Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[H-].[Na+].[CH:6]1([C:10](=[O:12])[CH3:11])[CH2:9][CH2:8][CH2:7]1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].S(=O)(=O)(O)O.O>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH:11]=[C:10]([CH:6]1[CH2:9][CH2:8][CH2:7]1)[OH:12])[CH3:18]
Reactant: CC(=O)C1CCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)C=C(O)C1CCC1
Reaction time: 8 h

Procedure:
Ethanol (4.39 mL, 75.2 mmol) was added dropwise to a suspension of sodium hydride (0.607 g, 15.2 mmol, 60% in mineral oil) in a flask that was held in an ice bath. Ten minutes after complete addition, a mixture of 1-cyclobutylethanone (1.5 mL, 14 mmol, Aldrich) and diethyl oxalate (2.01 g, 13.8 mmol, Aldrich) was added dropwise. After stirring overnight, 4.0M sulfuric acid in water (0.00759 L, 30.4 mmol) was added. The product was extracted into diethyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The material was used without further purification in Step B.
Reaction SMILES: [Cl:1][C:2]1[N:11]2[C:5]([C:6](=[C:16]3[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][CH:3]=1.[OH-].[K+]>C(O)(C)C>[Cl:1][C:2]1[N:11]2[C:5]([C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccccc3CCn3c(Cl)cnc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Clc1cnc2n1CCc1ccccc1C2=C1CCNCC1
Yield: 6.7 %

Procedure:
A mixture of intermediate 12 (30.4 g) and potassium hydroxide (46 g) in isopropanol (370 ml) was stirred and refluxed for 6 hours. The solvent was evaporated. The residue was taken up in water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 1.65 g (90%) of 3-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (intermediate 13).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:20]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:19])#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCOC(=O)C(Cc1ccccc1Br)C(=O)OCC
Reactant: C#CCCCCCCCCCCC
Product: CCCCCCCCCCCC#Cc1ccccc1CC(C(=O)OCC)C(=O)OCC
Yield: 30.3 %

Procedure:
Reaction of diethyl(2-bromobenzyl)propan-1,3-dioate (11.87 g, 30 mmol) with 1-tridecyne (11.10 g, 45 mmol) as described in example 3 gave 3.89 g (29%) of the title compound as a pale yellow oil after chromatography. It had νmax (film) 1735, 1755, 2840, 2920 cm-1 ; δ(CDCl3) 0.87 (3H, distorted t, terminal CH3), 1.08 (6H, t, J 7 Hz, ester CH3), 1.28 (18H, m, alkylene chain), 2.42 (2H, t, J 6 Hz, C≡C--CH2), 3.31 (2H, d, J 7.5 Hz, ArCH2), 3.90 (1H, t, J 7.5 Hz, methine H), 4.12 (4H, q, J 7.5 Hz, ester CH2), 7.15 (3H, m, aromatics), 7.36 (1H, m, aromatic). M+ 428.2928 (C27H40O4 requires; 428.2926).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:32][C:33]1([NH:37][CH3:38])[CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[C:20]([N:35]2[CH2:36][C:33]([CH3:32])([NH:37][CH3:38])[CH2:34]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CNC1(C)CNC1
Agent: CS(=O)(=O)O
Product: CNC1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)C1

Procedure:
7-Fluoro-1-methyl-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b]-[1,8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3-(methylamino)azetidine dimethanesulphonate. The reaction mixture is heated for 1 and a half hours to approximately 90° C. 1.12 g of 7-fluoro-1-methyl-8-(3-methyl-3-methylamino-1-azetidinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at approximately 336° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=CC=2F)=NOC=1C)=O)C>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2F)noc1C
Agent: CCOC(=O)c1c(-c2ccccc2F)noc1C
Product: Cc1onc(-c2ccc(F)cc2F)c1CO
Yield: 38.9 %

Procedure:
As described for example 84d, 3-(2,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (61.9 g, 232 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (20.3 g, 39%) which was obtained as a light brown solid. MS: m/e=284.1 [M+OAc]−.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][C:19]=1[O:26][CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([OH:17])=[C:19]([O:26][CH3:27])[CH:20]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Reactant: COc1cc(CN)ccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)/C=C/c2ccc(C(C)(C)C)cc2)ccc1O
Reaction time: 16 h
Yield: 58.2 %

