Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:7][CH2:6]2.Cl[C:24]1[N:25]=[C:26]([NH:43][C:44]2[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[C:45]=2[C:46]([NH2:48])=[O:47])[C:27]2[CH:32]=[CH:31][N:30]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:28]=2[N:29]=1.Cl.O1CCOCC1>FC(F)(F)CO.C([O-])(O)=O.[Na+]>[F:53][C:49]1[CH:50]=[CH:51][CH:52]=[C:44]([NH:43][C:26]2[C:27]3[CH:32]=[CH:31][N:30]([S:33]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)(=[O:35])=[O:34])[C:28]=3[N:29]=[C:24]([NH:12][C:11]3[CH:10]=[C:9]4[C:5]([CH2:6][CH2:7][N:8]4[S:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)(=[O:14])=[O:15])=[CH:4][C:3]=3[O:2][CH3:1])[N:25]=2)[C:45]=1[C:46]([NH2:48])=[O:47]
Reactant: COc1cc2c(cc1N)N(S(=O)(=O)c1ccc(C)cc1)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: OCC(F)(F)F
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(S(=O)(=O)c1ccc(C)cc1)CC2
Reaction time: 8 h

Procedure:
A mixture of 5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-amine (4.0 g, 12.5 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (8.6 g, 18.79 mmol) and a 4 N solution of HCl in dioxane (16 mL, 62.5 mmol) in 2,2,2-trifluoroethanol (250 mL) was heated overnight in a sealed vessel at 80° C. The reaction mixture was diluted with a saturated NaHCO3 solution, and the resulting slurry was filtered and the solids were taken up into THF (1L). The resulting slurry was filtered and the filtrate was concentrated. The resulting orange solid was dissolved in THF (250 mL), and a 27% aqueous NH4OH solution (250 mL) was added and the reaction mixture was stirred overnight. The organic volatiles were evaporated, and the residue was extracted with CH2Cl2 (3×200 mL). The organic layers were combined, dried (Na2SO4), concentrated onto Celite and purified by silica gel chromatography using 0-2%THF/CH2Cl2 to obtain 2-fluoro-6-({2-({5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-yl}amino)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide as a yellow solid (2.8 g, 30% for 2 steps). ESIMS (M+H)+=742.17.
Reaction SMILES: COP([CH2:7][C:8](=[O:25])[CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1[N:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][N:34]=1>C1COCC1.C(OCC)(=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][C@H:12]1[CH2:13][C@@H:14]([CH3:15])[N:10]([CH2:9][C:8](=[O:25])[CH:7]=[CH:39][C:36]2[CH:35]=[N:34][C:33]([CH3:32])=[N:38][CH:37]=2)[C:11]1=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: COP(=O)(CC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)OC
Reactant: Cc1ncc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C=CC(=O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 25 °C

Procedure:
A stirred suspension of 4-3 (2.5 g, 6.61 mmol), potassium carbonate (1.83 g, 13.2 mmol), and 2-methyl-pyrimidine-5-carboxaldehyde (for preparation, see U.S. Pat. No. 6,048,861) (0.81 g, 6.61 mmol) in THF (50 mL) was heated at 60-65° C. for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 95:5% ethyl acetate/methanol) to give 5-1 as a white foam.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1>C(OCC)C>[Br:1][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc(C)c1
Reactant: BrBr
Solvent: CCOCC
Product: Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
Bromine (2.38 g, 14.9 mmol) was slowly added dropwise to a solution of 1-[3-methylphenyl]ethanone (2.00 g, 14.9 mmol) in diethyl ether (50 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 3.03 g (95.3%) of the desired product as an oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[P:21](Cl)([Cl:24])([Cl:23])=[O:22]>CCOCC>[Cl:23][P:21]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([Cl:24])=[O:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1OP(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dry triethylamine (0.38 mL, 2.8 mmol) and methyl 3-(2-hydroxyphenyl)propanoate, 80 (0.5 g, 2.77 mmol) in dry ether (9.2 mL) were added dropwise to a solution of dry ether (5 mL) containing phosphorus oxychloride (0.25 mL, 2.8 mmol) at −78° C. under nitrogen. Following the addition, the reaction mixture was slowly allowed to warm to rt, and stirred for 1 h. The solvent was removed under reduced pressure to give crude product as an oil containing a significant amount of solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:7][C:8]=1[CH:9]=[O:10].S(=O)(=O)([OH:23])N.Cl([O-])=O.[Na+].CCCCCC>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:6]=[CH:7][C:8]=1[C:9]([OH:23])=[O:10]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(-c2ccccc2C(F)(F)F)ccc1C=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2ccccc2C(F)(F)F)ccc1C(=O)O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
The 3-methoxy2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde of Step B (0.95 g, 3.41 mmol) and sulfamic acid (0.43 g, 4.43 mmol) were dissolved in a mixture of tetrahydrofuran and water (1:1, v/v, 30 mL). Sodium chlorite (0.31 g, 4.43 mmol) was added under stirring, and the solution turned yellow. After 30 minutes, additional sodium chlorite and sulfamic acid were added, and the solution stirred an additional hour. The solution was then concentrated, and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated to yield an oil, which solidified upon trituration with hexane to provide the title compound (0.84 g) as a yellow solid, which was used as such in the next step.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][N:51]=1.C1(C[C@@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:55]=[CH:54][N:53]=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ccncn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ccncn1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 74.4 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 4-aminopyrimidine (108 mg; 1.14 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate/hexanes) 271 mg (74%)of 3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrimidin-4-yl-propionamide as a white foam: EI-HRMS m/e calcd for C21H24N4O2 (M+) 364.1899, found 364.1893.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:53]=[CH:52][C:16]([C:17]([O:19][C:20]([CH3:51])([CH3:50])[C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[O:18])=[CH:15][C:14]=1[O:54][CH2:55][CH:56]1[CH2:58][CH2:57]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:48][CH2:49]2)[CH:36]=1)[O:23][C:21](=[O:22])[C:20]([O:19][C:17](=[O:18])[C:16]1[CH:52]=[CH:53][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:54][CH2:55][CH:56]2[CH2:58][CH2:57]2)[CH:15]=1)([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(OC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.6 %

