Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@H:7]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH2:10]1)(=[O:5])[CH3:4].[OH-:38].[Na+].OO>C(O)C.O.C1COCC1>[C:3]([O:6][C@H:7]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]([OH:38])[CH2:10]1)(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@@H](CN1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reactant: [OH-]
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)O[C@@H](CN1CCC(CCOC(c2ccccc2)c2ccccc2)C(O)C1)c1ccc(F)cc1

Procedure:
With reference to FIG. 8, general procedure II was used. The quantities of the chemicals in order of addition are as follows: NaBH4 (0.029 g, 0.762 mmol), THF (10 ml), BF3-ether complex (0.1 ml, 0.81 mmol), (R)-2-(4-(2-(benzhydryloxy)ethyl)-5,6-dihydropyridin-1(2H)-yl)-1-(4-fluorophenyl)ethyl acetate 7c (0.180 g, 0.38 mmol), water (0.3 ml), ethanol (0.4 ml), 3N NaOH (0.3 ml) and 30% H2O2 (0.2 ml, 1.9 mmol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>CO.C(#N)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 2-fluoro-6-nitrobenzoic acid (712 mg, 3.85 mmol) in methanol/acetonitrile (10 mL/10 mL) was dropwise added TMSCHN2 at 0° C. under N2 until yellow color persistent, and stirred additional 30 min. Then the reaction was quenched with HOAcat 0° C. until the yellow color disappears. Partial of the solvent was removed o rotary vacuum, the residue was dissolved in small amount of EtOAc, purified on flash chromatography eluting with 30˜50% EtOAc/hexanes (600 mL) to afford the expected product, methyl 2-fluoro-6-nitrobenzoate, (716 mg, 94% yield) which was used in step-2; 1H NMR (400 MHz, CDCl3) δ ppm 3.96 (s, 3H), 7.40-7.48 (m, 1H), 7.58 (td, J=8.31, 5.54 Hz, 1H), 7.94 (d, J=8.31 Hz, 1H); Mass spec. 200.05 (MH+), Calc. for C8H6FNO4 199.03.
Reaction SMILES: Br[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(OCC)(=O)C>[C:13]([S:15][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:16])[CH3:14]
Reactant: CC([O-])=S
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 6 h

Procedure:
In a 3 l-jacketed reactor, with mechanical stirring, refrigerator and thermometer, (R)-2-bromo-3-phenyl-propionic acid (385.8 g, 1.68 moles), ethyl acetate (1,143 ml) and ALIQUAT 336° (4.2 g, 0.01 mole) were charged at 15° C. under nitrogen flow. The mixture temperature was brought to 0° C. and potassium thioacetate (222 g, 1.944 moles) was added in two portions. The reaction temperature was kept at 15° C. for 6 hours, then the mixture was twice washed with an aqueous solution of sodium thiosulfate pentahydrate (84.6 g in 820 ml of water over-all), then twice with demineralized water (600 ml total). The phases were separated and the organic one was concentrated under vacuum in a thermostated bath at 35-40° C. The resulting organic solution was cooled and filtered over celite, then added with ethyl acetate (600 ml). On the basis of the HPLC analysis, the yield in solution was equal to 87%.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[N:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[N:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cn4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)nc2)CC1
Yield: 22.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(6-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)piperazin-1-yl) propan-2-ol (100 mg, 0.150 mmol) was hydrolyzed with lithium hydroxide (13 mg, 0.300 mmol) in THF/methanol/water (5/2/1 mL) to yield 17 mg (22.0% yield) of desired product. 1H NMR (CDCl3, 400 MHz): δ 9.01 (s, 1H), 8.879-8.874 (d, 1H), 8.60-8.59 (d, 1H), 8.42-8.41 (d, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.69-7.67 (d, 1H), 7.742-7.41 (d, 1H), 7.34-7.29 (m, 2H), 7.07-6.96 (m, 3H), 5.39 (s, 2H), 4.00 (3.90, m 1H), 3.60-3.50 (bs, 1H), 3.36-3.32 (m, 4H), 2.95-2.90 (m, 2H), 2.70-2.60 (m, 2H), 2.50-2.30 (m, 2H), 1.19-1.18 (d, 3H). MS: m/z=512.35 (M+1), HPLC: 91.12% in method A.
Reaction SMILES: I.[CH3:2]C1C(C)NC(SC)=N1.I.CSC1NCCN=1.[NH2:19][C:20]1[N:21]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:22]2[N:23]([CH:29]([CH3:33])[CH:30]([CH3:32])[N:31]=2)[C:24](=[O:28])[C:25]=1[N:26]=O>>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:21]2[C:20]3[NH:19][CH:2]=[N:26][C:25]=3[C:24](=[O:28])[N:23]3[CH:29]([CH3:33])[CH:30]([CH3:32])[N:31]=[C:22]23)=[CH:36][CH:37]=1
Reactant: CC1N=C2N(Cc3ccc(Cl)cc3)C(N)=C(N=O)C(=O)N2C1C
Reactant: CSC1=NC(C)C(C)N1
Agent: CSC1=NCCN1
Agent: I
Product: CC1N=C2N(Cc3ccc(Cl)cc3)c3[nH]cnc3C(=O)N2C1C

