Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:11]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[C:1]([NH:4][C@@H:5]([CH2:6][S:7][S:20][CH2:19][C@H:18]([NH:17][C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])[C:21]([OH:23])=[O:22])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)(C)C(=O)N[C@@H](CS)C(=O)O
Product: CC(=O)N[C@@H](CSSC[C@H](NC(=O)C(C)(C)C)C(=O)O)C(=O)O

Procedure:
The compound was obtained following the procedure given in Example 18, starting from N-acetyl-L-cysteine and N-pivaloyl-L-cysteine.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:28][C:29]1[S:33][CH:32]=[N:31][CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:32]4[S:33][C:29]([CH3:28])=[CH:30][N:31]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: Cc1cncs1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ncc(C)s4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 5-methylthiazole
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:18][C:19]1[C:34]([Cl:35])=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])=[C:21]([OH:36])[CH:20]=1.Cl[CH:38]([CH3:42])[C:39](=[O:41])[CH3:40].Cl>C(#N)C>[ClH:35].[NH2:18][C:19]1[C:34]([Cl:35])=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[O:24])=[C:21]([O:36][CH:38]([CH3:42])[C:39](=[O:41])[CH3:40])[CH:20]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(=O)C(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)=O
Reaction time: 16 h

Procedure:
A solution of the tetra-n-butylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (0.53 g, 1.0 mmole) in acetonitrile (6 ml) was treated with 3-chloro-2-butanone (0.11 ml, 0.12 g, 1.1 mmole) and stirred at 20° for 16 hours. After removal of the acetonitrile at reduced pressure, the residue was treated with 10 ml water and extracted with ethyl acetate. The extracts were washed with dilute sodium carbonate, dried and concentrated to leave an oil which was converted to a monohydrochloride salt with 1.0 ml 1N hydrochloric acid. Crystallization of this salt from 2-propanol-ethyl acetate gave the title compound, mp. 176°-179°. This material was identical to that prepared in Example 7C.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])=[CH:10][C:9]=1[O:20][CH3:21])[CH2:4][CH2:5][CH3:6]>CO.O>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[O:20][CH3:21])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc(/C=C/C(=O)OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOc1ccc(/C=C/C(=O)O)cc1OC
Temperature: 60 °C
Yield: 92.3 %

Procedure:
10 g (0.15 mol) potassium hydroxide were dissolved in a mixture of 200 ml methyl alcohol and 5 ml water. 4.85 g (18.35 mmol) methyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate was added. The reaction mixture was subsequently heated to 60° C. After 2.5 h the mixture was concentrated by evaporation. The residue was dissolved in 100 ml cold water and acidified to pH=1 with 13.5 ml hydrochloric acid 37 wt. %. The product was filtered off, washed with water and dried at 50° C. under vacuum to give 4.24 g (92%) (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoic acid as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:39])[O:14][CH2:15][C@@H:16]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[Cl:37])=[O:27])[CH2:17][C:18]([F:24])([F:23])[CH2:19][N:20]=[N+]=[N-])=[CH:5]2.C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:39])[O:14][CH2:15][C@@H:16]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[Cl:37])=[O:27])[CH2:17][C:18]([F:23])([F:24])[CH2:19][NH2:20])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(F)(F)CN=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(F)(F)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a mixture of (S)-5-azido-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 6-fluoroisoquinolin-3-ylcarbamate (25.0 g, 0.0441 mol), THF (300 mL) and water (100 mL) was added triphenylphosphine (13.9 g, 0.0529 mol) and aq. HCl solution (53 mL, 2N, 0.106 mol). The resulting mixture was stirred at RT for 1 h and concentrated down to about 200 mL. Water (200 mL) was then added. The resulting mixture (pH<4) was extracted with EtOAc (300 mL) and the EtOAc solution was discarded. The remaining aq. solution was adjusted to pH>8 by adding NaOH (2N) and extracted with DCM (200 mL×3). The organic layer was washed with water and brine, dried over Na2SO4. The organic layers were combined and concentrated. The resulting residue was purified on silica gel column (DCM/MeOH) to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 6-fluoroisoquinolin-3-ylcarbamate (12.1 g, 50.7%). LRMS (M+H+) m/z 542.5.
Reaction SMILES: O[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6](OC)[C:5](OC)=[C:4](OC)[CH:3]=1.CO[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.CC([O-])(C)C.[K+]>C(O)C>[C:22]1([CH:23]=[CH:9][C:8]([C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH:25]=[CH:26][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1OC
Reactant: COc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 143.6 %

