Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH2:18]1[C:22]2[CH2:23][NH:24][CH2:25][C:21]=2[CH2:20][N:19]1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][C:21]3[CH2:20][N:19]([C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:35])([F:37])[F:36])=[O:27])[CH2:18][C:22]=3[CH2:23]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc([N+](=O)[O-])cn1)C2

Procedure:
2-Chloro-5-nitropyridine (510 mg, 3.22 mmol), (3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (1.046 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.28 mmol) were stirred in 20 ml of DMF at 80° C. for 5 h. After concentrating under reduced pressure, ethyl acetate and water were added, and the precipitated solid was filtered off with suction. The organic phase was removed and concentrated. The two precipitates were combined. Yield: 845 mg (79%), M+H+: 405.04.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22]1[CH2:26]OC[CH2:23]1>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:22]([CH3:26])=[CH2:23])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(Br)c(OC)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)c1cc(C(=O)OC)c(OC)cc1OC

Procedure:
To potassium isopropylidene trifluoroborate (4.87 g, 32.7 mmol) and 5-bromo-2,4-dimethoxybenzoic acid methyl ester (7.5 g, 27.3 mmol) in THF (195 ml) was added Cs2CO3 (26.6 g, 81.8 mmol) in water (39 ml). The reaction was degassed and Pd(PPh3)4 (1.58 g, 1.36 mmol) added. The reaction was heated at reflux for three days then quenched by adding water and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to leave an orange solid. The product was taken up in EtOAc again and the precipitate filtered. The filtrate was evaporated to dryness to yield 5-isopropenyl-2,4-dimethoxy-benzoic acid methyl ester (6.2 g). 1H NMR (Me-d3-OD) 7.68 (1H, s), 6.66 (1H, s), 5.10-5.08 (1H, m), 5.02-5.00 (1H, m), 3.93 (3H, s), 3.92 (3H, s), 3.84 (3H, s), 2.08-2.06 (3H, m). MS: [M+H]+ 237.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:5]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH:12][S:15]([CH3:14])(=[O:17])=[O:16])[CH:5]=1
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2-amino-ethyl)-benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55 mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred at room temperature for 18 h and was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (522 mg) as a white solid. MS 275 (M+18).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C1(C)C=CC=CC=1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:12][CH2:11][CH2:10][O:5]1
Reactant: O=Cc1ccccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccccc1C1OCCO1

Procedure:
A 12 L 3-necked flask fitted with an overhead stirrer was charged with 2-bromobenzaldehyde (800 g, 4.324 moles), ethylene glycol (402.6 g, 6.485 moles), p-toluenesulfonic acid. H2O (3.95 g, 0.021 moles) and toluene (3.785 kg, 41.074 moles).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:16](OC(OCC)OCC)C.COCC(O)C>C(O)C>[NH:8]1[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:1]=[CH:16]2)=[N:11][N:10]=[N:9]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Solvent: COCC(C)O
Solvent: CCO
Product: O=c1c2ccccc2ncn1-c1nnn[nH]1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
A mixture of 326 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide, 680 ml of triethoxymethane and 2 liters of 1-methoxy-2-propanol was heated at reflux. The ethanol which formed was removed through a reflux head. After about 30-60 minutes with a pot temperature above 100° C., HPLC showed that all the starting material had reacted. The mixture was then cooled to 10° C. and the solid which formed was separated by filtration, washed with methanol and dried. The crude product was dissolved in hot dimethylformamide and the solution was diluted with methanol and cooled. The solid which precipitated was separated by filtration to give 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 259°-260° C. This compound has the following structural formula: ##STR4##
Reaction SMILES: [CH3:1][C:2]1[C:3](N2CCCCC2)=[CH:4][C:5]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=O)=[N:6][CH:7]=1.O.NN.[OH-].[K+].O>C(O)COCCOCCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)([N:6]2[CH2:7][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:6][CH:7]=1
Reactant: Cc1cnc(C(=O)c2cccc3ccccc23)cc1N1CCCCC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CC1=CNC(Cc2cccc3ccccc23)(N2CCCCC2)C=C1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-methyl-2-(1-napthoyl)-4-piperidinopyridine in 1 ml of triethylene glycol was added 30 mg of 100% hydrazine hydrate, and the mixture was stirred at 120° C. for 1.5 hours. Potassium hydroxide (42 mg) was added to the reaction mixture, and the mixture was heated at about 200° C. for 1 hour. The reaction mixture was poured into water, and extracted with ether. The ether layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluted with chloroform and then with chloroform/methanol (=50/1)] to give 5-methyl-2-(1-naphthylmethyl)-2-piperidinopyridine as an oil. The oil was treated with an ethanol solution of hydrogen chloride and recrystallized from acetone/ether to give 44 mg (yield 40%) of the captioned compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C([OH:31])(C)C>O1CCCC1.O.OOS([O-])=O.[K+]>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:26])=[O:31])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC(C)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(cis-4-Hydroxymethyl-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (120 mg, 0.307 mmol) was dissolved in a solvent mixture of isopropyl alcohol (4 ml), tetrahydrofuran (1 ml) and water (0.5 ml) and oxone™ (132 mg, 0.215 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2 increasing to 97:3, by volume). The resulting foam was triturated with diethylether (5 ml) to give the product (108 mg) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[NH2:32]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]3[O:27][N:32]=[C:31]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: NC(=NO)c1ccncc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccncc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 37.7 mg (0.275 mmol) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 88.7 mg (69% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:15]2=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:23][C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:29])[N:16]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:17]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC(F)(F)F)c3cc(F)ccc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1n(CC(F)(F)F)c2cc(F)ccc2n1C1CCNCC1
Reaction time: 9 h

