Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:4].Cl.[NH2:34][OH:35].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][C:14](=[N:34][OH:35])[CH2:13][CH2:12]1)[C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (67 mg, 0.148 mmol) was dissolved in methanol (1.5 ml) and hydroxylamine hydrochloride salt (62 mg, 0.888 mmol) was added. After stirring for 2 hours at room temperature and 2 hours at reflux, the pH of the solution was adjusted to 8-9 by addition of a 10% sodium hydroxide solution. The resulting solution was then refluxed for 30 minutes and cooled to room temperature. It was then quenched with water (5 ml) and extracted with ethyl acetate (3×5 ml). The combined ethyl acetate layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (0% to 60% EtOAc/Hex) to obtain 49 mg (71%) of 3-[(4-Hydroxyimino-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=3)[C:4]=2[O:3]1.[CH3:21][O:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:24]([N:23]([O:22][CH3:21])[CH3:27])=[O:25])=[CH:15][N:14]=3)[C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1(C)Cc2cccc(COc3ccc(N)cn3)c2O1
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(OCc2cccc3c2OC(C)(C)C3)nc1
Yield: 83.2 %

Procedure:
2.0 g of 2-(2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyloxy)-5-aminopyridine was dissolved into 5 ml of pyridine, and 1.1 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto under cooling with ice. After 2-hours' continuous stirring, pyridine was distilled off under a reduced pressure, and the residual oily matter was dissolved into 30 ml of toluene. After the mixture was subsequently washed with water, diluted hydrochloric acid and saturated sodium chloride aqueous solution, toluene was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 2.2 g of 1-[2-(2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyloxy)-5-pyridyl]-3-methoxy-3-methylurea.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.Cl.O1CCOCC1>CC(O)C>[CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH:16][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28](=[O:29])[NH:30][CH3:31])[C:22]([Cl:36])=[CH:21][N:20]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)C(=O)N1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)N(C)C)CC3)ncc1Cl
Temperature: 120 °C
Yield: 80.9 %

Procedure:
7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-carboxylic acid dimethylamide (80 mg, 0.343 mmol, 1.0 eq) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (112 mg, 0.378 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (94.5 μL, 0.378 mmol, 1.1 eq) was added and the reaction was heated at 120° C. in a microwave for 10 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 7-[5-chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid dimethylamide as a yellow foam (137 mg, 81%). LCMS (m/e) 494 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.08 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.11 (s, 1H), 7.51 (d, 1H, J=7.8 Hz), 7.50-7.40 (m, 1H), 7.40 (s, 1H), 7.30-7.25 (m, 1H), 7.14-7.02 (m, 2H), 6.93 (s, 1H), 6.32-6.21 (m, 1H), 3.46-3.38 (m, 4H), 3.05 (d, 3H, J=4.8 Hz), 2.98-2.90 (m, 4H), 2.87 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:3]=1
Reactant: Ic1n[nH]c2cnccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1nc(I)c2ccncc21
Temperature: 25 °C

Procedure:
To a suspension of 3-iodo-1H-pyrazolo[3,4-c]pyridine (6.24 g, 22.9 mmol) and potassium carbonate (7.29 g, 52.7 mmol) in CH3CN (50 mL) was added tert-butyl bromoacetate (4.06 mL, 27.5 mmol) dropwise at RT and the resulting mixture was heated to reflux for 2 h. The mixture was cooled to RT and filtered, the solid was washed with CH3CN and the filtrate was concentrated under vacuum. The residual oil was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:4, to 1:2, to 1:1) to give the title compound. MS (LC/MS): 360.0 [M+H]+; tR (HPLC conditions d): 2.93 min.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=O)[C:14](C)(C)C)[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.BrCC#[N:34]>C1COCC1.CCCCCC>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]2[CH2:9][CH2:10][C:11](=[O:19])[N:12]2[CH2:13][C:14]#[N:34])=[CH:3][CH:2]=1
Reactant: N#CCBr
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCN1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 g (5.97 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1, R1═H) is dissolved in 15 ml dry THF and cooled to −78° C. After the addition of 4.13 ml butyl lithium in hexane (1.59 M) the yellow solution is stirred at −78° C. for 30 min. Subsequently, 475 l (855 mg, 7.16 mmol) bromoacetonitrile is added and the mixture is warmed up to room temperature overnight. The reaction is then quenched on addition of 10 ml saturated NH4Cl solution followed by the addition of 6 ml water and the mixture is extracted with 2×40 ml ethyl acetate. The combined organic layers are separated, dried over MgSO4, filtered and evaporated. The resulting residue is purified by column chromatography (dichloromethane:methanol=99:1) to give ((S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidin-1-yl)acetonitrile (1-a, R1=cyanomethyl) as off-white solid. NMR (400 MHz, DMSO-d6, /ppm): 7.65 (m, 4H); 7.47 (t, J=7.4, 2 H); 7.40 (m, 3H); 4.57 (d, J=17.7, 1H); 4.44 (d, J=17.7, 1H); 3.91 (m, 1H); 3.19 (dd, J=3.9, 13.8, 1H); 2.70 (dd, J=9.2, 13.8, 1H); 2.18 (m, 2H); 1.95 (m, 1H); 1.77 (m, 1H). MS (ESI, m/e) 291 [M+H]+. IR (solution in CH2Cl2, /cm−1): 3025; 2985; 2257; 1697; 1688; 1486; 1421; 1323; 1271; 1182; 760; 699.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>O1CCOCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[S:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 2-amino-5-bromopyridine (5.0 g, 29 mmol) in dioxane (60 mL) was added ethoxycarbonylisothiocyanate (3.4 mL, 29 mmol) in a dropwise manner and the mixture was allowed to stir for 18 h at room temperature. The mixture was then concentrated and the residue triturated with 10% ethyl acetate in hexanes. The solid was collected by filtration and dried to afford ethyl {[(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate (6.2 g, 69%) as a colorless solid. MS (EI) for C9H10BrN3O2S: 305 (MH+).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([NH:40][C:41]3[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=3)[C:37]3=[C:53]([CH3:57])[N:54]=[C:55]([CH3:56])[N:36]3[N:35]=2)=[CH:30][CH:29]=1>>[CH3:57][C:53]1[N:54]=[C:55]([CH3:56])[N:36]2[C:37]=1[C:38]([NH:40][C:41]1[CH:42]=[C:43]([O:51][CH3:52])[C:44]([O:49][CH3:50])=[C:45]([O:47][CH3:48])[CH:46]=1)=[N:39][C:34]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:1](=[O:5])[CH2:2][CH3:3])=[CH:33][CH:32]=1)=[N:35]2
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: CCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCC(=O)Nc1ccc(-c2nc(Nc3cc(OC)c(OC)c(OC)c3)c3c(C)nc(C)n3n2)cc1