Procedure:
400 mg (1.96 mmol) of para-tert.-butyl-trans-cinnamic acid were dissolved at 5° C. in DMF (10 ml) together with 290 mg (1.94 mmol) of 4-hydroxy-3-methoxybenzyl-amine hydrochloride and 0.48 ml (6.50 mmol) of triethylamine. After the addition of a solution of 870 mg (1.97 mmol) of BOP in DCM (9 ml), stirring was continued for 16 h at RT. The reaction solution was then poured into water and extracted twice with a mixture of DIPE/EA (1:1). The combined organic phases were washed with 2M eq. hydrochloric acid and three times with 1 M eq. of sodium hydrogen carbonate solution and dried over magnesium sulfate. Follwing removal of the solvents and recrystallisation from DIPE, 384 mg (1.13 mmol, 58% of theoretical) of para-tert.-butyl-trans-N-(4-hydroxy-3-methoxybenzyl)-cinnamic acid amide were obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1.O.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCO.[Pd]>[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)([OH:35])(=[O:34])=[O:33].[F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1ccc(OC[C@@H]2CCN2C(=O)OCc2ccccc2)c(F)n1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(OC[C@@H]2CCN2)c(F)n1
Reaction time: 16 h
Yield: 60.3 %

Procedure:
2-Fluoro-6-methyl-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine from Example 117d (714 mg, 2.16 mmol) was combined with 10% Pd/C (50 mg) and p-toluenesulfonic acid monohydrate (830 mg, 4.36 mmole) in 30 mL of EtOH, and the mixture was stirred under an H2 atmosphere for 16 hours. The mixture was filtered, concentrated, the residue was triturated with ether, and the product was recrystallized from ethyl acetate/ether to yield 480 mg (60%) of the title compound. mp 141-143° C. 1H NMR (D2O 300 MHz) δ: 2.40 (s, 6H), 2.65-2.71 (m, 2H), 4.07-4.16 (m, 2H), 4.43(d, J=4.5, 2H), 4.81-95 (m, 1H), 7.16 (d, J=8.0, 1H), 7.37 (d,J=8.0, 2H), 7.55 (dd, J=8.0, 2.5, 1H), 7.70 (d,J=8.0, 2H). MS (DCI/NH3) m/e 197 (M+H)+ 214 (M+NH4)+. Anal. calcd. for C10H13FN2O.C7H8S: C, 55.42; H, 5.75; N, 7.60. Found: C, 55.27; H, 5.69; N, 7.44. [α]D −3.2 (c 1, MeOH).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.Cl.Cl[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])N.Cl>C(O)(C)C.CO.O1CCOCC1>[N:23]1[CH:24]=[CH:25][C:20]([N:2]2[CH2:3][CH2:4][C:5]3([CH2:6][CH2:7][NH:8][CH2:9][CH2:10]3)[CH2:1]2)=[CH:21][CH:22]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Agent: Cl
Agent: NC(=O)[O-]
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CO
Product: c1cc(N2CCC3(CCNCC3)C2)ccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The reaction was performed under an N2 atmosphere. tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (869 mg, 3.62 mmol), 4-chloropyridine hydrochloride (1.08 g, 7.20 mmol) and TEA (2.5 ml, 18 mmol) were suspended in isopropanol (10 ml). The mixture was heated to 80° C. and stirred overnight at 80° C. Then the solvent was removed in a rotary evaporator. The residue was taken up in DCM and concentrated to small volume again. This process was repeated twice more. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2). The product obtained still contained impurities and was used in the next stage in that condition. 2. The reaction was performed under an N2 atmosphere. The carbamate (1.034 g, max. 3.26 mmol) was dissolved in MeOH (5 ml) and mixed with 4 M HCl in dioxane (5 ml). The reaction batch was stirred for 2 h at RT. Then the solvent was removed. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2→95:5→9:1). Yield: 455 mg, 58% over 2 stages.
Reaction SMILES: N[C:2]1[C:12]([Br:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].FC(F)(F)C(O)=O.N(OCCC(C)C)=O.[PH2](O)=O>C(O)C>[Br:13][C:12]1[CH:2]=[C:3]([CH:9]=[C:10]([CH3:14])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(C)cc(Br)c1N
Agent: CC(C)CCON=O
Agent: O=[PH2]O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1cc(C)cc(Br)c1
Yield: 87.3 %

