Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9](=O)[NH:8][C:7]=2[CH:19]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][NH:8][C:7]=2[CH:19]=1
Reactant: COc1ccc2c(c1)NC(=O)C(c1ccccc1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)NCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an inert atmosphere, the compound obtained in Step B (3.26 g; 12.77 mmol) is dissolved in 70 ml of anhydrous tetrahydrofuran (6 ml/1 mmol), and then lithium aluminium hydride (5 eq.; 63.85 mmol; 2.42 g) is added in portions at 0° C. The mixture is stirred at ambient temperature for 16 hours, and then the solution is hydrolysed at 0° C. with 2.4 ml of water, 2.4 ml of a 15% sodium hydroxide solution and 7.2 ml of water. The solution is stirred for 30 minutes, and the salts that have formed are filtered off using a Büchner funnel and the solvent is removed under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (8/2)). The title product is obtained in the form of a solid.
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[N:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:5][CH:4]=1>C(Cl)Cl>[CH2:13]([NH:14][CH2:2][C:3]1[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([CH:13]=[N:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:5][CH:4]=1)[CH:6]([CH3:7])[CH3:5]
Reactant: O=C(NN=Cc1ccc(CO)c2ccccc12)c1ccc(O)c(Cl)c1
Solvent: ClCCl
Product: CC(C)CNCc1ccc(C=NNC(=O)c2ccc(O)c(Cl)c2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (Resin—[Building block 1]—[Building block 2]) (50 mg, ˜0.05 mmoles) was swelled in CH2Cl2 (1 mL) for 15 min, then washed with CH2Cl2(2×0.5 mL). 0.4 mL CH2Cl2 and 0.4 mL diisopropylethylamine was subsequently added and the suspension was cooled to 0° C. Methanesulfonylchloride (0.1 mL) was dissolved in CH2Cl2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0° C. for 30 min, then at 25° C. for 1 hour. The resin was isolated by filtration and washed with CH2Cl2 (2×0.5 mL) and DMSO (0.5 mL). DMSO (0.5 mL) was added followed by 50 μL isobutylamine and 100 μL diisopropylethylamine. The mixture was shaken at 25° C. for 16 hours, filtered and washed successively with DMSO (2×0.5 mL), THF (3×0.5 mL), CH3OH (0.5 mL), CH2Cl2 (0.5 mL), CH3OH (0.5 mL), CH2Cl2 (4×0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25° C. with a 50% solution of trifluoroacetic acid in CH2Cl2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH3OH (0.5 mL) and acetonitrile (0.5 mL) and concentrated in vacuo to give the title compound
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C:7](=[CH:8][CH:9]=[C:10]3[C:19]=2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[CH:14]2)[CH:6]=1)(=O)C.[C:23]([O-])(=O)C>>[CH2:23]=[C:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@@H:20]1[C:7](=[CH:6][C:5](=[O:4])[CH2:22][CH2:21]1)[CH2:8][CH2:9]3
Reactant: CC(=O)Oc1ccc2c3c(ccc2c1)[C@@H]1CC=C[C@@]1(C)CC3
Reactant: CC(=O)[O-]
Product: C=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
ESTRA-1,3,5,7,9,16-HEXAEN-3-YL ACETATE (Acetate of E10/N1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](Br)=[C:13]([CH3:18])[CH:12]=2)=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>O.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([C:35]3[CH:36]=[CH:37][S:33][CH:34]=3)=[C:13]([CH3:18])[CH:12]=2)=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: COc1ccc(NC(=O)c2ccc(Br)c(C)c2)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2ccc(-c3ccsc3)c(C)c2)cc1N1CCN(C)CC1
Yield: 68.3 %

