO-d6) δ 10.78 (s, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.51 (dd, J=8.7, 2.2 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 7.37 (m, 2H), 6.95 (m, 1H), 6.88 (dd, J=3.4, 0.8 Hz, 1H), 4.26 (d, J=6.9 Hz, 2H), 1.94 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([Si:14]([CH3:24])([CH3:23])[O:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH:19]=O)([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:19]/[CH2:18][C:17]([CH3:21])([CH3:22])[CH2:16][O:15][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(CC=O)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Yield: 100 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.52 g, 3.64 mmol) was reacted with 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde (0.84 g, 3.64 mmol) in CH2Cl2 at room temperature for 18 h to give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.25 g, 100%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH3:33])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[NH2:45][C@H:46]1[C:53](=[O:54])[N:52]2[C@@H:47]1[CH2:48][S:49][C:50]([CH2:62][OH:63])=[C:51]2[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56].C(=O)(O)[O-].[Na+]>CC(C)=O.O.C(N(CC)CC)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH3:33])[C:27]([NH:45][C@H:46]2[C:53](=[O:54])[N:52]3[C@@H:47]2[CH2:48][S:49][C:50]([CH2:62][OH:63])=[C:51]3[C:55]([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:56])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1=C(CO)SC[C@@H]2[C@@H](N)C(=O)N12
Reactant: CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCON=C(C(=O)N[C@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(CO)SC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.75 h

Procedure:
549 mg of the syn isomer of 2-[2-tritylaminothiazol-4-yl]-2-ethoxyimino acetic acid were dissolved in 5.5 ml of acetone and 0.18 ml of triethylamine and 228 mg of tosyl chloride were added immediately with stirring for 45 minutes. A solution of 285 mg of the product of Step C in 1 ml of water, 1.5 ml of a 1M sodium bicarbonate solution and 2 ml of acetone was added to the reaction mixture with stirring for 35 minutes. The acetone was distilled off under reduced pressure, and extraction was effected with methylene chloride. The organic phases were dried and concentrated to dryness. The residue was chromatographed on silica under pressure and elution with a methylene chloride-ethyl acetate mixture (75-25) to obtain 602 mg of syn isomer of racemic cis 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-ethoxyimino-acetamido]-3-hydroxymethyl-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: COc1cc(-c2ncc(C(F)(F)F)cn2)ccn1
Yield: 17 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.66 g, 7.06 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (1.3 g, 7.1 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (307 mg, 16%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 2H), 8.34 (d, J=5.3 Hz, 1H), 7.89 (dd, J=5.3, 1.4 Hz, 1H), 7.81 (s, 1H), 4.01 (s, 3H).
Reaction SMILES: [Li+].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:15]([O-])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.[C:51]([O:55][NH2:56])([CH3:54])([CH3:53])[CH3:52].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:51]([O:55][NH:56][C:15](=[O:16])[C@H:14]([N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])([CH3:54])([CH3:53])[CH3:52]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CCCCN(C)C)C(=O)[O-])cc1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CCCCN(C)C)C(=O)NOC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(N,N-dimethylamino) hexanoic acid lithium salt (4.42 g, 10.18 mmol) in methylene chloride (100 mL) containing N- methylmorpholine (6.73 mL, 61.06 mmol), 1-hydroxybenzotriazole monohydrate (1.64 g, 10.687 mmol) and O-t-butylhydroxyl amine hydrochloride (1.41 g, 11.20 mmol) is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.90 g, 20.36 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature and stirring is continued overnight. The mixture is diluted with methylene chloride, washed with saturated sodium bicarbonate, then with brine, dried (Na2SO4) and the solvent is evaporated. The crude product is purified by silica gel chromatography (10:1:0.5 ethyl acetate/methanol/ammonium hydroxide) to provide N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(N,N-dimethylamino) hexanamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([NH:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:35]>>[CH2:34]([N:36]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:35]
Reactant: CCNCCc1ccccn1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CCc1ccccn1)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-[2-(ethylamino)ethyl]pyridine. ES-MS m/e (%): 519 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:22][O:23][C:24]1[C:29]2[S:30][CH:31]=[CH:32][C:28]=2[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:22][O:23][C:24]1[C:29]2[S:30][CH:31]=[CH:32][C:28]=2[C:27]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c2ccsc12
Reactant: COc1ccc(Nc2ccc3ncc(Br)n3n2)cc1OC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Nc2ccc3ncc(-c4ccc(OC)c5sccc45)n3n2)cc1OC
Yield: 56.4 %