Procedure:
Procedure 1 is repeated with substitution of 4,5-dimethyl-2-(methylthio)-2-imidazoline hydroiodide for the 2-(methylthio)-2-imidazoline hydroiodide specified. The resulting 7-amino-2,3-dihydro-2,3-dimethyl-8-[(4-chlorphenyl)methyl]-6-nitrosoimidazo[1,2-a]pyrimidin-5(8H)-one is converted to the corresponding 6-formylamino compound by the method of Procedure 2 and the latter is converted to the desired product by the method of Procedure 4.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1>N1C=CC=CC=1>[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: Brc1nccs1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Solvent: c1ccncc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2nccs2)C[C@H]1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of 2 parts of 2-bromothiazole and 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide was stirred for one hour at 60° C. The mixture solidified. It was suspended in 10 parts of pyridine and stirring was continued overnight at reflux. The reaction mixture was evaporated. The residue was taken up in a saturated sodium carbonate solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (93:7 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and the free base was liberated in the conventional manner and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 0.6 parts (11%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]benzamide; mp. 140.9° C. (compound 44).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[H-].[H][H].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NCCOCc2ccccc2)c1
Yield: 101.7 %

Procedure:
2-Benzyloxy-N-(2-chloro-5-methoxy-phenyl) acetamide (2) (18.9 g, 62.0 mmol) in THF (100 mL) was stirred and lithium aluminuim hydride (4.9 g, 130.0 mmol) was added slowly over 15 min. There was a rapid evolution of hydrogen gas as the first of the lithium aluminium hydride was added. The reaction was then heated to reflux for 4 h and allowed to stand at RT over the weekend. The reaction was then quenched by the dropwise addition of water (50 mL) to the stirred solution. There was a violent evolution of hydrogen causing the reaction mixture to reflux. The reaction was then concentrated in vacuum to a slurry. Water (200 mL) and ethyl acetate (200 mL) were added and the mixture vigorously shaken. The reaction was then filtered through celite to remove the precipitated aluminium hydroxide and the ethyl acetate solution was separated, dried over magnesium sulfate and concentrated in vacuo to afford 18.4 g (quantitative) of (2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl) amine (3) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 43.3, 55.3, 68.2, 73.0, 98.1, 101.8, 111.6, 127.6, 127.7, 128.4, 129.3, 137.9, 144.8, and 159.5.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([N+:14]([O-])=O)[CH:6]=1)[CH:2]=[CH2:3].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)=[O:31])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([C:30]([NH:29][C:26]4[CH:25]=[CH:24][C:23]([N:20]5[CH2:19][CH2:18][O:17][CH2:22][CH2:21]5)=[CH:28][CH:27]=4)=[O:31])=[CH:39][CH:38]=3)[NH:14][C:7]=2[CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: C=CCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: C=CCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)[nH]c2c1

Procedure:
Compound 632 was prepared according to the procedure similar to that described in Scheme III from 1-allyloxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C27H26N4O3: 455.21; found: 455.00.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:25][CH2:26]Cl)[S:21]([CH3:24])(=[O:23])=[O:22].O>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@@H:3]([N:2]1[CH2:26][CH2:25][N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](N)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)N(CCCl)CCCl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 44.1 %

