Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:14]S(C(F)(F)F)(=O)=O)([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8].O[C@H:23]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[S:7]([O:14][C@H:23]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:9])=[O:8]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(C[C@@H](O)C(=O)OCc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc2ccccc2)c1

Procedure:
To a solution of pyridine (0.78 mL, 9.7 mmol) in CH2Cl2 (50 mL) at −10° C. is added triflic anhydride (1.68 mL, 10.0 mmol) over 15 min. A solution of benzyl (R)-2-hydroxy-3-(3-methylphenyl)-propionate (1.5 g, 5.55 mmol) in CH2Cl2 (15 mL) is then added dropwise over 30 min., and the mixture is warmed to room temp. over 1 h. The solution is diluted with CH2Cl2 (100 mL), washed with water (2×100 mL) and brine (100 mL), dried (MgSO4), and evaporated to yield benzyl (R)-2-trifluoromethanesulfonyloxy-3-(3-methylphenyl)-propionate as a yellowish oil.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N+:14]([O-])=[C:13]([CH3:18])[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1.C(OC(=O)C)(=[O:22])C.[OH-].[Na+]>>[CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][OH:22])[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1
Reactant: Cc1c(OCC2OCC3(CC3)CO2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CO
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 28.9 %

Procedure:
The 4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-2,3-dimethylpyridine 1-oxide (1.8 g, 6.78 mmol) obtained by the step (2c) was mixed with acetic anhydride (5.77 ml, 61 mmol). The mixture was stirred at 85° C. for 45 minutes and then acetic anhydride was distilled off. The residue was cooled on ice and dissolved in methanol. To this, a 5N aqueous sodium hydroxide solution (2.98 ml, 14.9 mmol) was added under ice-cool and the mixture was stirred at room temperature for 2 hours. Methanol was distilled off and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and thereafter the solvent was distilled off. Purification was performed by silica gel column chromatography (silica gel: 100 g, elution solvent: ethyl acetate/heptane=1/4 to 4/1). To the purified product, heptane (15 ml) was added and the mixture was refluxed. After the solution was confirmed to reach a homogeneous state, it was gradually cooled. The precipitated product was obtained by filtration. In this manner, the title compound (520 mg, yield: 28.9%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[N:10][C:11]=4[CH3:27])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CC3)cn2)cn1
Yield: 51 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (42 mg, 51%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC then silica, ethyl acetate). MS: m/e=404.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5](Cl)=[CH:6][CH:7]=1.[CH3:15][S-:16].[Na+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5]([S:16][CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)ccc(Cl)c1C1=NOCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1ccc(Cl)c(C)c1C1=NOCC1
Reaction time: 8 h

Procedure:
20 g (0.083 mol) of 3-(3,6-dichloro-2-methylphenyl)-4,5-dihydroisoxazole are dissolved in 120 ml of NMP. At 0° C., 6.7 g (0.09 mol) of sodium thiomethoxide are added over a period of 40 min, and the mixture is then stirred overnight. The reaction mixture is stirred into 360 ml of water and extracted four times with 70 ml of toluene, the combined organic phases are washed once with 70 ml of water and the organic phase is concentrated. The residue (an isomer mixture) is distilled at 150-170° C. under a reduced pressure of 1 mbar. The main fraction is purified chromatographically. This gives 4.5 g of a product which is 83% pure (17% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19]>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CNN(c2cc(Cl)c(C(C(=O)O)c3ccc(Cl)cc3)c(Cl)c2)C(=O)N1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirred and refluxed solution of 1.5 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetic acid in 100 parts of acetic acid were added 3 parts of zinc. Stirring was continued for 30 minutes at reflux temperature. The zinc salts were filtered off and the filtrate was evaporated. The residue was washed with water whereupon the solid product was filtered off and dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The solution was dried, filtered and evaporated. The residue was washed with ethyl acetate and 2,2'-oxybispropane and dried, yielding 0.98 parts (67.2%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetic acid; mp. 194.2° C. (compound 1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C[C:15](=[O:19])[O:16]CC>>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[C:15]([OH:19])=[O:16]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: O=C(O)C(O)c1ccc(F)cc1C(F)(F)F

Procedure:
The 2-trifluoromethyl-4-fluorobenzaldehyde (48.4 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 50.1 g. (84%). EA, MS(FD).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].[C:24](Cl)(=[O:27])[CH2:25][CH3:26].[K+].[Br-]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:27])[CH2:25][CH3:26])=[C:3]([C:12](=[O:23])[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[N+:20]([O-:22])=[O:21])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: Nc1c(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12
Agent: [Br-]
Agent: [K+]
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12