Procedure:
To a solution of 1-(6-hydroxy-2,3,4,-Trimethoxyphenyl)ethanone 5 (2.26 g, 10 mmol), 4-methoxybenzaldehyde (1.63 g, 12 mmol) and t-BuOK (2.11 g, 22 mmol) in ethanol (30 mL) was refluxed for 4 h. The reaction mixture was poured onto crushed ice (100 g). The resulting precipitate was filtered and washed with water. The residue was air-dried at room temperature. The crude product was recrystallized from ethyl acetate to afford chalcone as orange crystals (2.99 g, 87%): 1H NMR (CDCl3, 200 M Hz) δ 11.75 (br s, 1H), 7.84 (s, 2H), 7.60 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.29 (s 1H), 3.93 (s 3H), 3.90 (s, 3 M), 3.85 (s, 3H), 3.84 (s, 3H); 13C NMR (CDCl3, 50 M Hz) δ 192.7 (s), 162.6 (s), 161.5 (s), 159.9 (s), 154.9 (s), 143.3 (d), 135.2 (s), 130.1 (d, 2C), 128.0 (s), 124.0 (d), 114.4 (d, 2C), 108.7 (s), 96.5 (d), 61.8 (q), 61.2 (q), 56.0 (q), 55.3 (q).
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:22]([CH:24]([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1>CCOC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[C:16]1([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:22](=[O:23])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:30]2[OH:31]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(Cl)cc2)CCCCC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCCC2)C1=O
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Triflic acid (40.4 mL) was added dropwise via addition funnel to diethyl 2-(1-(4-chlorophenyl)cyclohexanecarbonyl)malonate (17.65 g, 46.3 mmol) at 0° C. The resulting mixture was stirred for 1 hour and then poured into a beaker of ice. The resulting mixture was diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 75 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (7.24 g) which was used without further purification. MS (m/z)=335 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)NCC1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A suspension of N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]acetamide 62 (20.0 g, 52.8 mmol) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol) at room temperature, and the resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The reaction mixture was then degassed three times again under a steady stream of argon before being heated to reflux for 7 h. When TLC and LCMS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl solution (50 mL), dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the crude desired N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 81 (18.8 g, 20.0 g theoretical, 94%) as a brown solid which was of sufficient purity to be used in subsequent reactions.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][O:1][C:2]2[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=3)[CH2:9][CH2:8][N:7]2[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OCC3CC3)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]=2[N:9]=[C:8]1[CH3:25])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:25][C:8]1[N:7]([CH2:6][CH2:5][OH:4])[C:15]2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10]=2[N:9]=1
Reactant: CC(=O)OCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCO)c2c1C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
1-[2,6,7-Trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]eth-2-yl acetate (11.1 g, 33.0 mmol), methanol (250 mL), and potassium carbonate (1.14 g, 8.25 mmol) were combined with stirring and heated to 45° C. under nitrogen. The reaction was complete after 30 minutes, and the reaction mixture was concentrated under reduced pressure to a solid, which was dissolved in dichloromethane. The resulting solution was subjected to flash chromatography using 9/1 dichloromethane/methanol. A white solid was isolated and dried to provide 9.1 g of product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:25]1[C:34]2[C:29](=[C:30]([O:35][CH3:36])[CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1>>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[N:28]=[CH:27][CH:26]=[C:25]2[N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:2][CH2:3]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Reactant: COc1cccc2c(Cl)ccnc12
Product: CCCN(CCN1CCN(c2ccnc3c(OC)cccc23)CC1)C1CCc2c(O)cccc2C1

Procedure:
This compound was prepared from 9b (0.668 g, 2.1 mmol) and 17 (0.4 g, 2.1 mmol) following the procedure I to get 18b as white wax (yield 0.76 g, 75%). 1H NMR (400 MHz, CDCl3) δ ppm 0.92-0.95 (t, 3H, J=6 Hz), 1.58-1.65 (m, 3H), 2.04-2.14 (m, 2H), 2.73-2.96 (m, 13H), 3.25 (bs, 4H), 3.48 (s, 1H), 4.04 (s, 3H), 6.57-6.59 (d, 1H, J=8 Hz), 6.66-6.68 (d, 1H, J=8 Hz), 6.86-6.87 (d, 1H, J=4 Hz), 6.92-6.96 (t, 1H, J=8 Hz), 6.99-7.01 (d, 1H, J=8 Hz), 7.37-7.41 (t, 1H, J=8 Hz), 7.54-7.56 (d, 1H, J=8 Hz), 8.72-8.73 (d, 1H, J=4 Hz).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31]I)[O:11][C@@H:10]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:42]([O:49]CC)([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45]>>[CH2:24]([O:23][C@H:13]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:10]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:11][C@@H:12]1[CH2:31][P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOP(OCC)OCC
Reactant: IC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Yield: 70 %