Procedure:
Ethanol (20 mL) was added to ethyl 2-amino-3-bromo-5-methylbenzoate obtained in Example (259d) (715 mg, 2.8 mmol). While the mixture was stirred, trifluoroacetic acid (0.82 mL, 11.1 mmol), isopentyl nitrite (649 mg, 5.5 mmol) and hypophosphorous acid (7.3 g, 55.4 mmol) were added under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was diluted and extracted with ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0/10, 2/8) to obtain 594 mg of the title compound as a light yellow oily substance (88%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: NCCCO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78947.4 %

Procedure:
28 ml (0.38 mmol) of 3-amino-1-propanol were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 47.15 g (0.30 mol, 83% yield) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([F:35])([F:34])[F:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2C(F)(F)F)cc1
Yield: 39.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.031 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:26]=[N:27][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1.[CH3:38]CN(CC)CC.CCOCC.C(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:38][C@@H:13]1[C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:26]=[N:27][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(c1)[C@]1(C[C@@H]1c1ccc3c(/C=C/c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Yield: 4 %

Procedure:
From two repeated batches of Example A31 using 5-methoxy-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (combined 491 mg, 1.0 mmol), purification using flash chromatography (silica gel, 1% Et3N in CHCl3/MeOH 96:4 to 92:8), followed by trituration with 1:1 Et2O/CH2Cl2 gave the minor diastereomer title compound as a pale yellow solid (18 mg, 4%). 1H NMR (400 MHz, CDCl3 with a few drops of CD3OD) δ ppm 8.21 (s, 1 H), 7.82 (d, J=8.5 Hz, 1 H), 7.75 (d, J=8.5 Hz, 1 H), 7.39 (s, 1 H), 7.27 (d, J=17.3 Hz, 1 H), 7.16 (d, J=17.3 Hz, 1 H), 7.05 (d, J=8.8 Hz, 1 H), 6.80 (d, J=8.3 Hz, 1 H), 6.72 (d, J=8.8 Hz, 1 H), 6.67 (d, J=9.3 Hz, 1 H), 6.54 (s, 1 H), 3.77 (s, 3 H), 3.58 (bs, 4 H), 3.18-3.27 (m, 1 H), 2.57 (bs, 4 H), 2.40 (dd, J=8.5, 5.3 Hz, 1 H), 2.35 (bs, 3 H), 2.09 (dd, J=9.0, 5.0 Hz, 1 H); MS ESI 507.3 [M+H]+, calcd for [C30H30N6O2+H]+ 507.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(COc2ccc(C3=NCCc4ccccc43)cc2)cc1
Temperature: 0 °C
Yield: 28.7 %

Procedure:
A solution of 4-benzyloxy-N-phenethylbenzamide (1.000 g, 3.0 mmol) in POCl3 (10 ml, 107.3 mmol) was refluxed under N2 for 18 hr, then the cooled reaction mixture was slowly added to ice-water (50 ml) with stirring. The resulting mixture was extracted with EtOAc (4×20 ml), then the remaining aqueous layer was basified to pH 10 with concentrated ammonia (80 ml). This was extracted with EtOAc (3×50 ml), then the combined extracts were dried over MgSO4 and concentrated in vacuo to give 0.270 g of yellow solid. Purification by flash chromatography, eluting with hexane:EtOAc (6:4) gave 0.151 g (16% yield) of yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]([CH:5]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])=[O:13]
Reactant: CCOC(=O)CCCCI
Reactant: COCC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(C(=O)COC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.4 %

Procedure:
To a suspension of tert-butyl 4-methoxy-3-oxobutanoate (3.09 g) and potassium carbonate (2.50 g) in dimethylformamide (20 mL) was added ethyl 5-iodopentanoate (4.62 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 1-tert-butyl 7-ethyl 2-(methoxyacetyl)heptanedioate as colorless oil (4.33 g).
Reaction SMILES: [O-:1][CH2:2]C.[Na+].[Br:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1.[Cl-].[NH4+]>CO>[Br:5][C:6]1[C:7]([O:1][CH3:2])=[N:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sodium ethoxide solution (28% in MeOH) (1 ml) was added to an MeOH (3 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 0.5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution and MeOH was distilled away under reduced pressure. An insoluble precipitate was washed with water and a white solid of 3-bromo-2-methoxy-5-nitropyridine (69 mg) was thus obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[O:18])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4ccncc4)cc3)oc2C)cc1
Yield: 72.8 %

