Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH2:21])=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O>C1(C)C=CC=CC=1.ClCCl>[Cl:22][CH2:23][C:24]1[N:21]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[O:20][CH:26]=1
Reactant: COc1cccc2c(C(N)=O)cn(CC3CCCCC3)c12
Reactant: O=C(CCl)CCl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc2c(-c3nc(CCl)co3)cn(CC3CCCCC3)c12
Yield: 81.1 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid amide (500 mg, 1.75 mmol) in toluene (4 ml) was added 1,3-dichloroacetone (333 mg, 2.62 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 30 minutes. The resulting black solution was diluted with dichloromethane (50 ml) and washed with 5% aqueous sodium carbonate solution (5×20 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting brown oil was purified by flash column chromatography using 5% (v/v) acetone in petroleum ether 40-60 to give 3-(4-chloromethyl-oxazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (510 mg, 1.42 mmol) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C1COCC1.C(OCC)(=O)C.O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: BrCCCCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of thiophene (50 g, 594 mmol) in anhydrous THF (200 mL) is added slowly a 1.6M solution of n-butyllithium in hexane (408 mL, 653 mmol) under nitrogen atomospere at −30° C. The reaction mixture is stirred for a further 2 hours, during which period it is allowed to warm to room temperature. The solution is recooled to 0° C. and a solution of 1,4-dibromobutane (141 g, 653 mmol) in anhydrous THF (100 mL) is added. The stirring is continued overnight. The mixture is diluted with ethyl acetate (1000 mL) and shaken with water (800 mL). The organic layer is washed with brine twice and dried over anhydrous Na2SO4. After removal of the solvent, the residue is distilled in vacuo to afford 2-(4-bromobutyl)-thiophene 1 as colorless oil (66 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:11][N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:15]1[NH:14][C:13](=[O:18])[N:12]([CH3:11])[C:16]1=[O:17]
Reactant: COc1ccccc1C=O
Reactant: CN1C(=O)CNC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1C=C1NC(=O)N(C)C1=O
Yield: 63.6 %

Procedure:
A mixture of 2-methoxybenzaldehyde (3.4 g,25 mmoles), 3-methyl hydantoin (3.0 g, 21 mmoles ), sodium acetate (6.0 g, 73 mmoles), acetic anhydride (3 ml), and acetic acid (20 ml) is stirred under an inert atmosphere and heated to reflux. After 15 hours the mixture is poured into water (200 ml), stirred, and the precipitate filtered off, rinsed three times with water and dried. Recrystallization from acetonitrile gave the pure product (3.1 g), mp 189°-190° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Li+].[Br-:34]>ClCCl.O>[Si:1]([O:8][C@H:9]([CH2:10][CH2:11][Br:34])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCO)CCc1ccccc1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H](CCBr)CCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
(S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, 36 mmol) was dissolved in dichloromethane (80 ml), triethylamine (12.6 ml, 90.5 mmol) was added, and the mixture was cooled to 0° C. Methane sulfonyl chloride (4.2 ml, 54.3 mmol) was slowly added dropwise and the resulting mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (50 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 ml×2). The organic layers were combined, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. Without further purification, the residue was dissolved in THF (60 ml). LiBr (7.86 g, 90.5 mmol) was added thereto and the mixture was refluxed for 4 hours. After completion of the reaction, water (80 ml) was added to the reaction solution which was then extracted with diethylether. The organic layers were combined, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give colorless and transparent (S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane (11 g. Yield 86%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C(O)(=O)C.[CH2:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OO>O.C(#N)C>[CH:17]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: C1CCCCC1
Agent: OO
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Temperature: 61 °C
Yield: 63 %

Procedure:
1-Oxyl-2,2,6,6-tetramethylpiperidin-4-one (10.97 g, 64.4 mmol) is divided into 2 portions. A solution of 0.216 g (1.09 mmol) of ferrous chloride tetrahydrate and 0.185 9 (3.08 mmol) of glacial acetic acid in 3 ml of water is added to a mixture of 2 g of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one, 20 ml of acetonitrile, and 13 ml of cyclohexane that is heated to near reflux. A solution of 17.21 g (253 mmol) of 50% aqueous hydrogen peroxide is added to the reaction mixture dropwise over 4.75 hours as the reaction temperature is brought to and maintained at 60-62° C. As the peroxide is being added, a solution of the remaining portion of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one in 20 ml of acetonitrile is added to the reaction mixture dropwise over 3.5 hours. During the addition of the 1-oxyl compound, cyclohexane (47 ml) and acetonitrile (50 ml) are added to the reaction mixture in several portions. A total of 0.326 g of ferrous chloride tetrahydrate, 0.284 g of glacial acid, and 4 ml of water is added to the reaction mixture in 3 portions during the peroxide addition. Work up according to the procedure of Example 44 affords 10.31 g (63% yield) of the title compound. GC assay is 99%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[N:3]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(=O)Cl)c2ccccc21