Procedure:
To a solution of 3 3-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (43 mg, 0.123 mmol, 1.0 equiv) in acetonitrile (1.23 mL) was added 2-(7-methoxybenzo[b]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46 mg, 0.160 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II)dichloride (9 mg, 0.0123 mmol, 0.1 equiv), then sodium carbonate (1.23 mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture was irradiated in the microwave at 150° C. for 10 min. Purification by column chromatography gave 30 mg of the yellow solid, 56%.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH3:7][CH:8]([CH3:13])[CH:9]([OH:12])[CH:10]=[CH2:11].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[O:4]1[CH:5]=[CH:6][C:2]([CH2:11][CH2:10][C:9](=[O:12])[CH:8]([CH3:13])[CH3:7])=[CH:3]1
Reactant: C=CC(O)C(C)C
Reactant: Brc1ccoc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)C(=O)CCc1ccoc1

Procedure:
The title compound was prepared according to General Method 4a using 3-bromofuran (17 mmol), 4-methyl-1-penten-3-ol (25.5 mmol), tetrabutyl ammonium chloride (17 mmol), sodium bicarbonate (42.5 mmol), DMF (15 mL), and palladium acetate (0.9 mmol). The title compound was flash chromatographed eluting with EtOAc:hexane (5:95 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: Nc1ccccc1Cl
Reactant: CC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CNc1ccccc1Cl
Temperature: 100 °C
Yield: 69.7 %

Procedure:
A mixture of 2-chloroaniline (13.2 ml, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen at 100° C. overnight. After cooling to rt, water was added and the mixture extracted with ether (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (Heptane:EtOAc 80:20) afforded 16.0 g (70%) of the title compound as a brown liquid.
Reaction SMILES: [OH:1][C:2]1([C:11]2[O:12][C:13]([CH3:16])=[CH:14][CH:15]=2)C(=O)N[C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH-].[Na+]>>[CH3:16][C:13]1[O:12][C:11]([CH:2]2[O:1][C:5](=[O:9])[NH:4][C:3]2=[O:10])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C2(O)C(=O)NC(=O)NC2=O)o1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C2OC(=O)NC2=O)o1

Procedure:
5-Hydroxy-5-(5-methyl-2-furyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (6.3 g.) was dissolved in 50 ml. of 1 N sodium hydroxide and stirred at room temperature for 15 minutes. The reaction mixture was extracted with 50 ml. of ethyl acetate, and acidified with glacial acetic acid. Product was then extracted into fresh ethyl acetate (three 30 ml. portions). The combined ethyl acetate extracts were filtered through a bed of anhydrous magnesium sulfate and evaporated to an oil. The oil was chromatographed on 50 ml. of silica gel, with 1:1 hexane:ethyl acetate/5% acetic acid as eluant. The column was monitored by tlc using the same eluant. Clean product containing fractions were combined, evaporated to dryness and triturated with hexane (311 mg., m.p. 135°-138° C.). Recrystallization from methanol/water afforded purified 5-(5-methyl-2-furyl)oxazolidine-2,4-dione (142 mg., m.p. 136.5°-137.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][S:27]([C:22]1[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)c2ccc(F)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2,4-dimethoxybenzylamine (3.35 mL, 22.3 mmol) and pyridine (9.02 mL, 111.5 mmol) in dichloromethane (75 mL), 3,4-difluorobenzenesulfonyl chloride (3.04 mL, 22.3 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 16 hours. To the reaction solution, 2 M hydrochloric acid (100 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate and vacuum concentrated to yield the title compound (7.66 g, 99%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([CH2:4][S:5][CH3:6])=[O:3].C([Li])CCC.CCCCCC.[F:18][C:19]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]>C1COCC1>[F:18][C:19]1[CH:26]=[C:25]([CH:4]([S:2]([CH3:1])=[O:3])[S:5][CH3:6])[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: CSCS(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC(c1cc(F)c(C#N)cc1F)S(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(Methylsulfinyl)(methylthio)methane (3.16 g, 0.0255 mol) was dissolved in 50 mL of dry THF under argon and then cooled to −78° C. Butyllithium in hexane (16 mL 1.6M, 0.0256 mol) was added dropwise with stirring. The mixture was stirred for 15 min. Meanwhile a solution of 2,4,5-trifluorobenzonitrile (2.0 g; 0.013 mol) in 50 mL of dry THF was cooled to −78° C. under argon and the former solution was added through a cannula to the latter solution over a period of 3–5 min. After 30 min, the cooling bath was removed and when the reaction had reached room temperature it was poured into 200 mL of water. The THF was evaporated and the remaining aqueous layer was extracted three times with diethyl ether. The combined ether phase was washed with water, dried (Na2SO4) and evaporated. The crude product started to crystallise and could be used as such in the next step. Yield: 2.8 g (84%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[CH:10][N:11]=1.[H-].[Na+].[CH3:17]I>C1COCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][N:12]([CH3:17])[C:9]2=[CH:10][N:11]=1
Reactant: c1cc2cc(C3OCCO3)ncc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(C3OCCO3)ncc21
Reaction time: 0.5 h
Yield: 86 %

