Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[CH3:15][O:16][C:17]([C:19]1([C:22]2[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=2)[CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+].C(O)(C)(C)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH:12]1[N:8]2[C:9]3[C:4]([CH2:5][CH2:6][C:7]2=[N:14][N:13]=1)=[CH:3][C:2]([C:24]1[CH:23]=[C:22]([C:19]2([C:17]([O:16][CH3:15])=[O:18])[CH2:20][CH2:21]2)[CH:27]=[N:26][CH:25]=1)=[CH:11][CH:10]=3
Reactant: COC(=O)C1(c2cncc(B(O)O)c2)CC1
Reactant: Brc1ccc2c(c1)CCc1nncn1-2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)C1(c2cncc(-c3ccc4c(c3)CCc3nncn3-4)c2)CC1
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 22 Step B (0.12 g, 0.48 mmol), the title compound from Example 71 Step C (0.13 g, 0.59 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.8 mg, 9.6 μmol), and potassium carbonate (0.200 g, 1.44 mmol) were added tert-butanol (5.3 mL) and water (0.67 mL). The vial was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The resulting material was diluted with acetonitrile and purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, aqueous 1 N HCl solution was added, and the resulting solution concentrated under reduced pressure to provide the title compound: LCMS m/z 347.00 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 10.1 (s, 1H), 9.21 (s, 1H), 9.02 (s, 1H), 8.99 (s, 1H), 8.12-8.03 (m, 3H), 3.70 (s, 3H), 3.51-3.48 (m, 2H), 3.41-3.38 (m, 2H), 1.85-1.82 (m, 2H), 1.59-1.56 (m, 2H).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:24])=[C:11]([CH:16]([CH2:22][CH3:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1)(C(C)(C)C)(C)C.[F-].[K+]>CN(C=O)C>[F:24][C:10]1[C:9]([OH:8])=[CH:14][C:13]([F:15])=[CH:12][C:11]=1[CH:16]([CH2:22][CH3:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: CCC(CC(=O)OC)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC(=O)OC)c1cc(F)cc(O)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
A screw-cap vial was charged with 90.F (0.23 g, 0.64 mmol), DMF (2.5 mL), and potassium fluoride (0.075 g, 1.3 mmol). The mixture was stirred for 5 minutes at room temperature, quenched with 1 N HCl, and diluted with EtOAc. The organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 90.G (0.13 g, 83% yield) as a colorless oil.
Reaction SMILES: C([CH:3]([CH:7]1[C:11]2=[C:12]([S:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:13]3[C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]([F:19])=[CH:17][C:18]=3[N:10]2[C:9](=[O:32])[CH2:8]1)[C:4]([O-:6])=[O:5])C.Cl>CC(=O)CC.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:12]2[C:13]3[C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]([F:19])=[CH:17][C:18]=3[N:10]3[C:9](=[O:32])[CH2:8][CH:7]([CH2:3][C:4]([OH:6])=[O:5])[C:11]=23)=[CH:26][CH:27]=1
Reactant: CCC(C(=O)[O-])C1CC(=O)n2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc12
Agent: Cl
Solvent: O
Solvent: CCC(C)=O
Product: CS(=O)(=O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2C(=O)CC1CC(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To the compound of Step 7 (40 mg) in 2-butanone (4 mL) was added 6N HCl (0.5 mL). The mixture was stirred at 80° C. for 3 hours, cooled to r.t., diluted with H2O and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 40% EtOAc/hexane containing 1% AcOH to give 23 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:14]=1[C:15]([O:17]CC)=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26]NOC.C[Mg]Br>C1COCC1>[C:15]([C:14]1[C:13]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH:10]([CH3:12])[CH3:11])=[N:23][CH:22]=[C:21]([Cl:24])[CH:20]=1)(=[O:17])[CH3:26]
Reactant: CNOC
Reactant: CCOC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 65.5 %