Procedure:
A stirred mixture of 1-methyl-3-indazolylcarboxylic acid (0.31 g), thionyl chloride (2 ml) and chloroform (10 ml) was refluxed for 2 hours and the solvent was evaporated to give a residue of 1-methyl-3-indazolylcarbonyl chloride.
Reaction SMILES: [Cl:1][C:2](Cl)([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]=[O:4].[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>C1C=CC=CC=1>[P:10]([O:13][CH3:14])([O:11][CH3:12])([O:4][CH:3]=[C:2]([Cl:1])[CH:5]=[C:6]([Cl:8])[Cl:7])=[O:15]
Reactant: COP(OC)OC
Reactant: O=CC(Cl)(Cl)C=C(Cl)Cl
Solvent: c1ccccc1
Product: COP(=O)(OC)OC=C(Cl)C=C(Cl)Cl
Reaction time: 0.25 h
Yield: 80 %

Procedure:
60 g of this 2,2,4,4-tetrachloro-but-3-enal in 100 ml of benzene were reacted with 45 g of trimethyl phosphite in 100 ml of benzene, while stirring, and at a temperature of 60 to 65° C over a period of 15 minutes, and subsequently heated under reflux for 1.5 hours. After the solvent had been removed, 81 g of crude product remained. This was distilled at 0.1 to 0.2 torr and yielded 65 g of product at 110 to 112° C. NMR-spectrum: δ(CH3O--) : 3.9 ppm, J = 12 Hz; δ(C=CH-C) : 6.68 ppm; δ(CH-O-P) : 7.4 ppm, J = 6 Hz.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Yield: 22.2 %

Procedure:
A mixture of (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (700 mg, 1.41 mmol), 5-bromo-1-methylpyridin-2(1H)-one (398 mg, 2.12 mmol), PdCl2(Ph3P)2 (70 mg), Cs2CO3 (1.5 mL, 3.0 mmol) in 1,4-dioxane (15 mL) was heated under reflux for 2 h. The mixture was diluted with EtOAc, and washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (150 mg, 22%). 1H NMR (CDCl3): δ=1.12 (s, 3H), 1.13 (s, 3H), 1.51 (t, 3H), 2.16 (m, 2H), 2.21 (m, 2H), 2.41 (m, 1H), 2.92 (m, 1H), 3.63 (s, 3H), 5.69 (q, 1H), 6.69 (m, 1H), 6.99 (m, 4H), 7.18 (m, 2H) δ7.27 (m, 2H) δ 7.42 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2].C(C1SC=C(CN2CC[C@H](NS([C:48]3[CH:57]=[CH:56][C:55]4[C:50](=[CH:51]C(OC)=CC=4)[CH:49]=3)(=O)=O)C2=O)C=1)#N.C(Br)C1C=CC=CC=1.CI>>[C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:51][C:50]3[CH:55]=[CH:56][CH:57]=[CH:48][CH:49]=3)[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Agent: BrCc1ccccc1
Solvent: CI
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 7-methoxynaphthalene-2-sulfonic acid[1-(5-cyanothiophen-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as in EXAMPLE 148, Part A, in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide and benzyl bromide for methyl iodide.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:18]#[N:19])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[C:8]([C:18]#[N:19])[S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C=C(C#N)S(=O)(=O)c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(=Cc1ccc(CBr)cc1)S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
56.8 g (0.2 mole) of 1-p-tolyl-2-cyano-2-phenylsulfonylethylene were dissolved in 1.000 ml of anhydrous carbon tetrachloride at 40° to 50° C. After addition of 35.6 g (0.2 mole) of N-bromosuccinimide and 1.2 g of dibenzoylperoxide, the whole was heated to the boil under reflux. After 5 hours, the mixture was filtered by still hot; as residue 17.2 g (about 86%) of succinimide melting at 125° C remained behind. The filtrate was evaporated on a rotary steamer and under the vacuum produced by a water jet and the residue was recrystallized from 400 ml of ethanol. 47.4 g (65 of the theory) of weakly yellow crystal melting at 120° to 122° C were isolated. Characteristical NMR-signal in CDCl3 /TMS: --CH2Br at δ = 4.6 ppm. ##STR15##
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 5.5 h

