Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>C1COCC1>[CH2:2]([O:1][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:3]([CH2:5][OH:6])[OH:4]
Reactant: OCC(O)CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC(O)COCc1ccccc1
Temperature: 25 °C

Procedure:
As an alternative procedure to a stirred solution of the protected glycerol (6.7 g, 0.05 mole) in dry THF (100 mL) was added NaH (1.8 g, 0.075 mole) portionwise at 0° C. The reaction mixture was refluxed for 1.5 h, and benzyl bromide (10.3 g, 0.06 mole) was added. The mixture was stirred at room temperature. Once the reaction was completed, 2 mL of methanol was added at 0° C. to destroy the excess of NaH. The reaction mixture was extracted with 3×50 mL of ethyl ether, and the combined ether layers dried over sodium sulfate. After solvent removal, the residue of (11.9 g, Y=61%). was combined with 60 mL of 10% acetic acid, then heated (oil bath, 100° C.), until the original emulsion disappeared (about 0.5 h), After concentration, the residue was distilled in vacuo, giving 8.1 g (b.p.116-118° C./50μ) (Y=89%).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3OC[CH2:20][NH:19][CH:18]([CH3:23])[C:16]3=2)[N:11]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:10]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C1COCC1>[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:5][CH2:3][CH2:2][N:19]([CH3:20])[CH:18]([CH3:23])[C:16]3=2)[N:11]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:10]=1
Reactant: CC1NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1c2c(ccc3c2c(Cl)cn3S(=O)(=O)c2ccccc2)OCCN1C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
10-Chloro-1-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole trifluoroacetate (Example 98, 59 mg, 0.15 mmol) in MeOH (1 mL) was converted to the free amine by PL-HCO3 MP SPE (Polymer Laboratories) column. Formaldehyde (37 wt. % in H2O, 0.20 mL, 2.4 mmol) was added to a solution of the free amine (0.15 mmol) in THF (1 mL). After stirring for 10 minutes at room temperature sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added and the mixture was stirred for an additional 30 minutes and evaporated. The crude material was purified by preparative HPLC (Xterra C18, 10 mM NH4HCO3 (pH 10) —CH3CN) to give the title compound as a white solid (28.9 mg). MS m/z 391 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH2:24]([NH:27][CH3:28])[CH:25]=[CH2:26]>>[CH2:24]([N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1)[CH3:28])[CH:25]=[CH2:26]
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Reactant: C=CCNC
Product: C=CCN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Allyl-methyl-amine were converted to yield Allyl-{4-[3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine, MS: 444 (MH+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:7]2[NH:8][C:9](=[O:26])[CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[C:23]([CH2:24]O)=[CH:22][N:21]=[N:20]4)[CH:14]=3)=[N:12][C:6]=2[CH:5]=1)[CH3:2].O=S(Cl)Cl.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:24][C:23]2[N:19]([C:15]3[CH:14]=[C:13]([C:11]4[CH2:10][C:9](=[O:26])[NH:8][C:7]5[CH:27]=[C:28]([C:29]([F:30])([F:31])[F:32])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:12]=4)[CH:18]=[CH:17][CH:16]=3)[N:20]=[N:21][CH:22]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Solvent: O=S(Cl)Cl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 7-ethoxy-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 52) (134 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and cyclopropylamine (10 eq.) as described in Example 47. Obtained as a yellow solid (55 mg).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].P([O-])([O-])([O-])=O>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
A mixture of aqueous solutions of 0.2 ml of 1 M D-glucose 0.2 ml of 0.05 M MgSO4.7H2O and 0.2 ml of 0.5 M phosphate buffer (pH = 7.2) is added to 0.2 ml of glucose isomerase extract and the solution is diluted with water to make 2 ml. The resulting diluted solution is maintained at a temperature of 70° C for 60 minutes to effect isomerization and the reaction is stopped by addition of 2 ml of a 0.5 M aqueous perchloric acid solution. Then the amount of fructose produced is determined by cystein-carbazole method. Then the activity titer expressed by the unit of U is given by the following equation: ##EQU2##
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
To a stirred solution of 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (4.4 gm, 19.05 mmol) in dichloromethane (100 mL) was added pyridine (6.15 mL, 76.19 mmol) under ice cold conditions, followed by addition of benzene sulfonyl chloride (6-01) (6.07 mL, 47.62 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (7-01) (2.3 gm, 32.51%) as an off white solid.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[OH:14][C:15]1[CH:24]=[CH:23][C:18]2[S:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1.O>CN(C)C=O>[Si:10]([O:14][C:15]1[CH:24]=[CH:23][C:18]2[S:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1oc2cc(O)ccc2s1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2sc(=O)oc2c1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
Imidazole (972 mg) and t-butylchlorodimethylsilane (2.15 g) were added to a solution of 6-hydroxy-1,3-benzoxathiol-2-one (2.00 g) in N,N-dimethylformamide (60 mL) to form a reaction solution. This reaction solution was stirred for 4 hours at normal temperature. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the target product (3.00 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH2:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 18 h
Yield: 111.1 %