Procedure:
A solution of (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(iodomethyl)tetrahydro-2H-pyran (0.7 g, 0.75 mmol, 1.0 equiv) in anhydrous triethyl phosphite (9.0 mL) was heated to 160° C. in a 50 mL sealed tube for 16 hours. The solvent was removed using a Kugelrohr distillation setup, and the material thus obtained was purified by silica gel chromatography, eluting with 50% EtOAc in petroleum ether, to give diethyl (((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate as a pale yellow oil (0.5 g, 70%). 1H NMR (300 MHz, CDCl3) δ 7.52-6.98 (m, 20H), 4.77-4.66 (m, 1H), 4.63 (d, J=6.2 Hz, 2H), 4.60-4.42 (m, 6H), 4.16-3.99 (m, 4H), 3.91 (dq, J=8.1, 5.1, 3.9 Hz, 1H), 3.88-3.82 (m, 1H), 3.78 (q, J=4.0 Hz, 4H), 2.25-1.95 (m, 2H), 1.33-1.22 (m, 6H). ESI (M+1) 675.2; calc for C39H47O8P 674.3.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.[ClH:18]>C(Cl)Cl.O1CCOCC1>[F:16][C:13]1[CH:12]=[N:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:15][CH:14]=1.[ClH:18]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ncc(F)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tert-butyl-1-(5-fluoropyrimidin-2-yl)ethylcarbamate (Method 56, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed give (S)-1-(5-fluoropyrimidin-2-yl)ethanamine as HCl salt as white solid (quantitative). MS: Calcd.: 141. Found: [M+H]+ 142.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:23])=[O:22])[CH:16]=2)[O:11][C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4]1.[CH:27]1([N:30]2[C:38]3[C:33](=[C:34]([C:42]4[NH:46][N:45]=[N:44][N:43]=4)[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=3)[CH:32]=[CH:31]2)[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:27]1([N:30]2[C:38]3[C:33](=[C:34]([C:42]4[NH:46][N:45]=[N:44][N:43]=4)[CH:35]=[C:36]([C:39]([N:8]4[CH2:7][CH2:6][C:5]5([CH2:4][C:3](=[O:2])[C:17]6[C:12](=[CH:13][CH:14]=[C:15]([C:18]7[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=7)[C:21]([NH2:23])=[O:22])[CH:16]=6)[O:11]5)[CH2:10][CH2:9]4)=[O:40])[CH:37]=3)[CH:32]=[CH:31]2)[CH2:28][CH2:29]1
Reactant: O=C(O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Reactant: NC(=O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(-c5nnn[nH]5)c5ccn(C6CC6)c5c4)CC2)O3)c1
Temperature: 50 °C
Reaction time: 23 h

Procedure:
3-(4-Oxospiro[chroman-2,4′-piperidin]-6-yl)benzamide hydrochloride (224 mg), 1-cyclopropyl-4-(tetrazol-5-yl)-1H-indole-6-carboxylic acid (135 mg), EDCI (115 mg), HOBT (91.2 mg) and triethylamine (0.209 ml) were dissolved in DMF (3 mL), and stirred at 50° C. for 23 hours. 1N hydrochloric acid and water were added to the reaction liquid, the formed solid was taken out through filtration, and the resulting solid was purified through silica gel thin-layer column chromatography (chloroform/methanol) to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.17-8.10 (2.0H, br m), 8.05 (1.0H, d, J=2.2 Hz), 7.99 (1.0H, dd, J=8.5, 2.2 Hz), 7.86-7.78 (4.0H, m), 7.63 (1.0H, d, J=2.9 Hz), 7.52 (1.0H, dd, J=7.7, 7.7 Hz), 7.40 (1.0H, s), 7.25 (1.0H, d, J=8.5 Hz), 7.15-7.13 (1.0H, m), 4.50-4.08 (1.0H, br m), 3.88-3.08 (4.0H, m), 2.96 (2.0H, s), 2.23-1.68 (4.0H, m), 1.15-1.08 (2.0H, m), 1.06-0.96 (2.0H, m). MS [M+H]+=588.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([F:18])([F:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:22]=1>>[F:17][C:8]1([F:18])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:30]#[C:29][C@@:27]([OH:31])([C:23]3[N:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH3:28])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: C#C[C@@](C)(O)c1cccnn1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(F)F
Product: C[C@@](O)(C#Cc1ccc2c(c1)-n1nc(C(N)=O)cc1C(F)(F)CO2)c1cccnn1