Procedure:
To a solution of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate (104 mg, 291 μmol) and N,O-dimethylhydroxylamine hydrochloride (45.5 mg, 466 μmol) in THF (1 mL) was added dropwise methylmagnesium bromide (1.4 M in 3:1 toluene:THF, 1.04 mL) at −20° C. The mixture was stirred at −20° C. for 45 min, at which point it was quenched carefully with cold saturated aqueous ammonium chloride (10 mL). The mixture was extracted with EtOAc (20 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 60%) to afford 62.3 mg of tert-butyl(S)-(1-(3-acetyl-5-chloropyridin-2-yl)-2-methylpropyl)carbamate (56% yield). LC-MS tR=1.08 min in 1 min chromatography, MS (ESI) m/z 327.4 [M+H]+.
Reaction SMILES: [N:1]12[CH2:9][C@@H:5]([CH2:6][CH2:7][CH2:8]1)[C@@H:4]([O:10]C(=O)C)[CH2:3][CH2:2]2>[OH-].[Na+]>[N:1]12[CH2:9][C@@H:5]([CH2:6][CH2:7][CH2:8]1)[C@@H:4]([OH:10])[CH2:3][CH2:2]2
Reactant: CC(=O)O[C@H]1CCN2CCC[C@@H]1C2
Agent: [Na+]
Agent: [OH-]
Product: O[C@H]1CCN2CCC[C@@H]1C2
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
(4S,5R)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester (5.45 g, 29.7 mmol) is dissolved in 10% aq. NaOH soln. and stirred for 1 h at 50° C. After cooling to rt, the mixture is extracted with THF/brine. The organic layer is dried over Na2SO4, filtered and the filtrate is evaporated to give 3.83 g (91%) of (4S,5R)-1-aza-bicyclo[3.3.1]nonan-4-ol, which is dissolved in 50 ml THF and cooled to 0° C. NHMDS (35 ml of 1 M THF soln.) is added dropwise, the reaction mixture is stirred at it for 0.5 h and then added to a precooled soln. (−15° C.) of 5-bromo-2-chloro-pyrimidine (5.89 g, 30.5 mmol) in THF. The mixture is stirred for 15 h at it, then diluted with THF and extracted with 1M aq. NaOH soln. and brine. The aq. layers are 2× reextracted with THF, the combined organic layers are dried over Na2SO4, filtered and the filtrate is evaporated. The resulting crude product (10.15 g) is recrystallized from CH3CN/MeOH to give 5.21 g (65%) of (4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O.Cl>CN(C)C=O>[C:21]1(=[O:31])[N:25]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(O)CCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 142.5 %

Procedure:
2 g of 17-bromoheptadecanoic acid are added to 2.14 g of potassium phthalimide in 40 cm3 of N,N-dimethylformamide and the mixture is heated for 6 hours at a temperature in the region of 80° C. The solution is cooled to about 20° C., it is poured into 100 cm3 of distilled water and 10 cm3 of 2N hydrochloric acid are added dropwise. The solid formed is separated by filtration. 5.13 g are obtained of a residue which is chromatographed on a column with a diameter of 4 cm containing 250 g of silica (0.020-0.045 mm) eluted with a 95/5 (by volume) mixture of methylene chloride and methanol. The first 4 fractions are discarded, the following 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 3.39 g of 17-phthalimidoheptadecanoic acid are thus obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.[CH3:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([NH2:46])[N:32]=1>>[NH2:46][C:33]1[N:32]=[C:31]([CH3:30])[C:36]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:35][N:34]=1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(CN2CCN(C(=O)C(C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(=O)[C@H](C)O)CC3)c(C)c2n1

Procedure:
1-[4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (200 mg) was coupled to 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 20 mg of 349. MS (Q1) 513.2 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([C:23]3[C:28]([CH3:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=3)[CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:33].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[Li+].[OH-].Cl>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].O1CCOCC1.C1(C)C=CC=CC=1>[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:25]2[N:24]=[C:23]([N:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:31])[CH2:7][CH2:8]4)[C:28]([CH3:29])=[CH:27][N:26]=2)=[CH:36][CH:35]=1)[CH3:33]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1nc(Cl)ncc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)O)c1nc(-c2ccc(CC)cc2)ncc1C
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a mixture of toluene (2.8 mL) and 1,4dioxane (0.56 mL) were added ethyl ((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)(propyl)amino]propoxy}-2,3-dihydro-1-H-inden-1-yl)acetate (Example 409, 50 mg, 0.11 mmol), 4-ethylphenyl boronic acid (67.3 mg, 0.45 mmol), and PdCl2(dppf).CH2Cl2 (8.2 mg, 0.01 mmol). A flow of argon was passed through the reaction mixture for 30 min, then Na2CO3 (0.56 mL, 1.12 mmol, 2 M aqueous solution) was added, and the reaction was stirred at 75° C. for 18 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was partly purified by preparative HPLC. The resulting crude ester was dissolved in a mixture of THF (2 mL), water (2 mL), and EtOH (1.0 mL), and then LiOH (24.2 mg, 1.01 mmol) was added. The reaction mixture was vigorously stirred for 18 h, acidified to pH ˜5 using HCl (1N aqueous solution), and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the product (11.5 mg, 21%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, 3H), 1.27 (t, 3H), 1.69 (q, 2H), 1.76-1.81 (m, 1H), 2.13-2.16 (m, 2H) 2.30 (s, 3H), 2.40-2.51 (m, 2H), 2.68-2.85 (m, 5H), 3.47-3.55 (m, 3H), 3.80 (t, 2H), 3.98 (t, 2H), 6.66 (d, 1H), 6.71 (s, 1H), 7.07 (d, 1H), 7.267 (d, 2H), 8.05 (s, 1H), 8.22 (d, 2H); LC-MS: RT=3.38 min, (M+H)+ 488.4.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: CC(=O)c1csc2ccc(Cl)cc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 261.2 %

