Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][C:8]2[N:12]=[C:11]([C@H:13]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]=[C:11]([C@H:13]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][C:15]([OH:17])=[O:16])[O:10][N:9]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101 %

Procedure:
tert-Butyl (3R)-3-{3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}-6-cyclohexylhexanoate (Preparation 56) (215 mg, 0.46 mmol) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (189 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.Cl[C:26]([O:28][CH3:29])=[O:27].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:29][O:28][C:26](=[O:27])[N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)Cl
Reactant: CCCC(CCC)NCCc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(CCC)N(CCc1ccccc1Br)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.85 g of N-[2-(2-bromophenyl)ethyl]heptan-4-amine in solution in 60 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at 0° C. 2.76 cm3 of triethylamine are added to the reaction mixture, then 1.52 cm3 of methyl chloroformate are introduced over 10 min using a syringe. The reaction mixture is kept stirring for 1 h at 0° C., then 3 h at 20° C. 20 cm3 of a saturated aqueous solution of ammonium chloride are added, then 100 cm3 of ethyl acetate. The organic phase is washed with 4 lots of 30 cm3 of water, then 30 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered through a pellet (30 g) of silica (particle size: 40-63 μm), rinsed with 50 cm3 of ethyl acetate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 6.4 g of methyl[2-(2-bromophenyl)ethyl](1-propylbutyl)carbamate are obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:5]1=[O:33])[CH2:2][CH3:3].CI.[C:36](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:36][N:29]1[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:6]3[C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][C:9](=[O:10])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]3=[O:33])=[CH:17][CH:18]=2)=[N:32][N:31]=[N:30]1
Reactant: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 3-propyl-6-propyloxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.1 g), methyl iodide (50 mg) and sodium bicarbonate (25 mg) in DMF (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in CHCl3 -water. The chloroform layer was dried and evaporated in vacuo to give a syrup. The syrup was column-chromatographed on silica gel to give a colorless syrup (90 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[C:6](=[O:18])[N:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[N:3]=1.[OH2:24].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:32]O>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[NH:32])[NH:17][OH:24])[C:6](=[O:18])[N:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCC#N)c(=O)c2[nH]c(Cl)nc21
Reactant: NO
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCCC(=N)NO)c(=O)c2[nH]c(Cl)nc21
Temperature: 70 °C
Yield: 85 %