Procedure:
13 mg (0.17 mmol) of propionic acid, 23 mg (0.17 mmol) of HOBt, 47 mg (0.46 mmol) of 4-methylmorpholine, 33 mg (0.17 mmol) of EDC and 65 mg (0.21 mmol) of N-[2-(4-aminophenyl)-5,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are reacted analogously to example 2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:27][S:2]([CH3:1])(=[O:4])=[O:3])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.94 ml) was added to a solution of ethyl 3-(4-benzyloxyphenyl)lactate (3.32 g), which is the product of Reference example 1(b), in anhydrous dichloromethane (30 ml). To this mixture triethylamine (2.47 ml) was added dropwise in an ice bath. The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane to afford the desired product (3.60 g) as colorless crystals.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>ClCCl.O>[F:23][C:22]([F:24])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of methyl chloroglyoxylate (2.98 ml, 32.4 mmol) in dichloromethane (10 ml) was added dropwise at a slow speed to a mixture of 4-amino-4′-(trifluoromethoxy)biphenyl (5.476 g, 21.6 mmol), sodium hydrogencarbonate (3.62 g, 43.2 mmol), dichloromethane (40 ml) and water (40 ml), and stirred at 0° for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.71 g, 91.5%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[CH:25][C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[CH:25][C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 70 %

Procedure:
4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.250 g, 0.633 mmol) and ethyl formate (0.148 mL, 1.90 mmol) were dissolved in anhydrous ethanol (1.3 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.48 mL, 3.17 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.187 g, 0.443 mmol, 70%).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:16]=[C:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[S:18][CH:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:17]2[S:18][CH:19]=[C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])[CH:16]=2)[CH:21]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1csc(-c2cccnc2)c1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1csc(-c2cccnc2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-bromo-2-(3-pyridyl)thiophene. The title compound (800 mg) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[N:8]1[CH:13]=[CH:12][C:11](CCO)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:5]([O:4][CH2:1][CH2:2][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1)(=[O:7])[CH3:6]
Reactant: OCCc1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1ccncc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11.3 ml of acetic anhydride in 100 ml of methylene chloride was added approximately 125 mg of dimethylaminopyridine, and the solution was cooled to 0° C. In a separate container 12.2 g (0.099 mol) of 4-pyridineethanol was suspended in 80 ml of methylene chloride and 12.14 g (0.120 mol, 16.7 ml) of triethylamine was added. This mixture was added to the acetic anhydride solution slowly by pipet. The resulting mixture was stirred at room temperature for approximately 90 minutes and quenched with about 100 ml of water. The mixture was placed in a separatory funnel and the organic layer was isolated and washed two times with 100 ml portions of water. The aqueous layers were combined and extracted two times with methylene chloride and one time with diethyl ether. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 16.2 g of the desired compound. Purification by high pressure liquid chromatography provided 11.19 g of 4-pyridineethanol acetate.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]1[CH2:9][NH:8][C@H:7]([C:10]2[NH:11][C:12]([C:15]3[CH:28]=[C:27]4[O:29][CH2:30][C:24]5[C:25]6[C:26]4=[C:17]([CH2:18][O:19][C:20]=6[CH:21]=[C:22]([C:31]4[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][C@H:38]([CH3:41])[N:37]6[C:42](=[O:52])[C@@H:43]([NH:47][C:48](=[O:51])[O:49][CH3:50])[CH:44]([CH3:46])[CH3:45])=[N:33][CH:32]=4)[CH:23]=5)[CH:16]=3)=[CH:13][N:14]=2)[CH2:6]1.[CH3:53][O:54][C:55]([NH:57][C@@H:58]([CH:62]([CH3:64])[CH3:63])[C:59](O)=[O:60])=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:50][O:49][C:48]([NH:47][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:42]([N:37]1[C@@H:38]([CH3:41])[CH2:39][CH2:40][C@H:36]1[C:34]1[NH:35][C:31]([C:22]2[CH:21]=[C:20]3[O:19][CH2:18][C:17]4[C:26]5[C:25]3=[C:24]([CH2:30][O:29][C:27]=5[CH:28]=[C:15]([C:12]3[NH:11][C:10]([C@@H:7]5[CH2:6][C@H:5]([CH2:4][O:3][CH3:2])[CH2:9][N:8]5[C:59](=[O:60])[C@@H:58]([NH:57][C:55](=[O:56])[O:54][CH3:53])[CH:62]([CH3:64])[CH3:63])=[N:14][CH:13]=3)[CH:16]=4)[CH:23]=2)=[CH:32][N:33]=1)=[O:52])=[O:51]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To the HCl salt of methyl (S)-1-((2S,5S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (40 mg) in DMF (1 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (13 mg, 0.075 mmol), HATU (21 mg, 0.055 mmol) and N-methylmorpholine (0.016 mL, 0.15 mmol). After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,4S)-2-[5-(7-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (43 mg). LCMS-ESI+: calculated for C45H56N8O9: 852.4; observed [M+1]+: 853.1.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[C:7]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)[CH:2]=[C:3]([Cl:9])[N:4]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2cc(Cl)nc(N3CCN(C)CC3)n2)CC1
Temperature: 0 °C