Procedure:
tert-Butyl 4-(3-methyl-4-nitrophenoxy)piperidine-1-carboxylate (5.2 g, 14.30 mmoles) was dissolved in ethyl acetate (60 ml) and methanol (10 ml). The solution was treated with 500 mg of 10% palladium on carbon (50% water w/w). The slurry was then shaken on a Parr hydrogenator and treated with a 40 psi atmosphere of hydrogen gas, at room temperature. After 18 hours, the slurry was filtered through a plug of Celite, which was subsequently washed with ethyl acetate (50 ml) and methanol (50 ml). The resulting filtrate was then evaporated at reduced pressure and then triturated with hexane to give a solid. This material was filtered off and dried at reduced pressure to give 4.87 g of tert-butyl 4-(3-methyl-4-aminophenoxy)piperidine-1-carboxylate (100% yield). 1H-NMR (400 MHz, DMSO-d6) δ 6.33 (d, 1H), 6.32 (s, 1H), 6.23 (s, 1H), 5.85 (bs, 2H), 3.70 (m, 1H), 3.39 (m, 2H), 3.29 (m, 2H), 2.35 (s, 3H), 2.00 (m, 2H), 1.75 (m, 2H), 1.42 (s, 9H). MS (EI): for C18H28N2O3: 320 (MH+).
Reaction SMILES: [C:1]1([C:7]([CH3:12])([CH3:11])[CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:8][C:7]([CH3:12])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C[Mg]Br)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
2-Phenyl-2,2-dimethylethylmagnesium bromide (10 mmol, 20 mL of 0.5 M solution in diethyl ether) was added to solution of diethyl oxalate (1.5 g, 10.5 mmol) in anhydrous THF (20 mL) cooled to −78° C. and maintained under argon. After 1 hour, TLC in hexanes-EtOAc (7:1) indicated most of the diethyl oxalate had been consumed. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give a light brown, thick oil which was purified by flash column chromatography over silica gel eluting with 5% EtOAc in hexanes to yield 4-methyl-2-oxo-4-phenylpentanoic acid ethyl ester as a light yellow oil (1.1 g, 51%).
Reaction SMILES: [OH:1][C:2]1[C:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([CH3:10])[O:9][C:5]2=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30](S(C)(=O)=O)[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:35][O:34][C:32]1[N:33]=[C:28]([O:27][CH3:26])[N:29]=[C:30]([O:1][C:2]2[C:15]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]3[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([CH3:10])[O:9][C:5]3=[CH:4][CH:3]=2)[N:31]=1
Reactant: COC(=O)c1c(C)oc2ccc(O)c(C(=O)OCc3ccccc3)c12
Reactant: COc1nc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)oc2ccc(Oc3nc(OC)nc(OC)n3)c(C(=O)OCc3ccccc3)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
A mixture comprising 2 g of benzyl 5-hydroxy-2-methyl-3-methoxycarbonylbenzofuran-4-carboxylate, 1 g of 4,6-dimethoxy-2-methylsulfonyl-1,3,5-triazine and 1 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for two hours. The mixture was returned to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the obtained solid was thoroughly washed with ethanol to obtain 2.4 g (yield: 86%) of the desired compound.
Reaction SMILES: [CH2:1](Br)[C:2]1C=CC=CC=1.ICC.[CH3:12][C:13]1[N:14]=[C:15]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:1]([N:25]1[CH2:26][CH2:27][N:23]([C:15]2[S:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:12])[N:14]=2)[C:24]1=[O:28])[CH3:2]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccccc1
Solvent: CCI
Product: CCOC(=O)c1sc(N2CCN(CC)C2=O)nc1C
Yield: 58 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with iodoethane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 58% yield: 1H NMR (300 MHZ, CDCl3) δ 4.29-4.04 (m, 4H), 3.64-3.33 (m, 4H), 2.63 (s, 3H), 1.38-1.05 (m, 6H); MS (ES+) m/z 284.3 (M+1).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:22][C:20]([CH3:21])=[N:23][C:11]=3[C:10]=2[CH:13]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Agent: Cl
Product: Cc1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 50 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and acetamidine hydrochloride. Yield: 50%.
Reaction SMILES: [CH3:1][Si:2](Br)([CH3:4])[CH3:3].C[O:7][P:8]([C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[O:9]C>>[CH3:1][Si:2]([O:7][P:8]([C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[O:9][Si:2]([CH3:4])([CH3:3])[CH3:1])([CH3:4])[CH3:3]
Reactant: COP(=O)(OC)C(=O)CCc1ccccc1
Reactant: C[Si](C)(C)Br
Product: C[Si](C)(C)OP(=O)(O[Si](C)(C)C)C(=O)CCc1ccccc1
Reaction time: 1 h

