Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Br: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][S:18](Cl)(=[O:20])=[O:19]>>[OH:2][CH2:1][CH2:3][NH:4][S:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5])(=[O:19])=[O:20]
Reactant: O=S(=O)(Cl)CCCCCCCCCCCCBr
Reactant: NCCO
Product: O=S(=O)(CCCCCCCCCCCCBr)NCCO
Yield: 73.6 %

Procedure:
Ethanolamine (0.67 g, 11 mmol) was reacted with 12-bromododecanesulfonyl chloride (1.74 g, 5 mmol) in the same manner as in Preparation Example 4, to give N-(2-hydroxyethyl)-12-bromododecanesulfonamide (1.37 g) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[CH3:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([NH2:54])(=[O:53])=[O:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH:54][S:51]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[CH3:44])(=[O:53])=[O:52])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Cn1ccc2ccc(CC(=O)NCC3CCCC3)cc21
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cn1ccc2ccc(CC(=O)NCC3CCCC3)cc21
Yield: 75.7 %

Procedure:
A solution of 4-[6-(cyclopentylmethylcarbamoyl)methylindol-1-ylmethyl]-3-methoxybenzoic acid (0.60 g), 4-dimethylaminopyridine (0.18 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.33 g), and 2-methylbenzenesulfonamide (0.25 g) in methylene chloride (70 ml) was stirred under a nitrogen atmosphere for 80 hr. The mixture was diluted with methylene chloride, washed with 10% v/v hydrochloric acid and water, and evaporated. The resulting white solid was precipitated from methylene chloride with hexane to give the title compound (0.62 g, 76%) as a white solid: mp 187°-188°.
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][C:27]12[CH2:34][CH2:33][CH2:32][N:31]1[CH2:30][CH2:29][CH2:28]2>CN(C)C=O>[CH2:28]1[C:27]2([CH2:26][NH:25][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[N:31]([CH2:32][CH2:33][CH2:34]2)[CH2:30][CH2:29]1
Reactant: O=C(O)c1cn2ccccc2n1
Reactant: NCC12CCCN1CCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CCCN1CCC2)c1cn2ccccc2n1

Procedure:
Imidazo[1,2-a]pyridine-2-carboxylic acid is reacted with carbonyldiimidazole in dimethylformamide and subsequently with 7a-aminomethylhexahydro-1H-pyrrolizine to afford the title compound upon workup.
Reaction SMILES: [C:1]([NH:4][C:5]([N:7]([CH3:9])[CH3:8])=[S:6])(=O)[CH3:2].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](=[O:18])[CH2:16]Br)=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>C(O)(C)C>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([C:16]2[S:6][C:5]([N:7]([CH3:9])[CH3:8])=[N:4][C:1]=2[CH3:2])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)NC(=S)N(C)C
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(C)O
Product: Cc1nc(N(C)C)sc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
The starting material is prepared as follows: A mixture of 3.7 g of N-acetyl-N',N'-dimethyl-thiourea and 7 g of 4-chloro-3-nitro-phenacyl bromide in 100 ml of isopropanol is refluxed for 2 hours, cooled and filtered. The residue is rendered basic and extracted with methylene chloride. The extract is dried and evaporated and the residue is recrystallised from a mixture of ethyl acetate and hexane, yielding 4-chloro-3-nitro-1-(4-methyl-2-dimethylamino-5-thiazoloyl)-benzene, which melts at 165°-169°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl>O1CCCC1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)[CH2:5][OH:6]
Reactant: O=C(O)c1cc(F)ccc1Sc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: OCc1cc(F)ccc1Sc1ccccc1
Temperature: 20 °C

Procedure:
144 g of 3-fluoro-6-(phenylthio)-benzoic acid in 1000 ml of tetrahydrofuran is treated dropwise under a nitrogen atmosphere and under reflux with a 70% sodium-dihydro-bis(2-methoxyethoxy)-aluminate solution in benzene. The mixture is held under reflux for a further 2 hours. After the addition of 400 ml of benzene, the mixture is cooled to 20° C, acidified with 435 ml of 3-N hydrochloric acid and subsequently treated with 600 ml of concentrated hydrochloric acid. The organic phase is washed with water, dried over sodium sulphate and evaporated. There is obtained 3-fluoro-6-(phenylthio)-benzyl alcohol as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:15]=[C:14]([N:16]3[C:24]4[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=4[N:18]=[CH:17]3)[S:13][C:12]=2[C:27]([NH2:29])=[O:28])[CH3:9])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl>[CH3:34][S:35]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[C:30]([F:33])([F:31])[F:32])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:37])=[O:36]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 120 mg of 3-{1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 57 mg of methanesulfonyl chloride, and 51 mg of triethylamine in 3 ml dichloromethane give [1-(5-carbamoyl-4-{1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][N:14]([C@H:17]([CH3:20])[CH2:18][OH:19])[C:10]=2[N:11]=[CH:12][N:13]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][N:14]([C@H:17]([CH3:20])[CH2:18][O:19][CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: C1=COCCC1
Reactant: C[C@H](CO)n1ccc2c(Cl)ncnc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](COC1CCCCO1)n1ccc2c(Cl)ncnc21
Yield: 100 %

