Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)CBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-methylpropane (336 mg), and the mixture was stirred at room temperature for 19 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([F:17])[C:4]([CH2:8][N:9]2[N:13]=[N:12]C(C(N)=O)=C2)=[C:5]([F:7])[CH:6]=1.FC1C=CC=C(F)C=1CCl.[N-]=[N+]=[N-].[Na+]>CS(C)=O>[F:7][C:5]1[CH:6]=[CH:1][CH:2]=[C:3]([F:17])[C:4]=1[CH2:8][N:9]=[N+:13]=[N-:12]
Reactant: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Agent: Fc1cccc(F)c1CCl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c(F)cccc1F

Procedure:
The process comprises the preparation of Rufinamide by reacting 2,6-difluorobenzyl chloride and sodium azide in the presence of DMSO to obtain 2,6-difluoro benzyl azide, which is then treated with propiolic acid to give carboxylic acid intermediate which on further reaction with thionyl chloride to give corresponding acyl chloride. The acyl chloride intermediate is further reacted with methanolic ammonia to yield Rufinamide.
Reaction SMILES: [OH-:1].[Na+].Br[CH:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].O>C(N(CC)C=O)C>[OH:1][CH:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [OH-]
Reactant: CC(C)(C)C(=O)C(Br)C(C)(C)C
Agent: CCN(C=O)CC
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)C(O)C(C)(C)C
Temperature: 110 °C

Procedure:
5 g (0.125 mol) of sodium hydroxide powder was added to 11.6 g (0.05 mol) of 4-Bromo-2,2,5,5-tetramethyl-3-hexanone in 10 g of dry diethylformamide. This reaction mixture was heated to 110° C. for 2 hours, cooled to room temperature and 600 mL of water and 200 mL of hexanes added. The hexane layer was collected and the aqueous layer was washed three times with 50 ml of additional hexanes. The hexanes fractions were then combined, washed three times with 50 ml water, then dried with MgSO4. The product was collected as a crystalline solid after hexanes removal by atmospheric distillation.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21]C)=O)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1[CH:27]=[CH:26]N=C1.OC1C=CC2C3C(=CC=CC=3)C(=O)C=2C=1.[Si](Cl)(C(C)(C)C)(C)C>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:16]2[C:15]3[C:14](=[CH:13][CH:12]=[CH:26][CH:27]=3)[C:19](=[O:21])[C:17]=2[CH:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: O=C1c2ccccc2-c2ccc(O)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1-2
Yield: 84 %

Procedure:
The procedure for this reaction was the same as described above for methyl 6-tert-butyldimethylsilyloxy-2-naphthoate. A solution of imidazole (0.5 g, 7.4 mmol) in 2 mL of dry DMF was added to a solution of 2-hydroxy-9-fluorenone (Aldrich, 0.55 g, 2.8 mmol) and tert-butyldimethylsilyl chloride (0.5 g, 3.3 mmol) in 5 ML of dry DMF to give after workup 0.74 g (84%) of a yellow oil: 1H NMR (CDCl3) delta 7.612-6.891 (m, 7H), 0.994 (s, 9H), 0.224 (s, 6H); 13C NMR (CDCl3 delta 193.69, 157.04, 144.87, 137.52, 136.04, 134.73, 134.50, 127.92, 125.59, 124.28, 121.24, 119.56, 116.22, 25.60, 18.18, -4.46. ##STR32##
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:52]([F:55])([F:54])[F:53])=[C:24]([CH:51]=1)[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][C:28]2[N:32]=[CH:33][C:34]([C:36]3[CH:40]=[CH:39][N:38]([Si](C(C)C)(C(C)C)C(C)C)[CH:37]=3)=[CH:35][C:27]1=2>O1CCCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:52]([F:55])([F:53])[F:54])=[C:24]([CH:51]=1)[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][C:28]2[N:32]=[CH:33][C:34]([C:36]3[CH:40]=[CH:39][NH:38][CH:37]=3)=[CH:35][C:27]1=2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3cc[nH]c3)cc21