Procedure:
To a solution of (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-2-methylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (168 mg, 0.192 mmol) in dry DCM (2 ml), HCl 4M in dioxane (144 μl, 0.577 mmol) was added with stirring at RT for 2 days. Additional HCl 4M in dioxane (144 μl, 0.577 mmol) was freshly added and the stirring was continued for further 3 days. The volatiles were removed under vacuum, and the crude was purified by preparative HPLC. After evaporation of the solvent, the residue was triturated with iPr2O and collected by filtration to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)-2-methylpropanoyloxy)ethyl)pyridine 1-oxide as a white solid (50 mg, 0.065 mmol, 33.6% yield, MS/ESI+ 773.29 [MH]+, [αD]=−18.13, c=0.60, MeOH).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=1)[CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])CC1C=CC=CC=1.C(O)C>CO.[H][H].[Pd]>[OH:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:28]=1)[CH2:3][NH:4][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: [H][H]
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)c1ccc(C)c(S(N)(=O)=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COc1ccccc1OCCNCC(O)c1ccc(C)c(S(N)(=O)=O)c1
Reaction time: 8 h

Procedure:
In 200 ml of methanol was dissolved 20 g of 5-{1-hydroxy-2-[N-benzyl-2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide. After adding thereto 20 ml of ethanol containing about 10% hydrogen chloride and 1 g of 10% palladium charcoal, the mixture was shaked in hydrogen gas stream. When the absorption of hydrogen stopped, the catalyst was filtered away and the filtrate was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol while it was hot and the solution was allowed to stand overnight in ice chamber, whereby 12.8 g of the α-type crystals of 5-{1-hydroxy-2-[2-(2-methoxyphenoxy)ethylamino]-ethyl}-2-methylbenzenesulfonamide were obtained as the colorless crystals. The physical and chemical properties of the product were as follows:
Reaction SMILES: [F:1][C:2]1[N:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Li+].CC([N-]C(C)C)C.CCCCCCC.[Br:31]C(Br)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Br:31][C:12]1[CH:13]=[N:14][C:2]([F:1])=[C:3]([C:11]=1[F:15])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: ClC(Cl)(Cl)C(Cl)(Br)Br
Reactant: CC(C)(C)OC(=O)c1c(F)ccnc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)c1c(F)ncc(Br)c1F
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
Into a solution of tert-butyl 2,4-difluoronicotinate (0.95 g, 4.4 mmol) in THF (15 mL) at −78° C. was added a solution of LDA in heptane (1.5 M×3.5 mL, 5.3 mmol) dropwise. The mixture was stirred for 10 min. Then a solution of dibromotetrachloroethane (1.86 g, 5.7 mmol) in THF (4.0 mL) was added dropwise. After 15 min, the temperature was allowed to rise to room temperature slowly. The reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to give a residue, which was purified by silica chromatography (5-50% dichloromethane in hexanes) to give tert-butyl 5-bromo-2,4-difluoronicotinate (0.55 g, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH:19]([CH3:28])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CCOC(C)=O.CCCCCC>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:19]([CH3:28])[C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C(C)C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.6 %