Procedure:
2,3-Dihydropyran (25.0 mL, 270 mmol) was added to (2R)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol (11.00 g, 51.97 mmol) (see Preparation 3) and pyridinium toluene-4-sulphonate (3.92 g, 15.6 mmol) in DCM (150 mL). The reaction mixture was washed with water (200 mL) and the aqueous phase was extracted with DCM (2×150 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 70:30) to afford the title compound as a yellow oil in 100% yield, 15.65 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][CH2:6][CH2:7]OS(C)(=O)=O.[CH3:17][NH2:18]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][CH2:6][CH2:7][NH:18][CH3:17]
Reactant: CS(=O)(=O)OCCOc1cc(F)cc(F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCOc1cc(F)cc(F)c1
Yield: 71 %

Procedure:
A mixture of methanesulfonic acid 2-(3,5-difluoro-phenoxy)-ethyl ester (1.2 g, 4.76 mmol), THF (30 ml) and 40% aqueous monomethylamine (30 ml) was heated under reflux for 8 hours. The reaction mixture was poured on water and extracted 3 times with diethyl ether (3×20 ml). The orghanic phase was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (9-1) to give [2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amine (0.63 g, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([OH:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(O)CC(C)(C)c1ccc(F)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(F)c(OC)c1
Yield: 89.8 %

Procedure:
2.78 g (9.78 mmol) of ethyl-4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate is oxidized as in Example 273 with SO3/Py in dichloromethane to the corresponding α ketoester. After chromatography on a Flashmaster, 2.48 g (89.9%) of the desired compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C([N-][CH:22]([CH3:24])[CH3:23])(C)C.[Li+]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1([CH2:8][C:9]2[CH:4]=[CH:5][CH:6]=[CH:24][C:22]=2[CH3:23])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
N-t-butoxycarbonyl isonipecotic acid methyl ester was transformed utilizing the alkylation procedure as described in Example 1, Step 3 substituting lithium diisopropylamide as the base to afford the product as a yellow syrup.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[Cl:12][C:13]1[C:18]([NH2:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:1][C:15]1[C:16]([O:20][CH3:21])=[CH:17][C:18]([NH2:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COc1ccc(Cl)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(N)c(Cl)cc1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (commercially available, for example, from Aldrich) (9.1 g, 32 mmol) was added over 20 minutes to a stirred solution of 6-chloro-3-methoxyaniline (commercially available, for example, from Apollo Scientific) (10.0 g, 63 mmol) in ethyl acetate (150 ml) at −5° C. The resulting solution was stirred at −5° C. for 1 hour then washed with a solution of potassium carbonate (6 g, 43 mmol) in water (40 ml and then with water (20 ml). The resulting solution was concentrated under reduced pressure to give 4-bromo-2-chloro-5-methoxyaniline as a pale brown solid (14.3 g, 95%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CS(C)=O>[I:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(I)cc(N2CCOCC2)c1
Temperature: 130 °C
Yield: 80 %

Procedure:
To a solution of 1-fluoro-3-iodo-5-nitrobenzene (4.0 g, 15 mmol) in DMSO (7.5 mL) was added morpholine (3.26 mL, 37.5 mmol), and the mixture (which instantly became purple) was heated to 130° C. for 30 min in the microwave. Purification was attempted by directly loading the mixture onto a CombiFlash column (80 g; load neat w/CH2Cl2 rinse; 100:0 to 60:40 hexanes:EtOAc over 35 minutes) but the mixture crashed at the top of the column and not all the mixture could be loaded. Nonetheless, after an inital spike in pressure, purification was possible, and the residual material was purified in a second purification (24 g; load w/CH2Cl2; 100:0 to 60:40 hexanes:EtOAc over 20 minutes). Concentration of the combined fractions from the two purifications provided 4-(3-iodo-5-nitrophenyl)morpholine (4.01 g, 12.0 mmol, 80%) as a bright yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H); 7.67 (s, 1H); 7.47 (s, 1H); 3.89 (s, 4H); 3.26 (s, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11].C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>ClCCCl>[S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)([O:11][CH2:10][C@H:9]1[O:12][CH2:8]1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reaction time: 26 h
Yield: 70.3 %