Procedure:
10.7 g of trimethylsilyl bromide were added dropwise at room temperature over a period of 1 hour to 8.5 g of dimethyl(3-phenylpropionyl)phosphonate. The mixture was then stirred for a further 1 hour and then evaporated at 30° C./0.1 mm Hg to give 12.5 g of bis(trimethylsilyl)-(3-phenylpropionyl)phosphonate in the form of a pale yellow oil. This oil was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3CCCCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (22 mg, 0.05 mmol) in dry MeOH (1 ml) was added 10% palladium on charcoal (3 mg). The resulting reaction mixture was placed under H2 atmosphere, stirred at room temperature for 16 h, and then filtered on celite and evaporated to dryness. The crude product was purified by flash chromatography using CH2Cl2:MeOH hexanes as eluent to give 5-cyclohexyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (7 mg, 32%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([O:27]C)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
22.19 g (39.90 mmol) of the compound from Example 54A and 44.78 g (399.0 mmol) of potassium tert-butoxide were reacted according to the General Method 7A. Yield: 18.29 g (100% of theory)
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([CH2:8][N:9]2[CH2:30][C@H:29]([OH:31])[CH2:28][C@H:10]2[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:9]2[CH2:30][C@H:29]([OH:31])[CH2:28][C@H:10]2[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]2)=[O:12])=[O:37])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H]2C[C@@H](O)CN2Cc2ccc(C(=N)N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(C(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
A solution of 1.60 g of t-butyl [[1-[(4R)-1-(p-amidino-benzyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at room temperature for 2 hours and evaporated. The residue is dissolved in ethanol and treated with ether. Suction filtration and drying of the precipitate gives 1.25 g of [[1-[(4R)-1-(p-amidino-benzoyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetic acid trifluoroacetate. M.p. 220° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=O)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:21].[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=3)=[O:18])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:21]
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Reactant: Cc1cc(CNC(=O)c2cc(C(=O)O)ncn2)ccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(CNC(=O)c2cc(C(=O)NCc3ccc(F)c(C)c3)ncn2)cc1
Reaction time: 5 h
Yield: 127.3 %

Procedure:
1.3 g (4.5 mmol) of 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid and 1.042 g (5.4 mmol) of ethyl (4-aminomethylphenyl)acetate were dissolved in 30 ml of DMF, after which 1.02 g (4.9 mmol) of dicyclohexylcarbodiimide and 0.607 g (4.5 mmol) of hydroxybenzotriazole were added at 5° C. The mixture was stirred for 5 hours (h) and filtered with suction. The solvent was removed in vacuo and the residue was taken up in ethyl acetate; this solution was washed with a saturated aqueous solution of NaHCO3. The organic phase was dried (MgSO4), filtered and evaporated under reduced pressure. This resulted in 2.66 g of product, which was further purified by means of preparative HPLC. MS (ES+): m/e=464.19.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]3)[CH:25]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][CH:12]=3)[O:8][C:7]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)[CH:25]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][CH:12]=3)[O:8][C:7]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5ccc6c(c5)C(=O)NC6)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3ccc4c(c3)C(=O)NC4)oc12
Reaction time: 4 h

Procedure:
To a solution of 6-{7-amino-4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one in THF (2.4 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 2.4 mL, 2.4 mmol). After 4 h, the reaction was diluted into EtOAc and washed with sodium bicarbonate and water. The aqueous layer was concentrated. The residual solid was rinsed with MeOH and EtOAc thoroughly, then purified by ISCO chromatography (0 to 10% 7 N NH3/MeOH:EtOAc) to afford 1.5 mg (3%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.44 (s, 1H), 8.34 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 7.92 (d, J=5.3 Hz, 2 H), 7.76 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 4.56-4.58 (m, 2H), 4.23-4.34 (m, 1H), 3.67-3.78 (m, 1H), 2.11-2.25 (m, 4H), 1.97-2.08 (m, 2H), 1.54 (m, 2H); MS (ESI): 430.17 [M+H]+; HPLC tR=0.90 min (TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:28])([CH3:27])[C:9]2=[O:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.CC(C)=O.O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:12]=3[O:11][C:10]([CH3:27])([CH3:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide (1 g) in acetone (3 mL) was added dropwise an aqueous sodium hydroxide solution (0.18 g/3 mL) at 25° C., and the mixture was stirred at the same temperature for 90 minutes. To the reaction mixture was added dropwise concentrated hydrochloric acid/acetone/water (0.24 g/0.5 mL/0.35 mL) at 25° C., and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration, washed with a solution of acetone/water (1:1.6 mL), and then dried under reduced pressure at 50° C. to obtain the title compound (0.79 g) as Form A crystals (yield: 95%, purity: 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:40]2[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)=[CH:15][N:14]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:11]2=[N:12][CH:13]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:40]2[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)=[CH:15][N:14]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:32])=[O:31])[C:11]2=[N:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4F)cnc32)cc1
Yield: 93.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (150 mg, 0.206 mmol) was deprotected in TFA/DCM (2/1 ml) to afford 120 mg (93% yield) of the titled compound. MS: m/z=625.1 (M+1).