Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])C2=CC=CC=C2C1=O)=[O:5])[CH3:2].[OH2:46].NN>C(O)C>[C:38]([O:46][C:18]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:19])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reactant: O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 184.2 %

Procedure:
In 10 ml of ethanol is dissolved 0.9 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 0.35 g of hydrazine hydrate is added to the solution. After the mixture is left standing at room temperature overnight, the mixture is concentrated under reduced pressure, diluted with water and extracted four times with 50 ml of ethyl acetate. Water (50 ml) and 1.0 g of sodium bicarbonate are added to the ethyl acetate layer, and 0.46 g of di-tertbutyl dicarbonate is added to the resulting mixture with stirring. After the mixture is stirred at room temperature for 30 minutes, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give 0.79 g of tert-butyl 3(R)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[N:15]=2)[N:3]=1.Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[N:15]=[C:16]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:17]=[CH:18][CH:19]=2)[C:5]([NH2:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(NCc2cccc(N3CCCC3=O)n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(NCc2cccc(N3CCCC3=O)n2)n1
Yield: 67.4 %

Procedure:
A mixture of as N-(2-amino-4-chloro-6-{[6-(2-oxo-pyrrolidin-1-yl)pyridin-2-ylmethyl]amino}pyrimidin-5-yl)formamide (3.41 g, 9.43 mmol) in ethanol (36 mL) was treated with hydrochloric acid (6-M, 8 mL), heated at reflux for 2 h, cooled and the pH adjusted to 13 with aqueous sodium hydroxide (5-M). The mixture was extracted with EtOAc (×3) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (2.12 g, 68%) as a coral pink solid; LC-MS retention time 1.64 min; (M+H)+ 334.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:46][C@H:47]1[CH2:53][CH2:52][S:51][C@H:50]2[CH2:54][CH2:55][CH2:56][C@@H:57]([C:58]3[O:59][CH:60]=[N:61][N:62]=3)[N:49]2[C:48]1=[O:63]>>[O:59]1[CH:60]=[N:61][N:62]=[C:58]1[C@H:57]1[N:49]2[C@@H:50]([S:51][CH2:52][CH2:53][C@H:47]([NH:46][C:9](=[O:10])[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][CH2:13][C@H:14]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:15]([NH:16][C@H:17]3[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]3=[O:30])=[O:31])[C:48]2=[O:63])[CH2:54][CH2:55][CH2:56]1
Reactant: N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCCCN(c2ccccc2)C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O)Cc1ccccc1

Procedure:
(2R,5R)—N1-((4S,7S,10aS)-7-(1,3,4-Oxadiazol-2-yl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-2,5-dibenzyl-N6-((S)-2-oxo-1-phenylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (10 mg, 0.020 mmol) and Intermediate 35 (7.1 mg, 0.023 mmol) to give a white solid (3.5 mg, 24% yield). Anal. Calcd. for C43H50N6O5S m/z 762.7. found: 763.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (1H, s), 7.40-7.32 (2H, m), 7.31-7.07 (13H, m), 7.02-6.90 (2H, m), 5.91 (1H, d, J=4.9 Hz), 5.27 (1H, t, J=4.4 Hz), 5.05-4.97 (1H, m), 4.78 (1H, dd, J=9.3, 6.6 Hz), 3.93 (1H, dd, J=15.1, 11.3 Hz), 3.59 (1H, dd, J=14.8, 4.9 Hz), 3.18-3.07 (1H, m), 2.90-2.68 (6H, m), 2.55 (1H, ddd, J=14.3, 5.5, 2.7 Hz), 2.46-2.33 (2H, m), 2.14-1.80 (8H, m), 1.77-1.65 (4H, m), 1.64-1.25 (4H, m).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:20]([NH:22][C:23]2([C:27](OCC)=[O:28])[CH2:26][CH2:25][CH2:24]2)=[O:21])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:20]([NH:22][C:23]2([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24]2)=[O:21])[CH:11]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)c(-c3ccc4cc(NC(=O)C5CC5)ncc4c3)c2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2(CO)CCC2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 10.5 %

Procedure:
To a solution of ethyl 1-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzamido)cyclobutanecarboxylate (153.8 mg; 0.3261 mmol) in tetrahydrofuran (5.0 mL; 62 mmol) at 0° C. was dropwise added lithium aluminum hydride (1.0 M in THF) (0.50 mL; 0.50 mmol). The reaction mixture was stirred at 0° C. for 1.5 hours, followed by the addition of lithium aluminum hydride (1.0 M in THF) (0.20 mL; 0.2 mmol). After an additional 3 hours, the reaction was quenched by the sequential addition of 27 μL water, 27 μL 15% aqueous NaOH, and 80 μL water. The reaction mixture was diluted with dichloromethane, dried over MgSO4, filtered through celite, and evaporated in vacuo to yield 109.2 mg crude product. 36.8 mg of the crude product was purified via preparatory reverse-phase HPLC and lyophilized to yield 14.7 mg of the title compound. LCMS (ESI): RT (min)=3.55, M+H=430.3, method=H; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 4.78 (t, J=5.8 Hz, 1H), 3.64 (d, J=5.8 Hz, 2H), 2.32 (s, 3H), 2.24 (m, 2H), 2.17-2.01 (m, 3H), 1.91-1.63 (m, 2H), 0.85 (m, 4H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=O)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O.[Na]>C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][CH2:18][Cl:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=S(Cl)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCCl)[C@@]4(C)CC[C@@H]32)C1