Procedure:
5-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (7.35 g, 47.3 mmol) was dissolved in 160 mL of DMF. Na2CO3 (5.02 g, 47.3 mmol) was added followed by 2-bromopropiophenone (7.2 mL, 47.3 mmol). The reaction stirred at room temperature for 2 days. The solution was diluted with AcOEt and the organic layer was washed with sat. NaHCO2, brine, dried (MgSO4), and concentrated. Flash chromatography (20-45% AcOEt/hexane) gave the desired product (1.58 g, 12% yield). 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.0 Hz, 3H), 1.7 (d, J=7.4 Hz, 3H), 4.2 (q, J=7.0 Hz, 2H), 5.4 (bs, 2H), 5.9 (q, J=7.0 Hz, 1H), 7.41-7.59 (m, 3H), 7.60 (s, 1H), 8.0 (d, J=8.0 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[N:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OCc1ccc2[nH]ncc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc2[nH]ncc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
1H-pyrazolo[4,3-b]pyridine-5-methanol (240 mg, 1.61 mmol) was dissolved in DCM (24 mL) at rt, and DMSO (5.71 mL, 80.45 mmol) and NEt3 (1.12 mL, 8.05 mmol) were added. After 10 min, SO3-pyridine was added, and the mixture was stirred at rt for ca. 1.5 hr. The reaction was quenched with sat. NH4Cl solution, stirred for 10 min, then extracted with DCM, washed with water and with brine, and dried with Na2SO4. The crude product (orange oil) was purified by a short manual flash column (hex/EtOAc 1:1) to afford 1H-pyrazolo[4,3-b]pyridine-5-carboxaldehyde (62 mg, 26.2%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([C:16](OC(C)(C)C)=O)[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reaction time: 2 h

Procedure:
To a solution of (3aR,6aR)-tert-butyl 1-(4-bromophenyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.86 g, 5.1 mmol) in CH2Cl2 (50 mL) at 23° C. was added TFA (8 mL) and the mixture was allowed to stir for 2 hrs. The solvents were removed under vacuum and the residue was taken up in MeOH (50 mL) followed by the addition of formaldehyde (37%, 3 mL, 40 mmol) and NaBH3CN (950 mg, 15.1 mmol). The mixture was stirred at 23° C. for 10 hours, concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL), washed sequentially with water (2×50 mL), brine (1×30 mL), and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product mixture was purified via chromatography (SiO2, O-10% MeOH in CH2Cl2) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ=7.28 ppm (m, 2H), 6.44 (m, 2H), 4.05 (m, 1H), 3.45 (m, 1H), 3.19 (m, 1H), 2.94 (m, 1H), 2.67 (m, 1H), 2.52 (m, 3H), 2.30 (s, 3H), 2.16 (m, 1H), 1.95 (m, 1H). MS (ESI, M+1): 280.8.
Reaction SMILES: [C:1]([S:9][CH2:10][CH:11]([CH3:15])[C:12](O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[C:1]([S:9][CH2:10][CH:11]([CH3:15])[C:12]([Cl:18])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(CSC(=O)c1ccccc1)C(=O)Cl