Procedure:
Anhydrous tetrahydrofuran (1 mL) and tetrabutylammonium fluoride, 1 M solution in tetrahydrofuran (0.761 mL) were added to 1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (107 mg, 0.000195 mol). The reaction was stirred at room temperature under nitrogen for two (2) hours and then concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as an off-white solid. LCMS: m/z=393.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.35 (2H, bs), 3.48 (2H, m), 3.63 (2H, m), 4.59 (2H, s), 6.26 (1H, s), 6.56 (1H, d, J=1.3 Hz), 6.74 (1H, t, J=2.0 Hz), 6.82 (1H, s), 7.34 (1H, d, J=8.3 Hz), 7.50 (1H, s), 7.60 (1H, s), 7.64 (1H, d, J=8.3 Hz).
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH:8]([NH2:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH:8]([NH:11][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])([CH3:10])[CH3:9]
Reactant: CC(C)N
Reactant: COC(=O)C(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)NC(C)C
Temperature: 70 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
Methyl 2-bromopropionate (10.0 g, 59.9 mmol) was dissolved in acetonitrile (200 mL) followed by addition of isopropylamine (15.3 mL, 180 mmol), potassium carbonate (24.8 g, l80 mmol) and benzyltriethylammonium chloride (1.36 g, 5.99 mmol), and then the mixture was stirred at 70° C. for 17 hours. Water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and methyl 2-(isopropylamino)propionate (6.70 g; yield 77%) was thus obtained.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2ccc(C#N)cc2)n1
Product: Cc1cc(Cl)nc(/C=C/c2ccc(C#N)cc2)n1
Yield: 76.9 %

Procedure:
In analogy to example 12c), by heating (E)-4-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (0.71 g, 3 mmol) in POCl3 (5.49 ml, 60 mmol) at 130° C. for 4.5 h there was obtained (E)-4-[2-(4-chloro-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (0.59 g, 76%) as a pink solid. EI mass spectrum, m/e: 255 (M calculated for C14H10ClN3: 255).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCC1CCOCC1
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 76.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.0237 g, 0.184 mmol) gives the title compound (0.0545 g, 77.0%): TOF MS ES+ 386.2 (M+H)+, HRMS calcd for C21H28N3O4 386.2080 (M+H)+, found 386.2076, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=4.3 min, 100% purity.
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[OH-].[Li+].C(O)(C(F)(F)F)=O>C1COCC1>[CH3:1][N:2]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:27]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(CN2CCC(N(C)CCc3ccc(Oc4ccccc4)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCN(Cc2ccc(C(=O)O)cc2)CC1
Yield: 12.7 %

Procedure:
A solution of methyl 4-[[4-[methyl[2-(4-phenoxyphenyl)ethyl]amino]-1-piperidinyl]methyl]benzoate (about 0.71 mmol) in aqueous THF was treated with an aqueous solution of lithium hydroxide. The reaction was acidified with TFA. Purification by preparatory HPLC gave 40 mg of 4-[[4-[methyl[2-(4-phenoxyphenyl)ethyl]amino]-1-piperidinyl]methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, 2H), 7.56 (dbr, 2H), 7.32 (ddd, 2H), 7.26 (d, 2H), 7.07 (tt, 1H), 6.88-6.96 (m, 4H), 4.27 (br, 2H), 3.25 (br, 3H), 2.86 (br, 4H), 2.72 (s, 3H), 2.14 (br, 2H) 1.85 (br, 2H) ppm.
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14]C)[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([N:5]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CC(C)(C)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 4-(1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (500 mg) in acetonitrile (30 mL) were added sodium iodide (567 mg) and chloro(trimethyl)silane (1.92 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (475 mg).
Reaction SMILES: COC1C=C(C2[C@H]3[C@H](CC=CC3)C(=O)NN=2)C=CC=1OC.ClCC1C=CC(C(O)=O)=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:43]2[C@H:52]3[C@H:47]([CH2:48][CH2:49][CH2:50][CH2:51]3)[C:46](=[O:53])[N:45]([CH2:54][C:55]3[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=3)[N:44]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:43]2[C@H:52]3[C@H:47]([CH2:48][CH:49]=[CH:50][CH2:51]3)[C:46](=[O:53])[N:45]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([C:59]([OH:61])=[O:60])=[CH:62][CH:63]=3)[N:44]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: O=C(O)c1ccc(CCl)cc1
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and 4-chloromethylbenzoic acid as described for compound 83. Crystallized from ethyl acetate. M.p. 192°-193° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH:16]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)[CH2:17][CH2:18][CH2:19][OH:20])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CCOCC>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:20][CH2:19][CH2:18][CH2:17][CH:16]([O:15][C:12](=[O:14])[CH3:13])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(=O)OC(CCCO)COc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(CCCOS(=O)(=O)c1ccc(C)cc1)COc1cccc(C(F)(F)F)c1
Reaction time: 1.17 h
Yield: 94 %