Procedure:
A solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanenitrile (3.0 g, 8.9 mmol) in EtOH (30 ml) was treated with water (15 ml), potassium carbonate (1.48 g, 10.7 mmol) and hydroxylamine hydrochloride (0.74 g, 10.7 mmol) and then heated at 70° C. overnight. A further potassium carbonate (1.5 g, 10.9 mmol) and hydroxylamine hydrochloride (1.0 g, 14.5 mmol) were cautiously added to the mixture which was then heated to 90° C. for 24 h. The mixture was cooled and concentrated in vacuo to remove most of the EtOH. The residual mixture was treated with water (30 ml) and acidified to pH 7 by the cautious addition of 2M aqueous hydrochloric acid. The precipitated solid was filtered off, washed with water, then with diethyl ether and thoroughly dried to yield the title compound as a white solid (2.80 g, 85%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1([Mg]Cl)C=CC=CC=1.[CH3:20][C:21]([CH3:25])([CH3:24])[CH:22]=[O:23]>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([CH:22]([OH:23])[C:21]([CH3:25])([CH3:24])[CH3:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1I
Reactant: CC(C)(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1,4-diiodo-2-nitrobenzene (3.0 g, 8.0 mmol) in anhydrous THF (20 mL) was cooled to minus 40° C., and then a solution of phenylmagnesium chloride (2 M in THF, 4.8 mL, 9.6 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for ten minutes, followed by addition of trimethylacetaldehyde (1.2 mL, 11.2 mmol), and the mixture was stirred for 30 minutes at minus 40° C. The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (60 mL), poured into water (120 mL), and extracted with ethyl acetate twice (60 mL each). The combined organic phase was washed with water (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield racemic (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propanol (2.17 g, 81%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 8.04 (d, 1 H, J=1.6 Hz, Ph-H), 7.88 (dd, 1 H, J=1.6 and 8.4 Hz, Ph-H), 7.51 (d, 1 H, J=8.4 Hz, Ph-H), 5.28 (d, 1 H, J=3.6 Hz, Ph-CH), 2.29 (d, 1 H, J=3.6 Hz, OH), 0.85 (s, 9 H, C(CH3)3). 13C NMR (100 MHz, CDCl3): δ 149.87 (C), 141.0 (CH), 136.2 (C), 132.3 (CH), 131.63 (CH), 91.85 (C), 74.33 (CH), 36.81 (C), 25.6 (CH3).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15](O)[CH3:16])[CH:10]=1)([O-:5])=[O:4].[F:18]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C>C1COCC1.CCN(CC)CC>[F:18][CH:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][N:9]1[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[N:8]1
Reactant: CC(O)CCCCn1cc([N+](=O)[O-])cn1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(F)CCCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 6-(4-nitro-pyrazol-1-yl)-hexan-2-ol (213 mg, 1.00 mmol) in THF (3.0 mL) was treated at rt with perfluoro-1-butanesulfonyl fluoride (0.36 mL, 2.00 mmol), triethylamine trihydrofluoride (0.33 mL, 2.00 mmol) and Et3N and the reaction mixture was stirred at rt overnight. Purification of the residue by FC (80:10 hept-EA) gave the title compound. TLC: rf (80:20 hept-EA)=0.28. LC-MS-conditions 02: tR=0.97 min; [M+H]+=216.20.
Reaction SMILES: [OH:1][CH:2]1[C:7]2([CH2:26][OH:27])[O:8][CH:9]([N:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][C:11]3=[O:25])[CH:3]1[O:4][N:5]([C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:6]2.[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](Cl)(C2C=CC=CC=2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:42][CH:41]=1>N1C=CC=CC=1>[CH3:52][O:51][C:48]1[CH:47]=[CH:46][C:45]([CH:44]([C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:61][CH:60]=2)[O:27][CH:26]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]23[CH:2]([OH:1])[CH:3]([CH:9]([N:10]4[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[N:12][C:11]4=[O:25])[O:8]2)[O:4][N:5]([C:28](=[O:37])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:6]3)=[CH:50][CH:49]=1
Reactant: O=C(Nc1ccn(C2OC3(CO)CN(C(=O)COc4ccccc4)OC2C3O)c(=O)n1)c1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C23CN(C(=O)COc4ccccc4)OC(C(n4ccc(NC(=O)c5ccccc5)nc4=O)O2)C3O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 165.1 %

Procedure:
To a solution of Compound 67 (1.80 g, 3.54 mmol) in anhydrous pyridine (15 mL) was added 4-N,N-dimethylaminopyridine (65 mg, 0.53 mmol) and 4,4′-dimethoxytrityl chloride (2.04 g, 6.02 mmol). After stirring at room temperature for 6 hours the reaction mixture was quenched with methanol and concentrated in vacuo. The residue was dissolved in CH2Cl2 (300 mL), washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and evaporated. Purification by silica gel chromatography (2% methanol in CH2Cl2) yielded 2.37 g (82%) of Compound 68 as a pale yellow foam.
Reaction SMILES: C([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1)#N.Cl.[C:27](=[O:30])(O)[O-:28].[Na+]>C(O)(=O)C>[C:27]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1)([OH:28])=[O:30]
Reactant: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C(=O)O)cc2)c2ccccc12
Temperature: 0 °C

Procedure:
A solution of 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)-indole (5.8 g) in 100 ml of a 1:1 mixture of 20% aqueous hydrochloric acid and glacial acetic acid was heated at reflux for 20 hours. After cooling, the solution was poured into ice water (100 ml) and the pH was adjusted to 4.5-5 with saturated sodium bicarbonate solution. The resulting precipitate was extracted with ethyl acetate, the ethyl acetate extract was washed with water and evaporated to dryness to give 1-(4-carboxybenzyl)-3-methyl-2-(3-pyridyl)indole, m.p. 273°-5°.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[C:17]([CH2:19][C:20]([OH:22])=O)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[C:20](=[O:22])[CH2:19][C:17]#[N:18])[CH2:4]2)=[N:13][CH:12]=1
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)CC#N)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.9 %