Procedure:
The title compound were prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(5-chloro-2-nitrobenzoyl)indole (step 2) and propionyl chloride. m.p.: 245-246° C. IR (KBr) ν: 3078, 1665, 1628, 1580, 1526, 1497, 1340, 1313, 1238, 1022, 843 cm−1 1H-NMR (DMSO-d6) δ: 12.09 (1 H, br s), 9.26 (1 H, br s), 8.29 (1 H, d, J=8.7 Hz), 7.87 (1 H, dd, J=2.3, 8.7 Hz), 7.66 (1 H, d, J=2.0 Hz), 7.49 (1 H, d, J=8.6 Hz), 7.46 (1 H, d, J=2.0 Hz), 7.11 (1 H, dd, J=1.8, 8.7 Hz), 1.89 (2 H, q, J=7.9 Hz), 0.84 (3 H, t, J=7.9 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C>O>[C:12]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
7.6 g (0.05 mol) of 4-nitrobenzyl alcohol, 4.7 ml (0.05 mol) of acetic anhydride and 5.8 ml (0.1 mol) of acetic acid were introduced into a round-bottomed flask and the mixture was heated at reflux for eight hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in hexane, filtered and dried. 6.1 g (62%) of 4-nitrobenzyl acetate of melting point 77°-78° C. were recovered.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:18]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: OCCOc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCOc1ccccc1
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
2-Phenoxyethanol (50 g, 0.362 mol) was dissolved in dichloromethane (500 ml) and the solution was cooled to 0-5° C. Triethylamine (101 ml, 0.724 mol) was added to the cooled solution followed by pivaloyl chloride (53.5 ml, 0.434 mol) maintaining the temperature, below 5° C. After additions the mixture was stirred at 5° C. for 30 min and at room temperature for 12 h. The reaction was quenched by addition of 1M HCl-solution (300 ml) and stirred vigorously. The phases were separated and organic phase was washed with saturated NaHCO3-solution (2×150 ml), water (1×100 ml) and brine (1×100 ml). After drying (Na2SO4) and filtration the solvent was evaporated yielding the title compound (76.78 g, 0.345 mol, 95%) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.31-7.27 (2H, m, ArH), 6.96-6.93 (3H, m, ArH), 4.34 (2H, m, CH2CH2OPiv), 4.19 (2H, m, ArOCH2CH2), 1.13 (9H, s, 3×Me). 13C-NMR (100 MHz, DMSO-d6) δ (ppm): 177.7, 158.7, 130.1, 121.1, 114.9, 66.1, 62.9, 38.5, 27.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]2[C:21]([CH:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[CH2:8][NH:7][CH2:6]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C(O)CNCc2cccc(OC)c2C)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3c2ccc(OC)c3C)cc1OC
Yield: 89.2 %

Procedure:
510 mg of α-[[(3-methoxy-2-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 3.8 ml of trifluoroacetic acid, 0.12 ml of conc. sulfuric acid was added dropwise under ice cooling, and the mixture was allowed to react for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. The residue was dissolved in chloroform, and basified by addition of 28% aqueous ammonia. The chloroform layer was collected, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 430 mg of 7-methoxy-4-(3,4-dimethoxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 128°-129° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O.O1CCOC[CH2:32]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:32])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)O)cn2c1=O
Reactant: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)OC)cn2c1=O

Procedure:
2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (1,2 g) was reacted with thionyl chloride (0.6 ml) in dioxane (12 ml) at reflux temperature for 1 hour, then the mixture was evaporated to dryness in vacuo. The residue was reacted with excess methanol at 50° C. for 30 minutes, then the solution was concentrated in vacuo and the residue diluted with ice water. Filtration of the precipitate gave 1.2 g of 2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine7-carboxylic acid, methyl ester, m.p. 190°-193° C. By proceeding analogously the following compounds were prepared:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCOCC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (prepared below, 70 mg, 0.168 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (32.9 mg, 0.184 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 49% (48 mg, 0.083 mmol) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])([O-:3])=[O:2].B(Br)(Br)Br>ClCCl>[OH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:6]([N+:13]([O-:15])=[O:14])=[CH:7][C:8]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])c(CCC(=O)O)c([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)CCc1c([N+](=O)[O-])cc(O)c(O)c1[N+](=O)[O-]
Temperature: -20 °C