Procedure:
N-(4Methoxy-3-(4-methyl-1-piperazinyl)phenyl)-4-bromo-3-methylbenzamide (0.35 g, 0.84 mmol), sodium carbonate (89 mg, 0.84 mmol), tetrakis (triphenylphosphine)palladium(0) (49 mg, 0.05 equiv), 3-thiophenyl boronic acid (115 mg, 0.84 mmol) in water (18 ml) and DME (18 ml) were heated at reflux under argon for 18 h. The solution was partitioned between saturated aqueous potassium carbonate solution (50 ml) and chloroform (50 ml), the organic extracts dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The resulting oil was purified by column chromatography (silica, chloroform/methanol 5-30%) to afford the tide compound as an oil (242 mg, 63%) which was crystallised as an oxalate salt from methanol chloroform.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([Li])CCC.CCCCCC.[B:26]([O:35]C(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([O:27][B:26]([OH:35])[OH:31])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(OB(O)O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Compound (c) (10.0 g) dissolved in tetrahydrofuran (THF) (40 mL) was cooled to −78° C., a 1.6 M butyllithium/hexane solution (30 mL) was slowly added dropwise and the mixture was stirred at the same temperature for 2 hours. Triisopropyl borate (14.0 g) dissolved in THF (20 mL) was then slowly added dropwise at −78° C., and the mixture was stirred at the same temperature for 1 hour. The temperature was increased to room temperature and the final solution was stirred. After adding 3 M hydrochloric acid (200 mL) dropwise at ice-cooling temperature, the aqueous layer was extracted three times with ether. The organic layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 8.28 g of Compound (d).
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH2:44].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>C(#N)C.C(OCC)(=O)C>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]([N:16]1[C@H:20]([C:21]([NH:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: Nc1ccccn1
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccccn2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (Intermediate 4) (150 mg, 0.3 mmol), 2-pyridinamine (32 mg, 0.33 mmol) and 2-chloro-4,6-bis(methyloxy)-1,3,5-triazine (58 mg, 0.33 mmol) in acetonitrile (4 mL) under N2 was added 4-methylmorpholine (65 mg, 0.66 mmol) dropwise. The mixture was stirred at rt overnight. TLC showed that the reaction was complete. The mixture was diluted with ethyl acetate and washed with 5% citric acid, followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to provide the titled compound (110 mg, 70%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[C:4]([C:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=2)=[CH:3]1
Reactant: Cn1ccc2cc(NS(C)(=O)=O)ccc21
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2cn(C)c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 79.7 %

Procedure:
Beginning with 1.23 gm (5.5 mMol) N-methyl-5-methanesulfonylamino-1H-indole and 0.88 mL (7.1 mMol) 1-methyl-4-piperidone, 1.4 gm (80%) of the title compound were recovered as a tan, crystalline powder.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[C:6]([C:16]2[CH:17]=[C:18]3[CH:24]=[CH:23][NH:22][C:19]3=[N:20][CH:21]=2)=[N:5]1)([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:25][C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([C:6]3[C:7]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=4)=[CH:8][N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:17]=2)[NH:22][CH:23]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)n1cc(-c2ccnc(N)c2)c(-c2cnc3[nH]ccc3c2)n1
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccnc(N)c2)c(-c2cnc3[nH]cc(Cl)c3c2)n1
Reaction time: 4 h
Yield: 30.5 %