Procedure:
5-(1,3-Dioxolan-2-yl)-1H-pyrrolo[2,3-c]pyridine (C173) (1.05 g, 5.52 mmol) is dissolved in 20 mL THF in a dried flask under N2. 60% Sodium hydride (243 mg, 6.07 mmol) is added, the reaction is stirred 30 min, methyl iodide (360 μL, 5.8 mmol) is added, and the reaction is stirred overnight at rt. The reaction is concentrated in vacuo and the residue is partitioned between 10 mL saturated NaCl and CH2Cl2 (4×10 mL). The combined organic layer is dried over anhydrous K2CO3 and is concentrated in vacuo to a tan paste. The crude material is chromatographed over 50 g silica gel (230-400 mesh) eluting with 5% MeOH/CH2Cl2. The appropriate fractions are combined and concentrated to afford 5-(1,3-dioxolan-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (C175) (86% yield). HRMS (FAB) calculated for C11H12N2O2+H: 205.0977, found 205.0983.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:25])=[O:24]
Reactant: OCCCSc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCSc1cccc2nccn12

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.030 g, 4.95 mmoles) and triethylamine (1.03 ml, 7.4 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.46 ml, 5.9 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain crude 5-[3-(methanesulfonyloxy)propylthio]imidazo[1,2-a]pyridine as a yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18].[OH-].[Na+]>C(#N)C.O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:18])=[O:19])=[O:22])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccn1
Reactant: COc1cc(C)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccn2)n1

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 20 ml of dry acetonitrile at room temperature is added 2.2 g of 2-pyridinesulfonylisocyanate. The mixture is stirred for several hours and filtered. Evaporation of the filtrate yields a solid residue which is stirred in approximately 30 ml of water while adjusting the pH of this mixture to 11 by the addition of 10% NaOH. This solution is filtered, the filtrate pH adjusted to pH 7 by adding 10% hydrochloric acid and the resulting neutral solution again filtered. The desired product is then precipitated from this filtrate by adjusting the pH to 2, collecting in a sintered funnel and drying in a vacuum oven at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][CH2:35][CH2:36][CH:37]1[O:41][CH2:40][CH2:39][O:38]1>>[C:1]([O:5][C:6]([NH:8][CH:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:34][CH2:35][CH2:36][CH:37]2[O:41][CH2:40][CH2:39][O:38]2)=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCC1OCCO1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)OCCCC3OCCO3)cc2)c1

Procedure:
The title compound was prepared from 4-((3-(((tert-butoxycarbonyl)amino)-(phenyl)methyl)phenoxy)methyl)benzoic acid and 2-(3-chloropropyl)-1,3-dioxolane according to the method of Chiral Example 5 Step 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: COc1cccc(C=O)c1
Reactant: O=C1CNC(=O)N1
Solvent: NCCO
Solvent: O
Product: COc1cccc(C=C2NC(=O)NC2=O)c1
Yield: 79.9 %

Procedure:
A mixture of m-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g.) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added and the mixture was heated in an oil bath at 90°-92° for 4 hours with magnetic stirring. Isolation in the usual manner gave the title compound as a beige solid (2.56 g.), m.p. 229°-231°.
Reaction SMILES: C[N:2]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[C:56]([C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]([C:82]2[CH:87]=[CH:86][C:85]([O:88][CH2:89][C:90](=[O:94])[N:91]([CH3:93])[CH3:92])=[C:84]([O:95][CH3:96])[CH:83]=2)[C:67]2[NH:71][C:70](=[O:72])[N:69]([C:73]3[CH:81]=[CH:80][CH:79]=[CH:78][C:74]=3[C:75]([OH:77])=O)[N:68]=2)=[CH:61][CH:60]=1)(=[NH:58])[NH2:57]>CN(C=O)C>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[C:56]([C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]([C:82]2[CH:87]=[CH:86][C:85]([O:88][CH2:89][C:90](=[O:94])[N:91]([CH3:93])[CH3:92])=[C:84]([O:95][CH3:96])[CH:83]=2)[C:67]2[NH:71][C:70](=[O:72])[N:69]([C:73]3[CH:81]=[CH:80][CH:79]=[CH:78][C:74]=3[C:75]([NH2:2])=[O:77])[N:68]=2)=[CH:61][CH:60]=1)(=[NH:58])[NH2:57]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)ccc1OCC(=O)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(N)=O)c(=O)[nH]2)ccc1OCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 37.4 %

Procedure:
After adding 20.4 mg of BOP reagent, 5.3 mg of 1-hydroxybenzotriazole, 20.5 μl of N,N-diisopropylethylamine and 3.1 mg of ammonium chloride to a solution of 11.5 mg of 2-{3-[(4-carbamimidoyl-phenylamino)-(4-dimethylcarbamoylmethoxy-3-methoxy-phenyl)methyl]-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl}benzoic acid trifluoroacetate in 1 ml of DMF, the mixture was stirred at room temperature for 22 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 4.3 mg of the title compound.