Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[N:17]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:16]=[N:15]2)=[CH:10][CH:9]=1.[C:28]([CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=2)[O:32]1)(=[O:30])[NH2:29]>O1CCCC1>[CH:23]1([CH2:22][CH2:21][CH2:20][N:17]2[C:18](=[O:19])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][S:41]([C:36]4[CH:37]=[C:38]5[C:33](=[CH:34][CH:35]=4)[O:32][CH:31]([C:28]([NH2:29])=[O:30])[CH2:40][CH2:39]5)(=[O:42])=[O:43])=[CH:13][CH:12]=3)[N:15]=[N:16]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC(=O)C1CCc2cc(S(=O)(=O)Cl)ccc2O1
Reactant: Nc1ccc(-n2nnn(CCCC3CCCC3)c2=O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(=O)C1CCc2cc(S(=O)(=O)Nc3ccc(-n4nnn(CCCC5CCCC5)c4=O)cc3)ccc2O1
Temperature: 50 °C
Yield: 55.5 %

Procedure:
Pyridine (650 mL, 8.03 mmol) followed by a solution of 1-(4-aminophenyl)4-(3-cyclopentylpropyl)-5-tetrazolone (2.1 g, 7.32 mmol; prepared as described in WO 97/16189) in tetrahydrofuran (50 mL) were added to a cooled (0° C.) solution of the compound from Example 22 (2.02 g, 7.33 mmol) in tetrahydrofuran (50 mL). The mixture was heated to 50° C. overnight. Pyridine (650 mL) was added and the mixture re-heated to 50° C. After 72 hours the mixture was partitioned between ethyl acetate and water. The organic layer was washed with 5% aqueous hydrochloric acid (2×), saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried (MgSO4), and concentrated to a solid (3.7 g). The crude was recrystallized from ethyl acetate (260 mL). The recrystallization mixture was cooled to 0° C. before filtering to give colorless crystals (2.14 g). A second crop afforded 1.09 g. The combined yield was 3.22 g (83%). Mp 202-205° C.; 1H NMR (DMSO-d6, 300 MHz) δ 10.43 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.53 (m, 3H), 7.37 (br s, 1H), 7.26 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.5 Hz, 1H), 4.57 (dd, J=8.5 Hz, 3.3 Hz, 1H), 3.92 (t, J=7.0 Hz, 2H), 2.71 (m, 2H), 2.13 (m, 1H), 1.89 (m, 1H), 1.72 (m, 5H), 1.49 (m, 4H), 1.30 (m, 2H), 1.03 (m, 2H); MS (FAB) m/z 527 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:2]2[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(N)ncc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C)c(C#N)cn2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred mixture of 6-amino-4-methylnicotinonitrile 4-2, which was prepared by using a similar method described in WO199618616 (669 mg, 5.02 mmol) and N,N-dimethylformamide (15.0 mL) at 0° C. under an atmosphere of nitrogen gas was added sodium hydride (60% dispersion in mineral oil; 605 mg, 15.1 mmol). To the mixture was added 4-methoxybenzyl chloride (1.70 mL, 12.5 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with methanol (5.0 mL) and concentrated under reduced pressure. To the resulting residue was added water (50 mL) and the resulting mixture was extracted with dichloromethane (60 mL, 30 mL×2). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 30 g, step gradient eluting with 10:1, 5:1, and 2:1 hexane/ethyl acetate) to give 1.78 g (95%) of 4-3 as a pale brown solid: 1H NMR (300 MHz, CDCl3) δ 8.39 (1H, s), 7.11 (4H, m), 6.85 (4H, m), 6.32 (1H, s), 4.71 (4H, br s), 3.79 (6H, s), 2.33 (3H, s); ESI-MS m/z 374 [C23H23N3O2+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([O:38]CC)=[O:37])=[N:5]1.[OH-].[K+:42]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:34])([F:35])[F:33])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([O-:38])=[O:37])=[N:5]1.[K+:42]
Reactant: CCOC(=O)c1nn(CCO)c2c1CCc1cnc(Nc3cc(N4CCN(C)CC4)ccc3OC(F)(F)F)nc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(=O)[O-])nn3CCO)CC4)c2)CC1
Yield: 89 %