Procedure:
To a solution of 20 g (161.1 mmol) of p-fluorobenzaldehyde in 300 ml of DMF, 19.8 g (290.8 mmol) of imidazole and 44.5 g (322.24 mmol) of potasium carbonate are step by step added at r.t. After being stirred for 5.5 h at 100° C., the reaction mixture is cooled to r.t., diluted with ice water and then the mixture is extracted with AcOEt and CH2Cl2. The combined extracts are concentrated under reduced pressure to give 4-imidazol-1-yl-benzaldehyde as a pale yellow powder. 1H-NMR (400 MHz, CDCl3): 7.26 (s, 1H), 7.38 (2, 1H), 7.59 (d, 2H, J=8.56 Hz), 7.98 (s, 1H), 8.02 (d, 2H, J=8.56 Hz), 10.05 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=1)([CH3:6])[CH3:5])[CH3:2].[NH2:23][C@@H:24]([CH3:41])[CH2:25][N:26]1[CH:30]=[CH:29][C:28]([C:31]2[CH:38]=[C:37]([F:39])[C:34]([C:35]#[N:36])=[C:33]([Cl:40])[CH:32]=2)=[N:27]1>>[Cl:40][C:33]1[CH:32]=[C:31]([C:28]2[CH:29]=[CH:30][N:26]([CH2:25][C@@H:24]([NH:23][C:12]([C:10]3[N:11]=[C:7]([C:4]([O:3][CH2:1][CH3:2])([CH3:5])[CH3:6])[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=3)=[O:14])[CH3:41])[N:27]=2)[CH:38]=[C:37]([F:39])[C:34]=1[C:35]#[N:36]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CCOC(C)(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: CCOC(C)(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.15 mmol, 380 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.15 mmol, 320 mg). The product was purified by flash-chromatography. Yield 260 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.01 (s, 9H), 0.80-0.91 (m, 5H), 0.94 (t, 3H), 1.23 (s, 6H), 3.21 (q, 2H), 3.58 (t, 2H), 4.33-4.42 (m, 2H), 4.53-4.59 (m, 1H), 5.53 (s, 2H), 6.61 (d, 1H), 7.41 (d, 1H), 7.52 (d, 1H), 7.59 (d, 1H), 7.64 (s, 1H), 7.74 (s, 1H). LC-MS: [M+1]=589.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:37])[NH:25][C@@H:26]([CH2:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][O:33][CH2:32]3)[CH2:27][NH:28][CH3:29])[CH2:19]2)[O:10][CH2:11][CH2:12][NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C([C@@H]([C@@H]2CCCN(C(=O)N[C@H](CC3CCCOC3)CNC)C2)OCCNC(=O)OC)C=C(F)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:37])[NH:25][C@@H:26]([CH2:30][C@H:31]3[CH2:36][CH2:35][CH2:34][O:33][CH2:32]3)[CH2:27][NH:28][CH3:29])[CH2:19]2)[O:10][CH2:11][CH2:12][NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CNC[C@H](C[C@@H]1CCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cc(F)cc(Cl)c2)C1
Agent: CNC[C@@H](CC1CCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cc(F)cc(Cl)c2)C1
Product: CNC[C@H](C[C@H]1CCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cc(F)cc(Cl)c2)C1

Procedure:
The methyl 2-((R)-(3-chloro-5-fluorophenyl)((R)-1-((S)-1-(methylamino)-3-((S)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate, methyl 2-((R)-(3-chloro-5-fluorophenyl)((3R)-1-((R)-1-(methylamino)-3-(tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate Isomer 1, and methyl 2-((R)-(3-chloro-5-fluorophenyl)((3R)-1-((R)-1-(methylamino)-3-(tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate Isomer 2 was prepared as above.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:28][CH2:27][C:13]2[N:14]([C:22]([CH3:26])([CH3:25])[CH:23]=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1>C1COCC1.CCOC(C)=O.O>[CH3:9][N:10]1[CH2:28][CH2:27][C:13]2[N:14]([C:22]([CH3:25])([CH3:26])[CH:23]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2C(C)(C)C=O)CCN(C)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2C(C)(C)C(O)c2ccccc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
Phenyl magnesium bromide (1M solution in THF) (3.7 mL, 3.69 mmol) was added dropwise at −70° C. to a stirred solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-methyl-propionaldehyde (200 mg, 0.73 mmol) in THF (30 mL). The contents were stirred at RT for 16 h, diluted with EtOAc (50 mL) and water (40 mL). The layers were separated and the aqueous layer was again extracted with EtOAc (2×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum to obtain crude compound (300 mg), which was purified by column chromatography on silica gel (100-200 mesh) [Eluent: 0-5% MeOH in DCM] to afford 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-methyl-1-phenyl-propan-1-ol (120 mg) which was repurified by prep. TLC to yield free base (25 mg) compound. The free base was converted into the HCl salt. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.80 (m, 1H), 7.25-7.0 (m, 6H), 6.80 (d, 1H), 5.58 (s, 1H), 4.40 (m, 2H), 4.25 (m, 2H), 3.50 (m, 2H), 2.95 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H), 1.64 (s, 3H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[NH2:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH3:13].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])([OH:5])=[O:4]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCC(=O)O)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Yield: 74.8 %