Procedure:
To a solution of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (75 mg, 0.345 mmol) and 2-cyanoacetic acid (35 mg, 0.414 mmol) in THF (5 mL) were added HATU (157 mg, 0.414 mmol) and DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 20 hours. The precipitate was filtered, washed with EtOAc, and dried under reduced pressure to give the title compound (45 mg, 46%). MS (m/z): 285 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1([CH2:31]O)[CH2:30][CH2:29][CH2:28][CH2:27]1.OCC1CCN(CC2(C(OC)=O)CCCC2)CC1>>[CH:26]1([CH2:31][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: OCC1CCCC1
Agent: COC(=O)C1(CN2CCC(CO)CC2)CCCC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4CCCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 9 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, Step 2) and cyclopentylmethanol instead of 4-[(4-methoxybenzyl)oxy]-1,2-benzisoxazol-3-ol and methyl 1-{[4-(hydroxymethyl)piperidin-1-yl]methyl}cyclopentanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[NH2:10].[CH2:11]([N:13]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1)[CH3:12]>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:10]=[C:18]([C:16]1[CH:15]=[N:14][N:13]([CH2:11][CH3:12])[CH:17]=1)[N:8]2[CH3:9]
Reactant: CCn1cc(C=O)cn1
Reactant: CNc1ncnc(Cl)c1N
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Temperature: 90 °C
Yield: 103 %

Procedure:
To a solution of 6-chloro-N4-methylpyrimidine-4,5-diamine (300 mg, 1.9 mmol) in anhydrous DMF (8 mL) were added 1-ethyl-1H-pyrazole-4-carbaldehyde (236 mg, 1.9 mmol) and Iron (III) chloride hexahydrate (0.51 g, 1.9 mmol). The dark brown solution was heated to 90° C. for 14 hour in an open air vessel. The reaction mixture was cooled to room temperature and poured over ice (20 g). The resulting precipitate was collected by vacuum filtration, and triturated with 10 mL of ethanol at 50° C. for 30 min. The solids were collected by vacuum filtration to give 514 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (t, 2H), 8.19 (s, 1H), 4.25 (q, 2H), 3.95 (s, 3H), 1.43 (t, 3H); MS (EI) for C11H11ClN6: 263.3 (MH+).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([S:15](Cl)(=O)=O)[C:9]([O:19][CH3:20])=[CH:8][C:7]=2[CH2:6]1)(=[O:3])[CH3:2]>CC#N.CC#N.ClCCCl.[Zn]>[SH:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:19][CH3:20])[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:13]2.[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([S:15][S:15][C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][C:9]=3[O:19][CH3:20])[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:13]4)[C:9]([O:19][CH3:20])=[CH:8][C:7]=2[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCC(NC(C)=O)C2
Agent: [Zn]
Solvent: CC#N
Solvent: ClCCCl
Product: COc1cc2c(cc1S)CCC(NC(C)=O)C2
Product: COc1cc2c(cc1SSc1cc3c(cc1OC)CC(NC(C)=O)CC3)CCC(NC(C)=O)C2
Temperature: 81 °C