Procedure:
Trichloropyrimidine is added in portions to an ice cool solution of N-methylpiperazine (40 g) in ethanol (200 ml). The mixture is then heated at 60° for 2 h. The mixture is concentrated and chromatographed on silica gel with 2-5% methanol and methylene chloride to give 2,4-bis[4-methylpiperazino]-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 h. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give the title compound, TLC (methylene chloride/methanol/ammonium hydroxide - 91.5/8/0.5)Rf =0.3.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=O)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:54][NH2:55]>C(O)C>[F:52][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:54][NH2:55])=[O:40])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CCOCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Solvent: CCO
Product: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (EXAMPLE 39 Step A, 0.114 g, 0.153 mmol) was dissolved in ethanol (1.0 mL). Added hydrazine (0.144 mL, 4.59 mmol), and stirred at 85° C. in a screw cap vial (Pressure type) under a nitrogen blanket. Once complete, the solvent was removed by rotary evaporation and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.18 (m, 2H), 7.88 (s, 1H), 7.71 (m, 3H), 7.61 (d, 1H), 7.45 (d, 1H), 7.35 (s, 1H), 7.31 (d, 1H), 5.63 (d, 1H), 4.74 (d, 1H), 4.33 (m, 1H), 4.10 (m, 2H), 4.00 (m, s, 4H), 3.86 (m, 4H), 3.80 (m, 4H), 2.37 (s, 3H), 0.72 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(CBr)OC
Reactant: NCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CNCc1cc(Cl)cc(Cl)c1)OC
Temperature: 25 °C

Procedure:
A mixture of [(3,5-dichlorophenyl)methyl]amine (100 mg), 2-bromo-1, 1bis(methyloxy)ethane (123 μL) and K2CO3 (95 mg) in anhydrous DMF (2 mL) was processed by microwave irradiation at 150° C. for 10 min (3 cycles). The mixture was allowed to cool to rt, water was added and mixture extracted three times with AcOEt, the organic phases collected, washed with brine, dried and evaporated under vacuum to give a crude which was purified by flash cromathography eluting with CH:AcOEt=9:1 to 85:15 to afford the title compound (120 mg) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N-:11]=[C:12]=[S:13].[K+]>C(O)(=O)C>[N:11]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[C:12]=[S:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: [N-]=C=S
Agent: [K+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccnc1N=C=S

Procedure:
A 10 g sample of 2-chloro-3-nitropyridine, an 8 g sample of potassium isothiocyanate, and 75 ml of acetic acid were combined and refluxed for 2 h. The reaction mixture was then cooled and poured into 400 ml of ice/H2O. The resulting solid was washed with water, redissolved in ethyl acetate and washed (4x) with water. The ethyl acetate solution was then treated with activated carbon, dried over anhydrous Na2SO4, filtered and evaporated to dryness to provide 3.72 g of the title compound. m.p.=115°-118° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O.NN>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(-c2c[nH]cn2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(-c2c[nH]cn2)ccc1N
Yield: 100.7 %

Procedure:
4-(3-Methyl-4-nitrophenyl)-1-H-imidazole (9.2 g) was allowed to react with 85% hydrazine hydrate in methanol to give 7.9 g of 4-(3-methyl-4-aminophenyl)-1-H-imidazole, M.p. 195°-197° C. 4-(3-Methoxy-4-aminophenyl)-1-H-imidazole, M.p. 145° C. (dec.), was prepared analogously.