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,4-difluoro-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(pyridazin-3-yl)but-3-yn-2-ol to give a mixture of titled compound after purification by prep HPLC.
Reaction SMILES: [H-].[Na+].C(N1CCCCC(=O)C1)C1C=CC=CC=1.C(OP(CC(OCC)=O)(OCC)=O)C.C([N:39]1[CH2:45][CH2:44][CH2:43][CH2:42][C:41](=[CH:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40]1)C1C=CC=CC=1.[ClH:52].CCOC(C)=O>[Pd].CCO.C1COCC1>[ClH:52].[NH:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40]1
Reactant: CCOC(=O)C=C1CCCCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride and 1-benzylazepan-3-one were added to a THF solution of ethyl diethoxyphosphorylacetate with ice-cooling, and the mixture was stirred at ambient temperature for 2 hours to yield a stereoisomeric mixture of ethyl (1-benzylazepan-3-ylidene)acetate, which was treated with 4M HCl-EtOAc solution, followed by adding EtOH and 10% palladium on activated carbon and stirring under hydrogen atmosphere at ambient temperature for 15 hours to yield ethyl azepan-3-ylacetate hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[N:12][C:11]=1[C:24]([O:26]CC)=O.C[N:30](C=O)C.C(N)=O.C[O-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[N:12][C:11]=1[C:24]([NH2:30])=[O:26]
Reactant: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: NC=O
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(F)cc3F)c2cc1OC
Temperature: 100 °C
Yield: 96 %

Procedure:
To a 25 mL round bottom flask charged with a magnetic stir bar was added ethyl 4-[(2,4-difluorophenyl)amino]-6,7-dimethoxycinnoline-3-carboxylate (0.195 g, 0.50 mmol) (Method 27), anhydrous DMF (3 mL), formamide (0.135 g, 3 mmol), and 3 mL of a 0.5 M solution of sodium methoxide in MeOH. The reaction was warmed to 100° C. for 2 h before being allowed to cool to rt. The reaction was poured over water (˜50 mL) and the crude product precipitated from solution. The solid was collected via vacuum filtration using a Buchner funnel and was purified on 40 g silica using EtOAc/MeOH (4:1) as eluent providing 0.174 g (96%) of the title compound as a white solid. 1H NMR: 11.35 (s, 1H), 8.86 (s, 1H), 8.05 (s, 1H), 7.71 (s, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.18 (m, 1H), 6.69 (s, 1H), 4.06 (s, 3H), 3.50 (s, 3H); m/z 361.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.C1(=O)OC(=[O:28])C2=CC=CC=C12.C(=O)([O-])[O-].[Na+].[Na+].OO>ClCCl.O>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:28])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 81.6 %

Procedure:
To a solution of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole (11) (32.9 gm, 0.1 mole) in dichloromethane (200 ml) was added phthalic anhydride (20 gm, 0.135 mole) and cooled in an ice salt bath. This was followed by addition of sodium carbonate (18 gm, 0.17 mole) and water (20 ml). Hydrogen peroxide (12 ml, 45%, 0.16 mm mole) was added dropwise at −5 to 0° C. and the reaction mixture was stirred at the same temperature. When the reaction was complete as indicated by TLC, water (200 ml) was added, cooling bath was removed and the reaction mixture was stirred for 10 mins. The organic layer was separated and washed with 5% sodium carbonate solution. The separated dichloromethane solution was charcolised and filtered through celite. The filtrate was concentrated to 100 ml and ethyl acetate 100 ml was added thereto. The separated solid was filtered, washed with ethyl acetate and dried in vacuum oven to yield 28.20 gm of Omeprazole. Yield 82.4% of theoretical. Melting Point was 158-160° C. (dec.)