Procedure:
Ethyl 1-(2-hydroxy-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.7 g, 3.03 mmol) was suspended in ethanol 96% (50 mL) and treated with a 1.5 M solution of potassium hydroxide in ethanol (8 mL, 12 mmol) at room temperature, overnight. The precipitate was collected by filtration to give the title compound (1.54 g, 89% yield) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:14]1[C:23]2[C:18](=[C:19]([Cl:25])[CH:20]=[C:21]([Cl:24])[CH:22]=2)[CH2:17][N:16]([CH3:26])[CH2:15]1)(=[O:3])C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[C:19]([Cl:25])[CH:20]=1)[CH2:17][N:16]([CH3:26])[CH2:15][C@H:14]2[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]1[C:6](=[O:27])[CH2:5][O:4][C:1]1=[O:3]
Reactant: CC(=O)OCC(=O)Nc1ccccc1[C@@H]1CN(C)Cc2c(Cl)cc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)COC2=O)C1
Yield: 92.5 %

Procedure:
[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl-carbamoyl]methyl acetate (180 mg) was dissolved in methanol (5 ml). With stirring, potassium carbonate (305 mg, finely powdered) was added and the mixture was then stirred efficiently at room temperature for 4 h. Subsequently, the solvent was evaporated off, and the residue was taken up in ethyl acetate and washed three times with water. The ethyl acetate phase was dried with magnesium sulfate, filtered and concentrated. 160 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH:9]=[CH2:10])[O:3][Si:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6].[CH:12]#[C:13][CH2:14][CH2:15][CH2:16]CC>C1(C)C=CC=CC=1>[C:5]([Si:4]([CH3:8])([CH3:7])[O:3][Si:2]([CH3:1])([CH3:11])[CH:9]=[CH2:10])#[C:6][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCCCC
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: C=C[Si](C)(C)O[Si](C)(C)C#CCCCCC

Procedure:
As in reaction conditions of Example XIX Step 1, to 6.25 mL of toluene, the 0.05 g carbonylchlorohydridebis(triisopropylphosphine)ruthenium(II) was added, and the reaction was carried out between 2.87 g 1,1,3,3-tetramethyl-1,3-divinyldisiloxane and 0.49 g 1-heptyne. Raw 1-(1-heptynyl)-1,1,3,3-tetramethyl-3-vinyldisiloxane was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: O=Cc1nccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 1-isoquinoline-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil. Deprotection with TFA using General Procedure F gave (3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidin-4-yl-amine as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([O:27][CH2:28][CH:29]2[CH2:30][CH2:31]2)=[C:11]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1cccc(OCc2ccccc2)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C(c1cccc(OCc2ccccc2)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 93.2 %

Procedure:
To a solution of [3-benzyloxy-2-cyclopropylmethoxy-phenyl]-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (131, 0.99 g, 2.28 mmol) in tetrahydrofuran (120 mL), Dess-Martin periodinane (2.4 g, 5.69 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes. The reaction was quenched with a saturated solution of sodium thiosulfate, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was dried over vacuum to provide the compound as a yellow solid (132, 0.92 g, 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:22])[OH:18])=[CH:3][C:4]=1[O:9][CH2:10][CH3:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1Cl
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a solution of 31A (3.8 g, 16 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 13.6 mL, 21.8 mmol). The mixture was stirred at −78° C. for 40 min before triisopropyl borate (7.43 mL, 32 mmol) was added. The reaction was left stirring, from −78° C. to rt over 18 h. It was quenched with 1.0 N HCl (50 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. The crude residue was purified by flash column chromatography (CH2Cl2: EtOAc: MeOH=50:50:1) to give 1.85 g (57%) of 31B as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (t, J=7.03 Hz, 3H) 4.23 (d, J=7.03 Hz, 2H) 7.48 (d, J=7.91 Hz, 1H) 7.66 (d, J=6.15 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[NH2:17])=[CH:5][CH:4]=1.C([C:20]1[C:21]([N:29]=[CH:30][N:31]([CH3:33])C)=[N:22][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:26]1([C:23]2[CH:24]=[CH:25][C:20]3[C:33]([NH:17][C:11]4[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=4[S:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:31][CH:30]=[N:29][C:21]=3[N:22]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: COc1ccc(Sc2ccc(C)cc2Nc2ncnc3nc(C4CC4)ccc23)cc1