Procedure:
A solution of p-toluenesulfonyl chloride (65.2 g., 0.342 mole) in pyridine (130 ml.) is cooled in a cold water (10°-15°) bath while 4-acetoxy-5-(3-trifluoromethylphenoxy)-1-pentanol (90.7 g., 0.297 mole) is added dropwise with stirring during 70 minutes. The mixture is then stirred 2 hours in the same cold water bath. It is poured into 400 ml. of water. The oily product is taken up in ether, washed with water, 2N hydrochloric acid and dilute sodium bicarbonate solution and dried over magnesium sulfate. The solvent is evaporated in vacuo to leave 125 g. (94%) of the crude title compound as a nearly colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:14][C:13]([CH3:28])([CH3:27])[C:12]=3[N:11]=[C:10]([CH:29]([CH3:31])[CH3:30])[C:9]=2[CH:32]=[O:33])=[CH:4][CH:3]=1.C[Si]([C:38]#[N:39])(C)C.CO.Cl>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:38]([CH:32]([OH:33])[C:9]1[C:10]([CH:29]([CH3:30])[CH3:31])=[N:11][C:12]2[C:13]([CH3:28])([CH3:27])[CH2:14][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])[CH2:16][C:17]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:39]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(O)C#N)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl 4-(4-fluorophenyl)-3-formyl-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 1) (4.28 g, 9.09 mmol), trimethylsilyl cyanide (1.46 ml, 10.91 mmol) and zinc iodide (0.145 g, 0.455 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 2.5 h. MeOH (100 mL) was added and the reaction stirred 22 h at room temperature. Additional trimethylsilyl cyanide (2 mL) was added and stirring continued at room temperature for 24 h. 1M HCl (10 mL) was added and stirring continued for 24 h. The reaction mixture was concentrated and the residue taken up in Et2O (200 mL), washed with satd NaHCO3 (50 mL), water (25 mL), brine (25 mL), dried (Na2SO4), filtered and solvent removed to give 2-(trimethylsilyl)ethyl 3-(cyano(hydroxy)methyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (4.16 g) as a tan powder contaminated with about 20% of starting material. This was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=O)[NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=[O:5])[CH3:2].N1C(C)=CC=CC=1C.O=P(Cl)(Cl)Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:39]([C:45]([NH:47][NH2:48])=O)=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=2)(=[O:36])=[O:35])=[CH:30][C:29]=1[C:49]([F:52])([F:51])[F:50]>CC#N>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:39]([C:45]3[N:7]([C:8]4[CH:12]=[CH:11][O:10][N:9]=4)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:48][N:47]=3)=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=2)(=[O:35])=[O:36])=[CH:30][C:29]=1[C:49]([F:50])([F:52])[F:51]
Reactant: CCOC(=O)C(=O)Nc1ccon1
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1-c1ccon1
Temperature: 0 °C
Yield: 20.1 %