Procedure:
2-Oxoglutaric acid (1.46 g) and L-alanyl-L-proline (0.37 g) were treated with sodium cyanoborohydride (0.38 g) as described above. Crude N-(1,3-dicarboxypropyl)-L-alanyl-L-proline (0.47 g) was obtained, m.p. 140°-160°. The mass spectrum of silylated material showed an ion at 517 m/e equivalent to the molecular ion for the trisilylated derivative minus methyl (532-15). The nmr spectrum was consistent with structure. Methyl resonances were centered at 1.4 ppm.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH3:31])[C:8](=[O:30])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28]C)=[N:11][CH:10]=1.B(Br)(Br)Br.Cl.[OH-].[Na+]>ClCCl.O>[F:39][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH3:31])[C:8](=[O:30])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])=[N:11][CH:10]=1
Reactant: COc1ccccc1-c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(-c2ccccc2O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To a solution of 80 mg (0.14 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-(2-methoxy-phenyl)-N-methyl-4-o-tolyl-nicotinamide in 1.5 ml dichloromethane 0.17 ml of a 1M solution of boron tribromide in dichloromethane (0.17 mmol) were added dropwise at 0° C. The temperature was allowed to warm to room temperature over night. Water and a 1M aqueous solution of hydrochloric acid were added. After 5 min the mixture was neutralized by addition of 1M aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 67 mg (86%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1.C(Cl)Cl>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1
Reactant: COC(=O)C=Cc1cnc(C)nc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCc1cnc(C)nc1
Yield: 98.7 %

Procedure:
3-(2-Methyl-pyrimidin-5-yl)-acrylic acid methyl ester (450 mg, 2.53 mmol, 1 eq) and Pd/C, 10% (0.05 eq, 135 mg) were stirred in a DCM (4 ml)/ethanol (4 ml) mixture under hydrogen atmosphere at room temperature for 20 minutes. Pd/C was filtered off over a celite pad, the solvent was evaporated and obtained was 3-(2-methyl-pyrimidin-5-yl)-propionic acid methyl ester (450 mg, yield=90%, purity=88%). MS: [M+H]+=181.14 1H NMR (300 MHz; CDCl3) δ/ppm 2.60 (t, d, J=7.66 Hz, 2H), 2.66 (s, 3H), 2.87 (t, J=7.66 Hz, 2H), 3.63 (s, 3H), 8.47 (s, 2H)
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:24]=[C:23]([O:25]CC2C=CC=CC=2)[C:22]([C:33]([N:35]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:44])[CH:41]=3)[CH2:36]2)=[O:34])=[CH:21][C:12]=1[C:13]([N:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH3:16])=[O:14])C1C=CC=CC=1>[Pd].C1COCC1>[CH2:17]([N:15]([CH3:16])[C:13](=[O:14])[C:12]1[CH:21]=[C:22]([C:33]([N:35]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:44])[CH:41]=3)[CH2:36]2)=[O:34])[C:23]([OH:25])=[CH:24][C:11]=1[OH:10])[CH2:18][CH2:19][CH3:20]
Reactant: [H][H]
Reactant: CCCCN(C)C(=O)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(O)cc1O
Temperature: 22 °C
Reaction time: 20 h
Yield: 55.1 %

Procedure:
10 ml of THF, 200 mg of 5% Pd/C (50.5% of H2O) and 15.884 ml (0.708 mmol) of hydrogen are added to 200 mg (0.354 mmol) of 2,4-bisbenzyloxy-N-butyl-5-(5-hydroxy-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide in an autoclave, and the mixture is stirred for 20 h at 22° C. Filtration, subsequent evaporation and chromatography of the residue gives 75 mg (55.1%) of N-butyl-2,4-dihydroxy-5-(5-hydroxy-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide “A1”);