Procedure:
Phenyltrimethylammonium tribromide (3.6 g) was added in portions under nitrogen over 30 minutes to a stirred suspension of 3-acetyl-5-chlorobenzo[b]thiophen (2 g) in tetrahydrofuran (25 ml), then the mixture was stirred at ambient temperature for 3 hours and filtered. The filter cake was washed with tetrahydrofuran (10 ml), then the filtrate and washings were combined, and the solvent removed in vacuo to leave 3-(2-bromoacetyl)-5-chlorobenzo[b]thiophen as a grey solid (4.2 g) which was used without purification.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([C:24]([O:26]CC)=[O:25])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([C:24]([OH:26])=[O:25])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Temperature: 50 °C

Procedure:
To a solution of ethyl 5-[(adamantan-1-ylmethyl)carbamoyl]imidazo[1,2-a]pyridine-2-carboxylate (852 mg, 2.3 mmol) in MeOH (10 mL), is added 1 mL of 10 N NaOH aqueous solution. The reaction mixture is heated at 50° C. for 4 h. After cooling to RT, the solvent is removed in vacuo. The residue is diluted with water, and acidified with 2 N HCl aqueous solution until pH=3. Filtration affords the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[C:16]([Cu])#[N:17]>CN1CCCC1=O.ClCCl>[C:16]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6])#[N:17]
Reactant: N#C[Cu]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)O)ccc1OC(F)(F)F
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
3-Bromo-4-(trifluoromethoxy)benzoic acid (1.4 g, 4.91 mmol) and cyanocopper (0.572 g, 6.39 mmol) were mixed in N-methyl-2-pyrrolidinone (NMP) (14 mL). The mixture was heated in a microwave at 200° C. for 2 h. The reaction was diluted with dichloromethane (150 mL). Celite® was added and the mixture was stirred vigorously for 10 min. The solids were removed by filtration. The organic layer was washed with water (125 mL) and concentrated. The residue was purified by HPLC to give the title compound as an off-white solid (0.979 g). LCMS m/z=232.3 [M+H]+.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[NH2:11][C:12]([NH2:14])=[O:13]>>[Cl-:10].[NH:11]([CH2:8][P+:3]([CH2:1][NH:11][C:12]([NH2:14])=[O:13])([CH2:4][NH:11][C:12]([NH2:14])=[O:13])[CH2:6][NH:11][C:12]([NH2:14])=[O:13])[C:12]([NH2:14])=[O:13]
Reactant: NC(N)=O
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Product: NC(=O)NC[P+](CNC(N)=O)(CNC(N)=O)CNC(N)=O
Yield: 100.9 %