Procedure:
Reaction of oxalyl chloride (178 λL, 2.0 mmol) and benzoic acid 4 (379 mg, 1.0 mmol) with subsequent coupling to 4-pyridinylmethylamine (114 λL, 1.1 mmol) gave benzamide 10 (336 mg, 71%) as a white powder: mp (EtOAc) 169-172° C.; 1H NMR δ 9.24 (t, J=5.9 Hz, 1H, CONH), 8.50 (dd, J=4.4, 1.6 Hz, 2H, H-2′, H-6′), 8.03 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.92 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.67 (d, J=8.3 Hz, 2H, H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″), 7.32 (dd, J=4.4, 1.6 Hz, 2H, H-3′, H-5′), 4.63 (s, 2H, CH2SO2), 4.51 (d, J=5.9 Hz, 2H, CH2N), 2.41 (s, 3H, CH3), 2.14 (s, 3H, CH3); 13C NMR δ 165.7, 158.0, 150.0, 148.9 (2), 148.4, 144.5, 135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2), 126.0, 125.5 (2), 122.2 (2), 53.0, 41.8, 21.1, 9.7; MS m/z 462.8 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 65.10; H, 4.96; N, 9.10%.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:3]2[N:4]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cn2nc(Cl)cc(Br)c2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2nc(Cl)cc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 5a (10.6 g, 34.8 mmol) in acetonitrile (150 mL) was added DIEA (10.9 mL, 62.6 mmol) and morpholine (3.60 mL, 42.0 mmol). The reaction mixture was stirred at rt for 1 h, during which time the entire solution solidified. The resulting mixture was left at rt for 3 h, then was poured into ice water (200 mL), and the precipitates were collected by filtration, and dried under high vacuum. Compound 5b was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.25 (s, 1H), 6.10 (s, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.99-4.17 (m, 4H), 3.86-3.96 (m, 4H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][NH2:24])[CH2:20][O:19]1.CO>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([NH:24][CH2:23][CH:21]1[CH2:20][O:19][C:18]([CH3:25])([CH3:17])[O:22]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CNC(=O)OC(C)(C)C)NCC1COC(C)(C)O1
Yield: 32.6 %

Procedure:
The commercially available Tert-butyl-N-(2-hydroxypropyl)carbamate (10 g, 57.0 mmol)) and trietylamine (12 ml, 85.6 mmol) were dissolved in dichloromethane (60 mL) and cooled to 0° C. Methanesulfonyl chloride (4.9 ml, 62.7 mmol) was added dropwise to the ice-cold solution and the reaction was allowed to warm up to room temperature with stirring overnight. The reaction was then quenched with NaOH (1M, 5 ml). The organics were washed with water (2×100 ml) and then brine, collected, dried over MgSO4, filtered and evaporated under reduced pressure to give methanesulfonic acid 3-tert-butoxycarbonylamino-propyl ester (13.5 g). The crude methanesulfonic acid 3-tert-butoxycarbonylamino-propyl ester (13.5 g, 53 mmol) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (12 g, 91.6 mmol) were stirred overnight at room temperature. The mixture was dissolved in ethyl acetate (100 ml) and washed with water (3×100 ml) and brine. The organics were collected, dried over MgSO4, filtered and evaporated under reduced pressure to give an oil. This was purified by silica column chromatography eluting with ethyl acetate: methanol to give the desired product {2-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-propyl}-carbamic acid tert-butyl ester (4.74 g, 17.3 mmol). Mass Spec (ESI) m/z: [M+H]+=289.12. 1H NMR (CDCl3; 300 MHz) δ=5.15 (s, br, 1H), 4.19 (quin, 1H), 4.02 (t, 1H), 3.66 (t, 1H), 3.18 (q, 2H), 2.70 (m, 4H), 1.63 (quin, 2H), 1.42 (s, 9H), 1.40 (s, 3H), 1.40 (s, 3H). 13C NMR (CDCl3; 300 MHz) δ=156.00, 109.05, 78.85, 75.23, 67.47, 52.30, 47.91, 39.20, 29.69, 28.35, 26.81, 25.37.