Procedure:
A solution of 6 g (23.6 mmol) of methyl (R)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 5.2 g (23.6 mmol) of N,N-bis(2-chloroethyl)methanesulphonamide in 80 ml of N,N-diisopropylethylamine is heated at 125° C. with vigorous stirring for 18 h. After addition of water, the product is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography over silica gel eluted with a 5/5 heptane/ethyl acetate mixture. 3.8 g (44%) of methyl (R)-3-tert-butoxycarbonylamino-2-(4-methanesulphonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[N:17]=1.O>CN(C=O)C>[Cl:23][C:18]1[CH:19]=[C:20]([Cl:22])[N:21]=[C:16]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:12])[N:17]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: FC(F)c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
0.84 g (5 mmol) of 2-difluoromethylbenzimidazole dissolved in DMF (25 ml) was added and reacted with 60% sodium hydride (0.24 g, 6 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 2,4,6-trichloropyrimidine (0.92 g, 5 mmol) dissolved in DMF (25 ml) and stirred at room temperature for 1.5 hours. The reaction solution was poured into water and the resulting precipitates were recrystallized from methanol to obtain 0.98 g (yield: 62%) of 4,6-dichloro-2-(2-difluoromethylbenzimidazol-1-yl)pyrimidine. (2) 0.32 g (1.0 mmol) of 4,6-dichloro-2-(2-difluoro-methylbenzimidazol-1-yl)pyrimidine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate were added to DMF (10 ml) and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 84%) of 4-chloro-2-(2-difluoro-methylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)-pyrimidine. (3) 0.33 g (0.8 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethyl-morpholino)pyrimidine dissolved in morpholine (0.70 g, 8.0 mmol) was stirred at 70° C. for 1 hour. The solvent was removed under the reduced pressure from the reaction mixture and the residue was purified by silica gel column chromatography to obtain 0.326 g (yield: 90%) of the titled compound as colorless crystals.
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]2[N:25](CC3C=CN=CC=3)[C:26]([S:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=3)=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[O:21])(=[O:16])[O:9]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].[CH3:50][C:51]#[N:52]>>[C:1]1([O:7][P:8]([CH2:17][CH2:18][NH:19][C:20]([O:22][CH:23]([C:24]2[NH:25][C:26]([S:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=3)=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)[CH2:3][C:2]2[CH:1]=[CH:6][N:52]=[CH:51][CH:50]=2)=[O:21])(=[O:16])[OH:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)c1nc(COC(=O)NCCP(=O)(Oc2ccccc2)Oc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC#N
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1nc(C(Cc2ccncc2)OC(=O)NCCP(=O)(O)Oc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of phosphonate 31 (11 mg, 0.015 mmol) in CH3CN (0.5 mL) was added 1N LiOH (46 μL, 0.046 mmol) at 0° C. See Scheme 21 (FIG. 23). After the reaction mixture was stirred for 2 h at 0° C., Dowex 50WX8-200 (26 mg) was added and stirring was continued for an additional 30 min. The reaction mixture was filtered, rinsed with CH3CN, and concentrated under reduced pressure to give {2-[5-(3,5-dichloro-phenylsulfanyl)-4-isopropyl-1-pyridin-4-ylmethyl-1H-imidazol-2-ylmethoxycarbonylamino]-ethyl }-phosphonic acid monophenyl ester 32 (10 mg, 100%) as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 8.52 (d, 2H), 7.28 (m, 6H), 6.79 (m, 4H), 5.60 (s, 2H), 5.29 (s, 2H), 3.29 (m, 3H), 1.83 (m, 2H), 1.31 (d, 6H). 31P NMR (300 MHz, CD3OD) δ 20.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.CN(C)C=O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:5]2[C:6]([C:7]#[N:8])=[CH:9][C:2]([Br:1])=[CH:3][N:4]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C#N)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a mixture of 5-bromo-2-chloronicotinonitrile (1.00 g), 1-Boc-piperazine (0.94 g) and potassium carbonate (1.27 g) were added toluene (4.5 mL) and N,N-dimethylformamide (10 mL), and the mixture was stirred at 100° C. for 4 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.52 g).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[NH2:9].O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:9][C:8]1[CH:10]=[C:11]([CH3:13])[C:12]([S:1][C:2]#[N:3])=[C:6]([CH3:5])[CH:7]=1
Reactant: N#C[S-]
Reactant: Cc1cc(C)cc(N)c1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)cc(C)c1SC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
251.2 g (3.30 mol) of ammonium thiocyanate are rapidly added to a solution, maintained under a nitrogen atmosphere, of 121.2 g (1 mol) of 3,5-dimethylaniline in 1.75 l of anhydrous N,N-dimethylformamide. The temperature rises from 18 to 35° C. One and a half hours later, the temperature of the solution having returned to room temperature, 263.3 g (1.65 mol) of anhydrous cupric sulphate are added rapidly. The reaction medium is left stirring at room temperature for 3 days and is then poured into 8 l of water. The pH is brought to 7.5 by addition of 550 g (6.55 mol) of sodium bicarbonate. The medium is then filtered, the solid part being washed with ethyl acetate and the liquid part being extracted with ethyl acetate. The combined organic liquid phases are washed with 500 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The pasty residue obtained is crystallized from 500 ml of hexane to give 128.8 g (72%) of 4-amino-2,6-dimethylphenyl thiocyanate which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CN(C)C=O.C(OCC)(=O)C>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)cccc1Br
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Br)cccc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclohexanol (0.275 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (60%, 0.069 g). After 30 minutes, 2-bromo-6-fluorobenzonitrile (0.500 g) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 10% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2](/[CH:27]=[CH:26]/[C:25]([O:29][CH3:30])=[O:28])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 100 °C

Procedure:
A mixture of 0.194 g (0.500 mmol) of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411, 0.180 mL (2.00 mmol) of methyl acrylate, 22.4 mg (0.0999 mmol) of palladium acetate, 122 mg (0.400 mmol) of tri-o-tolylphosphine and 0.278 mL, (2.00 mmol) of triethylamine in 4.0 ml of N,N-Dimethylformamide was heated at 100° C. for 6 hours. The mixture was concentrated in vacuum and partitioned between ethyl acetate and water. The organic extracts were washed with dilute aqueous HCl, water, brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified on 4 g silica column eluting with heptane-ethyl acetate gradient to give (E)-methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate. Yield 0.11 g. M/z 394.2, calc. 393.18
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl-].[NH4+].C([N:18]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (5.0 g) in N,N-dimethylformamide (100 mL) were added ammonium chloride (7.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (9.5 mL), l-hydroxybenzotriazole (8.3 g) and N,N-diisopropylethylamine (24 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the precipitate was collected by filtration to give the title compound (3.1 g).