Procedure:
A solution of 1-tert-butoxycarbonyl-4-(5-fluoro-3-(2,2,2-tri-fluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine (4.17 g, 10 mmol.) in chloroform (50 mL) containing trifluoroacetic acid (5.5 mL) was stirred at room temp. under an inert atmosphere for 6-12 hours until reaction was complete. The solvent and excess TFA were removed and the residue redissolved in chloroform. This solution was washed with Na2CO3 /NaOH solution. The organic layer was dried (Na2SO4), filtered through a pad of charcoal, and the solvent evaporated to give 4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine as a viscous oil which was used as is. A sample of this material was converted to the HCl salt and after crystallization from methanol gave a white solid, mp: >280° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([NH:1][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH2:42][C:36]3[C:37](=[O:41])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[C:34](=[O:57])[C:35]=3[CH3:56])[CH:44]=[CH:45][C:46]=2[O:52][C:53](=[O:55])[CH3:54])=[N:3][CH:4]=1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
tert-Butyl 6-aminonicotinate (0.467 g, 2.406 mmol), triethylamine (0.244 g, 2.406 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.407 g, 2.406 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.300 g, 0.802 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.240 g, 0.436 mmol, 54%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:6][CH2:7][C:8]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:10])=[O:2]
Reactant: Cc1cc(C=O)cc(OCC(=O)O)c1
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(OCC(=O)Nc2ccncc2)c1
Yield: 61.1 %

Procedure:
2-(3-Formyl-5-methyl-phenoxy)-acetic acid (0.47 g) and 4-aminopyridine (0.46 g) were dissolved in dry DMF (10 ml). The resulting solution, stirring under a nitrogen atmosphere, was treated with TBTU (0.82 g). The resulting mixture was stirred for 68 h and then concentrated at reduced pressure to give a yellow viscous gum. This crude material was purified by preparative hplc. The purified product was partitioned between ethyl acetate and an aqueous solution saturated with sodium bicarbonate, sodium chloride and ammonium sulphate. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure giving the title compound as an off-white solid (0.40 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8]1[O:19][C:18]2[CH:17]=[CH:16][C:12]([CH2:13][Mg]Cl)=[CH:11][C:10]=2[O:9]1.Cl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[CH2:8]1[O:19][C:18]2[CH:17]=[CH:16][C:12]([CH2:13][C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]=3)=[CH:11][C:10]=2[O:9]1
Reactant: Cl[Mg]Cc1ccc2c(c1)OCO2
Reactant: Clc1cnccn1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cnc(Cc2ccc3c(c2)OCO3)cn1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of chloropyrazine (1.14 g) and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (106 mg) in dry tetrahydrofuran (40 ml) was added a solution of 3,4-methylenedioxybenzylmagnesium chloride (0.6 M in tetrahydrofuran, 29 ml) at 5° C. under nitrogen atmosphere over 15 minutes. After 1 hour of stirring at 5° C., 3N hydrochloric acid was added slowly under nitrogen atmosphere and the mixture was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water and dried over magnesium sulfate. The usual work up followed by flash chromatography on silica gel with a mixture of n-hexane and ethyl acetate (10:1-4:1) gave 2-(3,4-methylenedioxybenzyl)pyrazine (454 mg) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][OH:13])=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27].[Li+].[OH-]>C1COCC1.O>[OH:13][CH2:12][C:10]1[CH2:11][N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6](=[O:27])[CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[CH2:8][CH:9]=1
Reactant: COC(=O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of {6-hydroxymethyl-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 19, (0.16 g, 0.41 mmol) in THF/H2O (4 mL, 3:1) is treated with excess LiOH and stirred for 2.5 hours at room temperature. The solution is acidified to pH 7, concentrated in vacuo and purified by HPLC to afford 0.15 g of the desired product.
Reaction SMILES: [N:1]1[NH:2][C:3]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:5]=1.Cl.[CH:28]1([C:31]2([F:35])[CH2:34][NH:33][CH2:32]2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1[N:2]=[C:3]([NH:6][C:7]2[CH:12]=[C:11]([N:33]3[CH2:34][C:31]([CH:28]4[CH2:30][CH2:29]4)([F:35])[CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)[NH:4][CH:5]=1
Reactant: FC1(C2CC2)CNC1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncn[nH]3)n2)cc1)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Sc2nc(Nc3nnc[nH]3)cc(N3CC(F)(C4CC4)C3)n2)cc1)C1CC1
Yield: 10.7 %