Procedure:
2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine (Example 118) was reacted with the product from Example 119A using the procedure from Example 102 substituting 2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.30 (m, J=5.52 Hz, 4H), 2.21-2.42 (m, 1H), 2.31 (s, 3H), 3.71 (s, 3H), 6.85 (d, J=8.82 Hz, 2H), 6.99-7.12 (m, 2H), 7.24 (d, J=8.82 Hz, 2H), 7.63 (d, J=8.46 Hz, 1H), 8.53 (s, 1H), 8.72 (d, J=8.46 Hz, 1H), 10.33 (s, 1H); MS (ESI)+ m/z 415 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2)(C)(C)C>Cl.C(OCC)(=O)C>[ClH:25].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(OCC(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccc(Cl)cc2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 177.6 %

Procedure:
Tert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[[3-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide hydrochloride (0.16 g, 88.9%) as crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.CCOCC.[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)(Cl)Cl.CO>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:39](=[O:40])[C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[CH3:36])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were added to 20 ml of dry ether, and the resulting mixture was stirred. To the mixture was added 710 mg of 2-methylbenzoyl chloride, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was subjected to thin-layer chromatography on silica gel, together with the product in Example 1 as an authentic compound, using a mixed solvent of chloroform/methanol (39/1), thereby indicating that in the mixture was formed 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)uridine. The Rf value was 0.62.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[NH:10][CH2:9][CH2:8][S:7]1)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:15]2>ClCCl.CN(C)C=O>[CH3:2][O:3][C:4]([CH:6]1[N:10]([C:25](=[O:26])[CH2:24][NH:23][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=3)=[O:22])[CH2:9][CH2:8][S:7]1)=[O:5]
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C1NCCS1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1SCCN1C(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 79 %

Procedure:
(±)-Thiazolidine-2-carboxylic acid methyl ester hydro-chloride (1.02 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (1.02 mmol) were coupled according to Procedure A (1:1 dichloromethane-dimethylformamide solvent) and the crude product triturated with 1:1 ether-hexanes giving a light yellow solid. Yield 79%; HPLC (60/40) 4.47 minutes (95%); TSPMS 382/384 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2](/[CH:7]=[CH:8]\[CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[K+:22].C(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([O-:6])=[O:5].[K+:22]
Reactant: CC(=CC(=O)O)/C=C\CC(C)CCCC(C)C
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C=CCC(C)CCCC(C)C)=CC(=O)[O-]

Procedure:
To a solution of 0.5 g. of trans/cis 3,7,11-trimethyldodeca-2,4-dienoic acid in 15 ml. of benzene is added with stirring an equivalent amount of potassium bicarbonate. The mixture is stirred until the evolution of carbon dioxide ceases and then evaporated to yield potassium 3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Br:15][C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.O>[Br:15][C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:14][CH:12]([OH:13])[CH2:11][CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(Br)nc2)c(Cl)n1
Temperature: 83.5 °C
Reaction time: 28 h
Yield: 36.9 %