Procedure:
A mixture 4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyridin-2-amine (H-1-10) (40 mg, 0.13 mmol) and N-chlorosuccinimide (19.3 mg, 0.14 mmol) in CH2Cl2 (2 ml) was stirred at room temperature for 18 hours. Another portion of N-chlorosuccinimide (5 mg, 0.04 mmol) was added and stirring continued at room temperature for an additional 4 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to give 14 mg (31% yield) 4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyridin-2-amine (H-1) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.82 Hz, 6H) 4.43-4.69 (m, 1H) 6.22-6.63 (m, 4H) 7.72 (d, J=2.78 Hz, 1H) 7.82 (d, J=5.81 Hz, 1H) 7.92 (d, J=1.77 Hz, 1H) 8.23 (s, 1H) 8.30 (d, J=2.02 Hz, 1H) 12.08 (d, J=1.77 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[NH:9][N:8]=2)[CH:2]=1.[OH-].[Na+]>C(O)C.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(-c2cccnc2)n[nH]1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (1.577 g, 7.26 mmol) in Ethanol (60 ml) and THF (60 ml) was reacted with 1M NaOH solution (40 ml, 7.26 mmol) and heated to 60° C. for 2 h. The solvents were evaporated under reduced pressure and the residue was diluted with water. The solution was made acidic by the addition of 2 N HCl solution. The resultant mixture was stirred in ice-cold bath for 4 h and the solid precipitated was filtered, dried and weighed. Yield 378 mg. 1H NMR (400 MHz; d6-DMSO): δ 7.39 (m, 2H), 8.21 (d, 1H), 8.53 (bs, 1H), 9.06 (bs, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=4)=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[CH3:40][N:41](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([NH:41][CH3:40])=[O:30])=[CH:31][CH:32]=4)=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC)cc3)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
To a mixture of 0.055 g (0.12 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-144) and 0.06 g (0.15 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.03 mL (0.186 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.09 mL (0.186 mmole) of 2M methylamine in tetrahydrofuran was then added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water. The aqueous phase was twice extracted with ethyl acetate, and the combined organic layers were washed with water, brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (30:70) to give 0.029 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-methyl-benzamide (I-146).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=3)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=3)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCCCn2c(-c3ccccc3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCCCn2c(-c3ccccc3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 89.2 %

Procedure:
Methyl 4-[4-(2,4,5 triphenylimidazolyl]butyloxy)-benzoate (1.5 g) was dissolved in methanol (50 ml) and treated with 10% potassium hydroxide solution (15 ml) for 0.5 hours. The methanol was removed under reduced pressure and the remaining aqueous was acidified (pH4) and the pre-cipitate was collected by filtration and recrystallised from methanol to give 4-[4-(2,4,5-triphenylimidazolyl)-butyloxy]-benzoic acid (1.3 g) as white prisms m.p. 202°-203° C.; Found: C, 78.79; H, 5.75; N, 5.81% (C32H28N2O3);Requires: C, 78.66; H, 5.78; N, 5.73%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 40 g. of 4-benzyloxyphenol, 45.8 g. of ethyl bromoacetate, 40.0 g. of potassium carbonate, 2 g. of potassium iodide and 400 ml. of acetone was heated at reflux for 24 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue was recrystallized from an ether-petroleum ether mixture to give 50 g. of ethyl 4-benzyloxyphonoxyacetate, m.p. 72°-73° C.
Reaction SMILES: [O-2].[Ca+2:2].[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].O>CCCCCC>[NH2:3][C@H:4]([C:10]([O-:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[Ca+2:2].[NH2:3][C@H:4]([C:10]([O-:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Solvent: CCCCCC
Product: NCCCC[C@H](N)C(=O)[O-]
Reaction time: 5 h
Yield: 99.3 %