Procedure:
To a suspension of 37.5 g of potassium carbonate (0.27 mol) and 250 ml of 1,2-dichloroethane, was added dropwise at 24-28° C. 20 g of (S)-3-chloro-1,2-propanediol (0.18 mol) (optical purity: 98.9% ee). After finishing the addition, the solution was stirred for 26 hours and cooled. To the reaction solution were added dropwise under stirring at 5-10° C. 20.1 g of triethylamine (0.2 mol) and 0.4 g of N,N-dimethylaminopyridine (0.0033 mol) and 34.5 g of p-toluenesulfonyl chloride (0.18 ml) in order. After finishing the addition the mixture was stirred for 3 hours and the resulting salt was dissolved by adding 150 ml of 3% hydrochloric acid. The organic layer was washed with 150 ml of 1% hydrochloric acid and 150 ml of water. The excess solvent was removed under vacuo. The chemical purity and optical purity at that time were 93.7%, 96.6% ee respectively. The residue was recrystallized from isopropyl alcohol/hexane=1/1 (V/V) to give 28.9 g of (S)-glycidyl tosylate (yield 70%). Chemical purity: 98.3%, optical purity: 97.5% ee
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.CO.Cl.[CH3:14]N(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:14][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: Cc1cccc(C(=O)O)n1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Suspend 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL). Cool to 0° C. Add methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (18.2 g, 94.8 mmol). Stir the mixture at room temperature for 6 hours, wash with water and brine, and dry over sodium sulfate. Filter the mixture and concentrate in vacuo. Chromatograph the residue on SiO2 (50% ethyl acetate/hexanes) to obtain the desired subtitled intermediate, 9.66 g (92%), as a colorless liquid.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][N:4]=1)#[N:2].[ClH:20].[H][H]>CO.[Pd]>[ClH:20].[NH2:2][CH2:1][C:3]1[N:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:8]=1
Reactant: COC(=O)c1c(F)cccc1-c1cnc(C#N)nc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1c(F)cccc1-c1cnc(CN)nc1
Reaction time: 0.5 h