Procedure:
To a vial equipped with a teflon coated septum and a nitrogen inlet were added ethyl(isoxazol-3-ylcarbamoyl)formate (370 mg, 2.0 mmol), MeCN (2 mL) and 2,6-lutidine (0.6 mL, 5.2 mmol). The vial was cooled to 0° C. POCl3 (0.4 mL, 4.3 mmol) was added, and the solution maintained at 0° C. for 30 min. The solution was then warmed to 40° C. for 3 h. After cooling to room temperature, solid 4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)-benzenesulfonamide (500 mg, 1.2 mmol) was added, and the reaction heated to 80° C. for 1 h. The volatiles were removed in vacuo. Ethanol (9 mL) and triethylamine (1 mL) were added, and the solution heated to 90° C. for 4 h. After cooling to room temperature, the volatiles were removed in vacuo, and the resulting residue purified by flash chromatography on 12 g of silica gel (50→100% gradient of EtOAc in hexanes). The pure fractions were collected, and the solvent removed in vacuo to afford the title compound (139 mg, 20% yield). HPLC retention time=2.96 minutes. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.0, 1H), 8.19 (d, J=2.0, 1H), 8.12 (d, J=2.4, 1H), 7.98 (d, J=2.0, 1H), 7.90 (dd, J=2.4, 8.4, 1H), 7.58 (d, J=8.4, 1H), 6.62 (d, J=2.0, 1H), 4.41 (q, J=7.2, 2H), 1.40 (t, J=7.2, 3H). MS (ES) [M+H]+ expected 577.0. found 577.0.
Reaction SMILES: O[CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC(O)COc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(COc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 1.5 g of rac-tert-butyl (2-hydroxy-3-phenoxypropyl)carbamate (5.6 mmol, 1 equivalent), 0.99 g of phthalimide (6.73 mmol, 1.2 equivalents) and 2.21 g of triphenylphosphine (8.4 mmol, 1.5 equivalents) were initially charged in 23 ml of dry tetrahydrofuran. 1.70 ml of diisopropyl azodicarboxylate (8.4 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. LC/MS showed complete conversion of the reaction. The reaction mixture was concentrated and purified by chromatography on silica gel (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 1.08 g of the title compound (48% of theory).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:9][C:10](=[O:41])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[NH:12][S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22](C(=O)C(F)(F)F)[CH2:23]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:8]>O.C(O)C>[CH2:7]([O:9][C:10](=[O:41])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[NH:12][S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH2:23]2)=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A solution of sodium carbonate (11.5 g, 108.5 mmol) in water (115 ml) was added to a stirred solution of N-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanine ethyl ester (Preparation 21; 11.5 g, 22.6 mmol) in ethanol (115 ml) and the resulting mixture stirred for 3 hours at room temperature. The bulk of the ethanol was then removed under reduced pressure, water added and the resulting suspension extracted with dichloromethane. The organic extract was washed with saturated brine, dried (MgSO4 ) and evaporated under reduced pressure, then the residue dissolved in the minimum volume of dichloromethane. Dilution of this solution with ethanol, followed by concentration and overnight standing of the mixture, provided the title compound as a white solid (6.4 g), after filtration and washing with ether. Rf 0.26 (SS 6). m/e 414 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([OH:19])[CH2:18][CH2:17][N:16]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)C2(O)CCNCC2)cc1
Reactant: Fc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)C2(O)CCN(Cc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 25.6 mg (0.09 mmol) 4-Hydroxy-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide, 19.9 mg (0.1 mmol) 4-fluorobenzyl bromide and 27 mg (0.27 mmol) NEt3 in 2 ml DCM was stirred for 3 h at room temperature. The mixture was concentrated and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 5.4 mg (17%) of the title compound as off-white solid. MS (m/e): 371.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46])[CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([NH:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:46])[CH3:47])[CH:38]=3)[CH2:33][CH2:32]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1OC[C@@H](c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)N3C(=O)OC[C@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure AF and Scheme H using 4-nitrophenyl (4R)-4-(3,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 8.08 (t, 1H, J=5.5 Hz), 7.45 (S, 2H), 7.38 (d, 1H, J=8.6 Hz), 7.24–7.12 (m, 3H), 7.06 (m, 1H), 6.97 (d, 1H, J=8.6 Hz), 5.40 (dd, 1H, J=3.9, 8.8 Hz), 4.71 (t, 1H, J=8.8 Hz), 4.23 (dd, 1H, J=4.4, 9.1 Hz), 3.32 (qt, 2H, J=6.1 Hz), 2.99 (d, 2H, J=11.0 Hz), 2.49 (qt, 2H, J=7.0 Hz), 2.41 (t, 2H, J=7.0 Hz), 1.99 (m, 2H), 1.82–1.68 (m, 6H), 1.23 (d, 6H, J=7.3 Hz); ESMS m/e: 529.1 (M+H)+.