Procedure:
The product from Example 4 (2.0 g) was slurried in dichloromethane (100 ml) under nitrogen, cooled to -20° C. and boron tribromide (1.3 ml) added. The resultant mixture was stirred at -20° C. for half an hour and then at room temperature overnight. The mixture was poured into ice water, extracted in ethyl acetate and evaporated. The product was recrystallized from acetic acid.Yield: 0,6 g, melting point 162-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)c(Br)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
3-Bromo-4-fluoro-benzaldehyde (5.0 g, 24.6 mmol), malonic acid (5.6 g, 53.7 mmol), and piperidine (0.5 mL, 4.9 mmol) were added to pyridine (11.4 mL). The reaction mixture was stirred at 100° C. for 3 hours and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was recrystallized from ethanol to give 3.3 g of the titled compound as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Brc1cncnc1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cncnc2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 5-Bromopyrimidine instead of 3-bromopyridineto yield the final compound as a off-white solid, MS (ISP): m/e=354.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][N:8]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH2:7][CH2:6][C:5]2=1.C(C1C(=O)C(Cl)=C(Cl)C(=[O:28])C=1C#N)#N.C1COCC1.O>C1COCC1>[C:15]([N:8]1[CH2:7][C:6](=[O:28])[C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH2:9]1)(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccc(Cl)cc23)C1
Solvent: C1CCOC1
Solvent: O
Product: O=C1CN(C(=O)c2ccccc2)Cc2[nH]c3ccc(Cl)cc3c21
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
(6-chloro-1,3,4,9-tetrahydro-β-carbolin-2-yl)-phenyl-methanone (1.76 g, 5.66 mmol, 1 equiv.) and DDQ (2.31 g, 10.2 mmol, 1.8 equiv.) were mixed as solids and cooled to −78° C. 15 ml of a 9:1 THF/H2O solution was cooled to −78° C. and the resulting slurry was added to the cooled solids followed by an additional 15 ml of THF (also cooled to −78° C.). The deep blue solution was stirred at −78° C. for 2 hours and then gradually warmed to room temperature and stirred an additional two hours. The reaction was quenched by the addition of 1 N NaOH, and extracted with 3×150 ml EtOAc. The combined organic layers were washed with 2×100 ml 1 N HCl, 1×100 ml brine, dried over MgSO4, filtered and concentrated to yield 1.38 g (75%) of 2-benzoyl-6-chloro-1,2,3,9-tetrahydro-β-carbolin-4-one as oily orange solids. 1H-NMR (300 MHz, DMSO-d6): δ 12.11-12.48 (br, 1H), 7.29-7.88 (m, 8H), 4.93-5.18 (br, 2H), 4.60-4.46 (br, 2H). Exact Mass: 324.07. Formic acid standard conditions. DAD RT=2.15 min. M+H=325.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37](ON1C(=O)CCC1=O)=[O:38]>CN(C)C=O>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][C@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:38]
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 60 °C
Reaction time: 33.5 h
Yield: 89.7 %

Procedure:
In 300 ml of dimethylformamide are dissolved 18 g of tert-butyl trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 12 g of succinimido indolecarboxylate as synthesized by a known method, and the solution is stirred at 60° C. for 33.5 hours. The reaction mixture is poured to ice-water, and the mixture is stirred to separate crystals, which are collected by filtration and washed with water and dried to give 22 g of tert-butyl trans-3-(2-indolecarboxamido)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, m.p. 196°-200° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.2 %

Procedure:
To a stirred mixture of MS3A (1.0 g), methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (350 mg, 1.50 mmol) and (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (359 mg, 1.65 mmol) in chloroform (10 mL) was added acetic acid (500 uL) at 0° C. and stirred at r.t. for 7 hours. To the reaction mixture was added sodium triacetoxyborohydride (670 mg, 3.00 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 1.5 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The MS 3 Å was removed by Celite filtration and the content was extracted with ethylacetate, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethylacetate=5/1 to 3/1). Target fractions were collected and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (223 mg, 62% yield.). For major isomer; 1H-NMR (400 MHz, CDCl3) δppm; 7.40-7.21 (m, 6H), 6.85 (s, 1H), 4.00-3.95 (m, 1H), 3.91 (s, 3H), 3.88 (d, 2H), 3.84-3.76 (m, 1H), 2.83-2.73 (m, 2H), 2.25 (s, 3H), 1.83-1.69 (m, 4H), 1.13 (d, J=6.4 Hz, 6H).