Procedure:
3-Benzoylthio-2-methylpropanoic acid (11.6 g) in toluene (78 ml) was treated with thionyl chloride (4.6 ml). The resulting solution was warmed to 80° for 2.5 hours and then evaporated to dryness under reduced pressure to yield 3-benzoylthio-2-methylpropanoyl chloride. A solution of (±)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid hydrochloride (10.7 g) in pyridine (65 ml) was treated dropwise with the crude 3-benzoylthio-2-methylpropanoyl chloride with vigorous stirring. After stirring overnight, the reaction mixture was added to ice (900 g), acidified with 20% hydrochloric acid (130 ml), and extracted with ether (700 ml). The ether layer was dried over sodium sulfate and activated charcoal, and then concentrated to dryness to yield a viscous oil (25 g) which was dissolved in acetonitrile (100 ml) and treated with dicyclohexylamine (13 ml). The crystalline product, (±) 1-(3-benzoyl-2-methyl-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid dicyclohexylamine salt, was collected by filtration; yield 3.6 g, m.p. 170°-173°.
Reaction SMILES: [CH3:1][CH2:2][N:3](CC)CC.Cl.[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(#N)CO>O>[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:1][C:2]#[N:3])[CH2:12]1
Reactant: CCN(CC)CC
Reactant: COC1CCCNC1
Agent: Cl
Agent: N#CCO
Solvent: O
Product: COC1CCCN(CC#N)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Et3N (7.0 mL, 50 mmol) was added to a suspension of 3-methoxypiperidine hydrochloride (281) (McManus, J. M. et al., J. Med. Chem. 1965, 8, 766-776) (3.80 g, 25.0 mmol) and aqueous glycolonitrile (55%, 2.7 mL, 27.6 mmol), and the resulting solution stirred at 70° C. for 1.5 h. The solution was cooled to 20° C. and diluted with water (40 mL). The aqueous layer was extracted with Et2O (4×50 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 282 (3.76 g, 97%) as a colourless oil, which was used without further purification: 1H NMR δ 3.54 (s, 2H, CH2CN), 3.36-3.40 (m, 1H, H-3), 3.37 (s, 3H, OCH3), 2.77 (dd, J=10.9, 3.2 Hz, 1H, H-2), 2.44-2.56 (m, 3H, H-2, H-6), 1.75-1.85 (m, 2H, H-4, H-5), 1.52-1.57 (m, 2H, H-4, H-5).
Reaction SMILES: Cl.FC1C=CC(C2(C3C4C(=CC=C(OCCN[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])C=4)CCN3)CCC2)=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH2:55][CH2:56][NH2:57])[CH:52]=4)[C:47]([CH3:59])([CH3:58])[CH2:46][N:45]=3)[CH2:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[ClH:33].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([CH:44]3[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH2:55][CH2:56][NH:57][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:52]=4)[C:47]([CH3:59])([CH3:58])[CH2:46][NH:45]3)[CH2:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1
Reactant: CC1(C)CN=C(C2(c3ccc(Cl)cc3)CCC2)c2cc(OCCN)ccc21
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)NCC2
Agent: Cl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2(C)C

Procedure:
N-[2-({1-[1-(4-Chlorophenyl)cyclobutyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide hydrochloride was prepared analogously to N-[2-({1-[1-(4-fluorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide hydrochloride (cf. example 65) using 2-({1-[1-(4-chlorophenyl)cyclobutyl]-4,4-dimethyl-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine in place of 2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:15][CH:16]([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[C:3]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:4][C:5]([C:6]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[O:8])=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1cc(C(=O)O)cc(OC(C)C)c1Cl
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(OC(C)C)c(Cl)c(OC(C)C)c2)cc1
Yield: 96 %

Procedure:
Methyl 4-(4-chloro-3,5-diisopropoxybenzamido)benzoate (8) (86 mg, 96%) was prepared from 4-chloro-3,5-diisopropoxybenzoic acid (6) (60 mg, 0.22 mmol) using a procedure essentially the same as in step (i) for AAA-064 except that DIPEA was used instead of TEA, and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-fluorobenzoate: m/z 406 [M+H]+ (ES)+, 404 [M−H]− (ES)−.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:28]([SiH2:32][O:33][C:34]([CH3:43])([CH3:42])[C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1)([CH3:31])([CH3:30])[CH3:29].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[C:28]([SiH2:32][O:33][C:34]([CH3:43])([CH3:42])[C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)=[N:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(N)nc1
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(C(C)(C)O[SiH2]C(C)(C)C)cn2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid (2.03 g, 6.61 mmol) was dissolved in DCM (33 mL) with DMF (0.05 mL), and cooled to 0° C. Oxalyl chloride (1.16 mL, 13.22 mmol) was added dropwise and the mixture was allowed to stir for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove residual oxalyl chloride. The yellow oil was re-dissolved in DCM (33 mL), and 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (1.71 g, 7.17 mmol) and pyridine (0.86 mL, 10.5 mmol) were added. After 16 hours, the reaction mixture was concentrated under reduced pressure and partitioned in EtOAc (50 mL) and water (50 mL). The organic layer was rinsed with water (30 mL), and then a saturated sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated to brown oil. After chromatography on silica gel with a gradient from 5-30% ethyl acetate-hexanes, N-[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (1.25 g, 36.0% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.25 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.40 (d, J=3.0 Hz, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 7.05 (d, J=3.0 Hz, 1H), 6.60 (s, 1H), 4.65 (s, 2H), 4.60 (m, 1H), 4.15 (t, 2H), 2.95 (t, 2H), 1.05 (s, 3H), 1.0 (s, 3H), 0.85 (s, 9H), 0.00 (s, 6H); LCMS (m/z): 527.3 [C28H38N2O4SSi+H]+.