Procedure:
5.6 grams (0.1 Mole) of calcium oxide and 29.2 grams (0.2 Mole) of lysine were placed into a beaker provided with a reflux condenser and a Dean Stark water trap. 100 ml hexane was added and the mixture was stirred and boiled at atmospheric pressure for 5 hours. The reaction mixture was cooled, and was thereafter filtered yielding 32.8 grams of calcium lysinate having the physical characteristic of a fine white powder. In the course of reaction about 3.6-3.8 ml water was removed from the reaction media and acquired in the Dean Stark apparatus.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C1COCC1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reactant: NCc1cccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCc3cccnc3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 162: step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol), (Example 2: step c), 3-aminomethyl pyridine (0.046 g, 0.430 mmol), THF [4.0 mL]. Chromatography of the residue (25%–50% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C18H16BrN3O4S3: 515.44 (M+H); found 514.1, 516.0.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12](I)[CH:13]=[C:8]2[N:7]=1)C.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][O:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:16][N:15]1[C:9]2=[N:10][CH:11]=[C:12]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:13]=[C:8]2[N:7]=[C:6]1[NH2:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccn5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.7 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.250 g, 0.42 mmol), 2-(tributylstannyl)pyridine (0.235 g, 0.63 mmol), copper(I) iodide (0.040 g, 0.21 mmol) and triethylamine (0.130 g, 1.26 mmol) in N,N-dimethylformamide (5 mL) was added bis(triphenylphosphine)palladium(II) dichloride (0.018 g, 0.042 mmol). The mixture was irradiated in a microwave reactor at 140° C. After 1.5 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated. The residue was purified by prep-HPLC to afford 0.025 g (13%) of the product as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=4.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.84-7.76 (m, 1H), 7.74-7.72 (m, 1H), 7.32-7.29 (m, 1H), 7.12 (d, J=6.0 Hz, 1H), 7.00-6.77 (m, 3H), 6.82 (d, J=8.5 Hz, 1H), 6.83-6.74 (m, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H) ppm; (M+1)=469.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1.[Cl:16]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([Cl:16])=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Brc1cc2[nH]c(-c3cnco3)cc2cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1c(-c2cnco2)[nH]c2cc(Br)ncc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
5-(6-Bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)oxazole (Preparation 139, 80 mg 0.303 mmole) was dissolved in DMF (0.8 mL) and N-chlorosuccinimide (40.4 mg 0.303 mmole) was added. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate (20 mL) and washed with water (3×7 mL) and brine. The combined aqueous layers were back-washed with ethyl acetate. The organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (86 mg). 1H-NMR (d6-acetone, 500 MHz): 7.66 (d, J=0.95 Hz, 1H), 7.84 (s, 1H), 8.40 (s, 1H), 8.66 (d, J=0.63 Hz, 1H), 11.62 (br s, 1H, NH).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=1)=O.[NH2:27][C:28]([NH2:30])=[S:29]>C(O)C.C(Cl)(Cl)Cl>[NH2:30][C:28]1[S:29][CH:2]=[C:3]([C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:6]=2)[N:27]=1
Reactant: NC(N)=S
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)CBr)sc2-c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2cc(-c3csc(N)n3)sc2-c2ccc(F)cc2)cc1
Yield: 32.6 %

Procedure:
A mixture of 5-(bromoacetyl)-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (2 g) and thiourea (0.61 g) in ethanol (80 ml) was refluxed for 30 minutes. The mixture was dissolved in chloroform, washed with an aqueous solution of sodium bicarbonate and water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and acetone (10:1) to give pale yellow crystals to 5-(2-amino-4-thiazolyl)-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (0.62 g).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C(=O)C)[CH2:8][CH2:7]1)=[O:5].[ClH:20]>>[ClH:20].[Br:1][C:2]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2Br)CC1
Agent: Cl
Product: O=C(c1ccc(Br)cc1Br)C1CCNCC1

Procedure:
A stirred mixture of 1-[4-(2,4-dibromo-benzoyl)-piperidin-1-yl]-ethanone (11.00 g, 28.3 mmol) and aqueous 5M hydrochloric acid (60 ml) was heated under reflux under nitrogen for 7 h. The mixture was evaporated in vacuo to give the title compound as a white solid (10.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:12]=3[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH:32]=[CH:31][CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[C:10](=[O:34])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:42]=CC=C[CH:38]=1.C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([O:19][CH:37]([CH3:42])[CH3:38])=[CH:18][C:12]=3[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:30][CH:31]=[CH:32][CH2:33]4)=[O:28])=[CH:23][CH:22]=3)[C:10](=[O:34])[CH2:9]2)=[O:7])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccc(O)cc32)cc1)N1CC=CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22 mg (0.044 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-8-hydroxy-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 5 ml of THF. 15 mg (0.05 mmol) of triphenylphosphine, 0.004 ml (0.05 mmol) of isopropyl alcohol and 25 mg (0.05 mmol) of diethylazo dicarboxylate were added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.