Procedure:
A mixture of epoxide 129 (see Example 2AA) (1.004 g, 4.61 mmol), 6-bromo-3-pyridinol (4.015 g, 23.1 mmol) and powdered K2CO3 (3.319 g, 24.0 mmol) in anhydrous 2-butanone (10 mL) under N2 was stirred at 82-85° C. for 28 h. The resulting cooled mixture was diluted with water (100 mL) and extracted with 25% EtOAc/CH2Cl2 (3×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-40% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 40% EtOAc/petroleum ether gave 1-[(6-bromo-3-pyridinyl)oxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-butanol (137) (667 mg, 37%) as a cream solid: mp (MeOH/CH2Cl2/pentane) 112-114° C.; 1H NMR [(CD3)2SO] δ 8.56 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8, 3.2 Hz, 1H), 5.28 (br d, J=4.5 Hz, 1H), 4.24 (dd, J=14.0, 5.8 Hz, 1H), 4.18 (dd, J=14.2, 7.3 Hz, 1H), 3.99 (dd, J=10.0, 4.9 Hz, 1H), 3.96 (dd, J=10.0, 5.5 Hz, 1H), 3.82 (m, 1H), 2.06 (dtd, J=13.9, 7.7, 3.4 Hz, 1H), 1.90 (ddt, J=13.7, 9.2, 6.7 Hz, 1H); HRESIMS calcd for C12H13BrClN4O4 m/z [M+H]+ 394.9754, 392.9782, 390.9803. found 394.9753, 392.9777, 390.9797.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3,4-diamino-benzoic acid ethyl ester (5.00 g, 27.8 mmol) and 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h under argon. DCC (5.72 g, 27.8 mmol) was added and mixture heated to 80° C. for 45 min. After stirring the mixture was diluted with water and concentrated i.vac. The residue was diluted with ethanol and 1 M NaOH (aq). The mixture was heated to 100° C. and stirred overnight. Then ethanol was evaporated and the aq. phase was cooled, acidified with acetic acid, filtered and the solid washed with water.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[Br:10]Br.N([O-])=O.[Na+].[OH-].[Na+]>Br.O>[Br:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1
Reactant: BrBr
Reactant: CCc1cc(N)ccn1
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(Br)ccn1
Temperature: 0 °C

Procedure:
4-Amino-2-ethylpyridine (18 g) was dissolved with warming in 48 ml of 48% hydrogen bromide. The solution was cooled to 0° C. and 15 ml of bromine was added dropwise followed by a solution of 25.4 g of sodium nitrite in 37 ml of water over 1/2 hour while maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature over 2 hours and was then poured onto ice and made alkaline with 35% sodium hydroxide. The aqueous mixture was extracted three times with 200 ml of methylene chloride, the extract was concentrated and the residue was taken up in diethyl ether. The ether solution was dried over magnesium sulfate and concentrated in vacuo at below 40° C. to give, after chromatography (silica gel; 70:30 hexane-ether), 4.1 g of the title compound as an orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([O:22][P:23]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21].C(O)(C(F)(F)F)=O>>[CH2:25]([O:24][P:23]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([Cl:19])=[CH:4][N:3]=2)=[CH:33][CH:34]=1)(=[O:27])[O:22][CH2:20][CH3:21])[CH3:26]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)NC)n2)cc1)OCC
Yield: 23.8 %

Procedure:
A solution of 2-[(2,5-dichloropyrimidin-4-yl)amino]-N-methylbenzamide (29.7 mg, 0.100 mmol), diethyl(4-aminobenzyl)phosphonate (29.2 mg, 0.120 mmol), TFA (23 uL, 0.30 mmol) and TFE (1.0 mL) was heated at 100° C. for 30 minutes in a microwave reactor. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous NaSO4, filtered, and concentrated in vacuo to yield a yellow solid. This material was purified by preparative HPLC (MDP) to afford 12 mg of diethyl{4-[(5-chloro-4-{[2-(methylcarbamoyl)phenyl]amino}pyrimidin-2-yl)amino]benzyl}phosphonate (yield: 24%). 1H NMR (CD3OD, 400 MHz): δ=1.26 (t, J=7.07 Hz, 6H), 2.92 (s, 3H), 3.15-3.24 (m, 2H), 3.99-4.08 (m, 4H), 7.12 (td, J=7.64, 1.14 Hz, 1H), 7.21 (dd, J=8.59, 2.53 Hz, 2H), 7.48 (ddd, J=8.53, 7.26, 1.64 Hz, 1H), 7.55 (d, J=8.08 Hz, 2H), 7.65 (dd, J=7.83, 1.52 Hz, 1H), 8.06 (s, 1H), 8.70 (d, J=8.34 Hz, 1H). MS (ES+): m/z 506.15 [MH+] (TOF, polar).