Procedure:
Methyl 2-(2-cyanopyrimidin-5-yl)-6-fluorobenzoate (100 mg, 0.389 mmol) was dissolved in methanol (4.0 mL) under nitrogen. Palladium on carbon (840 mg, 10% wt/wt) and concentrated HCl (32 μL) were then added prior to exchanging the nitrogen for hydrogen. After 30 minutes the reaction was judged complete (LCMS). The reaction mixture was filtered through celite and the celite was washed with additional methanol. Removal of the solvent under reduced pressure provided methyl 2-[2-(aminomethyl)pyrimidin-5-yl]-6-fluorobenzoate hydrochloride (104 mg) of 90% pure material, as determined by proton NMR and LCMS.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH2:14]Br>CN(C=O)C>[Br:12][CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CCc1ccc(C(Br)CBr)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.67 g (0.0055 mol) p-hydroxy benzaldehyde and 0.237 g (0.0098 mol) sodium hydride in 10 mL DMF, 1 g (0.0034 mol) 2-bromo-[5-ethyl-2-pyridyl]-ethyl bromide dissolved in 10 mL of Do was added at 10-15° C. Reaction mixture was stirred for 1 hr at 25-30° C. and further warmed at 75-80° C. for 24 br. After subsequent work-up crude product was obtained which on purification gave titled compound, Yield of the product was 0.068 g (6%). The product obtained was characterized by satisfactory mass.
Reaction SMILES: [Na].[O-]CC.[Na+].[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:16][C:15]=1[C:31](=[O:33])[CH3:32])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:34](OCC)(=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([OH:40])=[CH:32][C:31]([C:15]1[CH:16]=[C:17]([CH:28]([CH3:30])[CH3:29])[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][C:14]=1[O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:33])[CH3:39]
Reactant: CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(O)=CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Sodium (2.8 eq) was added to ethanol under nitrogen at room temperature and stirred for 25 minutes to generate sodium ethoxide. 1-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-ethanone (1 eq) was dissolved in further ethanol and added to the sodium ethoxide solution. Diethyl oxalate (1.64 eq) was added and the reaction mixture heated to reflux for 4 hours. The mixture was allowed to cool to room temperature and enough 1MHCl (aq) was added to acidify the reaction mixture, which was then concentrated in vacuo. The resulting gum was partitioned between dichloromethane and brine, and the organic phase was dried over MgSO4, filtered and evaporated in vacuo to give 4-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as a yellow gum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O.C(O)C>[CH:25]1[CH:24]=[C:21]2[C:22]([N:2]([CH2:3][C:4]([NH2:6])=[O:5])[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=1)=[O:23]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a stirred solution of glycinamide hydrochloride (2.20 g, 20.0 mmoL) and sodium carbonate (2.54 g, 24 mmoL) in 25 mL of water is added N-carbethoxyphthalimide (4.38 g, 20.0 mmoL). The resulting suspension is stirred for 1.5 hour and then filtered to afford 3.22 g (79%) of the crude product as a white powder. The crude product is slurried in 200 mL of refluxing ethanol. The resulting suspension after cooling to room temperature is filtered and the solid dried in vacuo (60° C., <1 mm) to afford 2.65 g (65%) of N-phthaloylglycinamide as a white powder: mp 199°-201° C.; 1H NMR (DMSO-d6) δ 8.00-7.8 (m, 4 H, Ar), 7.70 (br s, 1 H, CONH2), 7.26 (br s, 1 H, CONH2), 4.16 (s, 2 H, CH2); 13C NMR (DMSO-d6) δ 167.8, 167.5, 134.4, 131.7, 123.1, 39.9. Anal. Calcd for C11H10N2O3. Theoretical: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.49; H, 4.59; N, 12.82.
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2=[N:18][CH:19]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:16]2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH2:31][C:32]([CH:34]1[CH2:38][CH:37]([N:39]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH:35]1[CH3:54])=[O:33]>CN(C=O)C>[CH2:47]([N:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:37]1[CH2:38][CH:34]([C:32](=[O:33])[CH2:31][N:22]([C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][N:13]([S:3]([C:6]4[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=4)(=[O:5])=[O:4])[C:17]3=[N:18][CH:19]=2)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:35]([CH3:54])[CH2:36]1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)C(=O)OC(C)(C)C)cnc32)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 0.058 g, 1.45 mmol) in DMF (5 mL) was added a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol, Example #3, Step E) in DMF (5 mL) dropwise at about 0° C. The resulting mixture was stirred at this temperature for about 30 min and then added dropwise to a solution of 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g, 1.823 mmol, Preparation #R.1) in DMF (10 mL). The resulting mixture was stirred at about 0° C. for about 1 h and the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc (100 mL each). The organic phase was dried over anhydrous MgSO4 and concd under reduced pressure to yield tert-butyl 2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (1.04 g, 97%) as a yellow amorphous solid: LC/MS (Table 1, Method a) Rt=3.30 min; MS m/z 708 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:32](=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:12][CH2:11]1)=[O:8]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and isovaleryl chloride (0.04 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give 2-(2,4-dichlorophenoxy)-N-[1-(3-methylbutyryl)piperidin-4-yl]benzamide (97 mg, 79%) as a colorless oil. Rf: 0.15 (hexane/AcOEt 4:6) LC/MS (APCI) tr=4.44 min, m/z 451.43 (68), 449.42 (M++H, 100). HPLC tr=3.17 min (98.27%) 1H NMR (270 MHz, CDCl3) δ 0.95 (6H, d, J=6.7 Hz, 2CH3), 1.33 (3H, m, CH2+½CH2), 2.19 (2H, d, J=6.7 Hz, CH2CO), 2.83 (1H, m, ½CH2), 3.15 (1H, m, ½CH2), 3.76 (1H, m, ½CH2), 4.16 (1H, m, CH), 4.44 (1H, m, ½CH2), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.86 (1H, d, J=8.6 Hz, ArH), 7.20 (1H, dd, J=8.7, 2.5 Hz, ArH), 7.25 (1H, m, ArH), 7.29 (1H, br s, NH), 7.41 (1H, m, ArH), 7.49 (1H, d, J=2.5 Hz, ArH) and 8.16 (1H, dd, J=7.7, 1.7 Hz, ArH).