Procedure:
Reaction of 80% THPC (23.82 g, 0.1 mol) with urea (24.02 g, 0.4 mol), following Example 3, gave 36.18 g (100.8%) of tetrakis(ureidomethyl)phosphonium chloride (I, R=R'=R"=H, X=Cl) as a colorless, brittle glass, identical (31P NMR) to the product of Example 11.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1)=[O:5].[BH4-].[Na+].C(OC(=O)C)C>CO>[NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 2-amino-3′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (7 g) in methanol (70 ml) was added sodium borohydride (1.1 g), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added acetic acid ethyl ester (100 ml). The mixture was washed with water and dried over anhydrous MgSO4, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography to give the object 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (6.9 g) as a colorless oily compound.
Reaction SMILES: [N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C@H:29]([CH3:36])[CH2:30][C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=3)=[O:21])=[CH:15][C:14]=2[O:37][CH3:38])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([CH:29]([CH3:36])[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=3)=[O:21])=[CH:15][C:14]=2[O:37][CH3:38])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2ccc(NC(=O)N3CCc4ccccc43)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)O)cc2)ccc1NC(=O)N1CCc2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A suspension of ethyl (R) 3-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-butyrate (1.3 g, Reference Example 4) in ethanol (40 mL) and water (15 mL) was treated with sodium hydroxide (5 mL, 1M). After stirring at 50° C. for 3 hours the mixture was evaporated to low bulk and then acidified with hydrochloric acid (1M). The resulting white precipitate was filtered, then washed with water, then with ether, and then dried to give the title compound (1.06 g) as a white powder. HPLC: RT=15.3 minutes (>95% by ELS). MS(ES+): 488(MH+); MS(ES−): 486(M−).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:56][S:57](Cl)(=[O:59])=[O:58].S(Cl)(Cl)(=O)=O>>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:10][CH:9]=5)[C:5]([OH:4])=[O:55])=[O:24])[N:26]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:40][CH:41]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3S(C)(=O)=O)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was reacted with methanesulfonyl chloride according to General Procedure E (with excess of sulfonyl chloride). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (14 mg) LCMS (m/z): 819.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[N:30]=[CH:29][C:28]2[CH:27](O)[CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([CH:27]1[CH2:26][CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:30]=[CH:29][C:28]1=2)=[N+:47]=[N-:48]
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydro-quinazolin-5-ol (2.0 g, 4.63 mmol) in 25 mL of toluene at −10° C. was added DPPA (1.2 mL, 5.56 mmol). To this stirred solution was then added DBU (0.83 mL, 5.56 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature for 16 h, the reaction was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/DCM=1:2) to afford the title compound as a white solid.
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[C:29](=[O:47])[NH:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:32]=1[C:43]([O:45][CH3:46])=[O:44])[O:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>C(OCC)(=O)C>[ClH:1].[OH:8][C:9]1[CH:10]=[C:11]([O:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH:26]=[CH:27][C:28]=1[C:29]([NH:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][C:32]=1[C:43]([O:45][CH3:46])=[O:44])=[O:47]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCNCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl acetate (1 mL) and a 4 mol/L hydrogen chloride-dioxane solution (0.50 mL) were added to the obtained tert-butyl 4-(3-hydroxy-4-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)phenoxy)piperidine-1-carboxylate (0.025 g), followed by stirring at room temperature for 3 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0.018 g of methyl 2-(2-hydroxy-4-(piperidin-4-yloxy)benzamido)-4-phenylbenzoate hydrochloride as a white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[N:8]2[CH:14]=[N:13][CH:12]=[C:9]2[S:10][CH:11]=1)=O)C.[BH4-].[Na+].Cl>CO>[OH:3][CH2:4][CH2:6][C:7]1[N:8]2[CH:14]=[N:13][CH:12]=[C:9]2[S:10][CH:11]=1
Reactant: CCOC(=O)Cc1csc2cncn12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCc1csc2cncn12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.1 %

Procedure:
900 mg of the 3-(ethoxycarbonylmethyl)imidazo[5,1-b]-thiazole prepared in Preparation 50 was dissolved in 20 ml of methanol. To this solution was added 810 mg of sodium borohydride with ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. To this was added 2 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure. To the residue was added 20 ml of water, and the pH of the mixture was adjusted to 7.5 by sodium hydrogencarbonate. The water was evaporated from the mixture under reduced pressure. To the residue were successively added 50 ml of dichloromethane and anhydrous magnesium sulfate. Insoluble matters were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was washed with a mixture of 10 ml of ethyl acetate and 50 ml of ether to give 476 mg (yield 66%) of the title compound. NMR (CDCl3) d: 1.95 (1H, br-s), 3.01 (3H, t, J=6 Hz), 4.02 (1H, t, J=6 Hz), 6.57 (1H, s), 7.04 (1H, s), 7.90 (1H, s) MS (EI, CHCl3, 100° C.): 168 (M+)