Procedure:
Compound I-6 was prepared according to the procedure of compound I-1 using N-(4-(4-(2H-1,2,4-Triazol-3-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (140 mg, 0.36 mmol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (62 mg), DiPEA (0.14 mL) in 1,4-dioxane (5 mL). After purification by column chromatography, the obtained material was further purified by preparative HPLC to yield 18 mg of desired product after evaporation and lyophilization, purity: 99+% (HPLC method A, Rf=8.466 minutes).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(-n2cncn2)nc1
Temperature: 25 °C

Procedure:
2-Chloropyrimidine-5-carboxylic acid (0.75 g), 1,2,4-1H-triazole (0.98 g) and potassium carbonate (1.96 g) in 3.75 mL of N,N-dimethylformamide are heated in microwave at 50° C. for 30 min, then cooled to room temperature and acidified with 3 mL of 1N HCl, followed by addition of conc. HCl to pH 2. The precipitate is filtered, washed with minimum amount of water, diethyl ether and dried in vacuo to afford the title compound. LC (method 20): tR=0.82 min; Mass spectrum (APCI): m/z=192 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:26]([NH2:28])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[C:10]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44]>CN(C)C=O>[OH:38][CH2:39][CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:26]([NH2:28])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[C:10]=2[CH:29]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCCl)cc32)nc1-c1cccc(Cl)c1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN(CCO)CCO)cc32)nc1-c1cccc(Cl)c1
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(3-chloro-propoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.34a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.029 mL (0.3 mmole) of 2-(2-hydroxy-ethylamino)-ethanol was stirred at 100 degrees for 3 hours. The mixture was concentrated under reduced pressure, and diluted with 20 mL of water. The precipitate was collected by filtration and the solid triturated with diethyl ether to give 0.029 g of 2-(6-{3-[bis-(2-hydroxy-ethyl)-amino]-propoxy}-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.35) as a white powder. MH+/Z=516
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:32]([CH2:36][Si](C)(C)C)[CH2:33]OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:36][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled solution of (4S)-4-benzyl-3-[(2E)-3-(4-chlorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one, from preparation 23 (5 g, 14.62 mmol) and N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (5.24 mL, 20.47 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (60 L, 0.73 mmol). The reaction mixture was stirred at 0° C. for 20 minutes and then warmed to room temperature and stirred for 24 hours. Sodium hydrogen carbonate solution (80 mL) was added and the reaction mixture was stirred for 10 minutes. The phases were separated and the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a yellow oil. Purification by column chromatography on silica gel using ethyl acetate:pentane (10:50-50:50) as eluent afforded the desired product (which is the second-eluting diastereomer) as a white crystalline solid, 733 mg (11%).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.II.C1(C)C=CC=CC=1.C1[O:35][CH:33]1C>O>[CH3:33][O:35][C:21]1[CH:20]=[CH:19][C:18]2[C:7]3[C:6](=[CH:5][CH:4]=[CH:3][CH:8]=3)[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:17]=2[CH:22]=1
Reactant: COc1ccc(-c2ccc(OC)cc2-c2ccccc2)cc1
Reactant: CC1CO1
Agent: II
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c3ccccc3c3ccc(OC)cc3c2c1
Reaction time: 18 h
Yield: 72 %

Procedure:
12.4 g (42.7 mmol) of 4,4′dimethoxy-o-terphenyl and 16 g (63.0 mmol) iodine chips was placed in a 250 mL reaction vessel. 200 mL of toluene was added followed by 30 mL of propylene oxide. The photoreactor was set up with a condenser cooled by a circulating chiller. A 400 W medium pressure mercury lamp was used as the light source. The reaction vessel was placed in a cabinet. The lamp was ignited and the chiller temperature was set such that the water exiting the reactor was maintained at between 20° C. and 25° C. (monitored by a thermocouple attached the exit stream). The reaction was left on for 18 hours. A solid was filtered off and washed with hexanes, only recovered 2.2 g of material. The filtrate was diluted with toluene and washed with sodium sulfate solution. The aqueous layer was back extracted with toluene and the organic layers were dried over magnesium sulfate, filtered, and evaporated. Material was dissolved in toluene and added sodium sulfite solution and stirred. The layers were separated, the aqueous layer extracted with toluene and the combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 0 to 100% ethyl acetate/hexane. 8.8 g material (72%) was obtained.