Procedure:
To a suspension of zinc dust (1.16 g; 17.7 mmol) and dimethylsilyl dichloride (2.4 mL; 17.7 mmol) in MeCN (40 mL) was added a solution of 6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (1.13 g; 3.55 mmol) in MeCN/DCE (40/10 mL), at room temperature. The reaction suspension was then heated at 81° C. for 4 h, cooled to room temperature, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by reverse-phase semi-prep HPLC eluting with a MeCN—H2O gradient to yield N-(6-mercapto-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide as a white solid and N-[6-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yldisulfanyl)-7-methoxy-1,2,3,4,-tetrahydronaphthalen-2-yl]acetamide as a tan solid.
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28](O)=[O:29])=[CH:20]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:2][CH2:1][CH:3]([NH:6][C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2([CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]2)[CH:20]=1)=[O:29])[CH2:4][CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C(=O)O)c3ccccc32)CC1
Reactant: CCC(N)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)NC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-ethylpropylamine (0.5 mL) was added to a stirred solution of compound (C4) (0.50 g, 1.52 mmol), EDAC.HCl (0.6 g, 3.00 mmol), HOBt (0.31 g, 2.32 mmol) in DMF (10 mL) and the solution was stirred at room temperature for 2 h. The solution was poured into water (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage SP1 on silica gel eluting with 5-70% EtOAc in hexanes to provide tert-butyl 3-(pentan-3-ylcarbamoyl)spiro[inden-1,4′-piperidine]-1′-carboxylate (F1) as a white solid (0.6 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 399 (M+1), Rt 3.66 minutes. 1HNMR (500 MHz, DMSO-d6) δ 7.78 (d, 1H), 7.55 (m, 1H), 7.43 (d, 1H), 7.23 (br m, 1H), 4.07 (m, 2H), 3.75 (m,1H), 3.15 (m, 2H), 1.98 (d, 2H), 1.55 (m, 2H), 1.45 (s, 9H), 1.25 (m,2H), 0.88 (m, 6H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.N1C=CC=CC=1.Cl>>[C:11]([OH:13])(=[O:12])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Benzaldehyde (10 g, 94 mmol), malonic acid (2 eq.), and piperidine (0.1 eq.) were dissolved in pyridine (5 eq.) and stirred at 80° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled down to the room temperature and neutralized with 3M HCl. The white solid thus obtained was filtered out and dried in a vacuum oven to yield cinnamic acid.
Reaction SMILES: CC(C)([O-:4])C.[Na+].O[CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]=[CH2:14].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([S:21]([OH:23])(=[O:4])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:11]([O:12][CH:13]=[CH2:14])[CH2:10][CH2:9][CH3:8]
Reactant: C=COCCCCO
Reactant: CC(C)(C)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: C=COCCCC
Product: O=S(=O)(O)c1ccccc1
Temperature: -40 °C

Procedure:
Into a 3 L flask equipped with a mechanical stirrer and N2 purge was added 1000 g of tetrahydrofuran and 220.7 g (2.3 mol) of sodium t-butoxide. Hydroxybutyvinyl ether (236 g, 2.03 mol) was added dropwise at a rate to maintain the temperature at ≤40° C. This reaction mass was cooled to -40° C. A solution of benzenesulfonyl chloride (353 g, 2 mol) in 300 g of tetrahydrofuran was added dropwise at a rate to maintain the reaction temperature at ≤-20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature to obtain the butylvinyl ether benzenesulfonate, ##STR8##
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1cccc([N+](=O)[O-])c1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2cccc([N+](=O)[O-])c2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H) -pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and 3-nitrophenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6 -(3-nitrophenoxycarbonyloxy)-2(1H)-pyrimidinone as the residue.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>C(#N)C.CCOC(C)=O>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CNCCO4)no2)cc1C#N
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2C1
Temperature: 80 °C
Yield: 62 %

Procedure:
A solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 35) (0.104 g, 0.276 mmol) was stirred in acetonitrile (2 ml). DIPEA (0.097 ml, 0.553 mmol) and ethyl 4-bromobutanoate (0.059 ml, 0.414 mmol) were added and the reaction mixture stirred and heated at 80° C. under Argon for 6 hours. Additional ethyl 4-bromobutanoate (0.059 ml, 0.414 mmol) and DIPEA (0.097 ml, 0.553 mmol) were added and the reaction mixture stirred and heated at 80° C. under argon overnight. Then the reaction mixture was dissolved in EtOAc, washed with saturated NaHCO3 solution (3×15 ml) and water (15 ml) and the organics dried (MgSO4) and evaporated. The crude was purified by flash chromatography, eluting with EtOAc/iso-Hexane 10-20% (Biotage Column) and evaporated to give the title compound (84 mg) as an oil. MS (ES): C27H30N4O5 requires 490; found 491 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: C1COCCN1
Product: O=C1OCc2nc(CCCN3CCOCC3)ccc21

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde and morpholine are reacted to provide the title compound.