Procedure:
3β-Acetoxychol-5-enic acid (4.16 g; 10 mmoles) was added to 60 ml of anhydrous benzene. The solution was cooled with ice, and with stirring, 4.5 ml of thionyl chloride was gradually added dropwise. After the addition, the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and to the resulting residue was added 20 ml of anhydrous benzene which had been obtained by dehydrating benzene with sodium. The mixture was repeatedly concentrated under reduced pressure to remove the thionyl chloride contained in the residue. The resulting crude solid product, 3β-acetoxychol-5-enyl chloride, was used as a starting compound in the subsequent step without purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7](N)[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].N([O-])=O.[Na+].[BrH:16]>>[Br:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: CC(C)Cc1cccc(N)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-isobutylphenylamine (3.80 g) in 48% hydrobromic acid (10 ml) was added aqueous sodium nitrite (2.11 g, 2 ml) below 10° C. over 20 minutes. The reaction mixture was added to a solution of cuprous bromide (7.3 g) in 48% hydrobromic acid(5 ml) at 25° C. After stirred at 25° C. for 1 hour, the mixture was extracted with hexane two times. The extracts were combined, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (150 g) eluting with hexane to give 1-bromo-3-isobutylbenzene (2.61 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-:12].[K+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:2])=[O:12])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 83 %

Procedure:
3.5 mol p-nitrobenzylchloride are dissolved in the hot in 2300 ml of ethanol and a solution of 3.8 mol potassium hydroxide in 1100 ml of aqueous ethanol (70:30) is added thereto drop by drop. After completion of the addition, cooling takes place in an ice bath to 0° C., the precipitate is filtered off and washed in hot water and warm aqueous alcohol (50:50). Drying is then carried out in a vacuum at 75° C. (yield: 83%).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[O:16][C@:17]4([CH2:25][N:26]=3)[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]4)[CH:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[O:16][C@:17]4([CH2:25][N:26]=3)[CH:22]3[CH2:23][CH2:24][N+:19]([O-:35])([CH2:20][CH2:21]3)[CH2:18]4)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)c2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc(-c4ccc(F)nc4)ccn3)O1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
(R)—N-(6-Fluoro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.11 g, 0.311 mmol) in THF (10 mL) was treated with m-CPBA (0.059 g, 0.342 mmol) and stirred at room temperature for 2 hours. Reaction was complete by TLC and the product was purified by chromatography (Biotage: 5-20% of 8:2 MeOH:NH4OH in CHCl3) and the pure fractions were combined to yield (S)-2-(6-fluoro-3,4′-bipyridin-2′-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.05 g, 0.134 mmol, 43.1% yield) as a yellow powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.11 (br. s., 1H), 8.64 (br. s., 1H), 8.21-8.43 (m, 2H), 7.04-7.44 (m, 3H), 3.77 (d, J=10.1 Hz, 2H), 2.98-3.65 (m, 6H), 2.18 (br. s., 2H), 1.74-2.01 (m, 3H). LC/MS: retention time 0.78 (M+1=370.2).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])C.C([CH2:33][C:34](=[NH:36])[S-])C1C=CC=CC=1.Br>N1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=[C:6]3[C:4]([OH:5])=[N:36][C:34]([CH3:33])=[N:11][C:10]=23)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Reactant: N=C([S-])CCc1ccccc1
Agent: Br
Solvent: c1ccncc1
Product: Cc1nc(O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A mixture of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (21.4 g, 57 mmol) and benzylthioacetimidate.HBr (12.6 g, 51 mmol) in pyridine was heated at 115° C. (see Yuan et al., Bioorg. & Med. Chem. Lett., 12, 2133–2136 (2002)). Additional benzylthioacetimidate.HBr (12.6 g) was added after 0.5 h and 1.5 h. The reaction mixture was stirred for an additional 1 h at 115° C. After cooling to room temperature, a yellow solid precipitated out of solution. The reaction mixture was poured over ice water and acidified with conc. HCl (210 ml). Additional ice was added to keep the reaction mixture cool. The yellow solid was collected by filtration and washed with H2O to give the desired product, I-4A-1a (24 g).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)=[C:10]([Cl:12])[N:11]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:18])=[C:10]([Cl:12])[N:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CCN2CCC2)nc1Cl
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCN2CCC2)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 157.3) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 488 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[BH4-].[Na+].CCOC(C)=O>CO.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(F)c([N+](=O)[O-])c1
Yield: 87.1 %

Procedure:
1-(4-fluoro-3-nitrophenyl)ethanone (1.0 g, 5.46 mmol) was dissolved in MeOH (15.0 ml) and stirred over ice bath. NaBH4 (0.62 g, 16.0 mmol) was added portionwise. Upon completion of the addition, the reaction mixture was stirred at rt for 10 minutes. The reaction mixture was poured into EtOAc and brine. The organic layer was separated, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 20% to 70% EtOAc/Hexane to afford the title compound (881 mg, yield: 87%). %). 1H-NMR (400 MHz, CDCl3) δ 1.53 (d, 4H) 4.99 (dd, 1H) 7.22-7.33 (m, 1H) 7.66 (ddd, 1H) 8.09 (dd, 1H)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[NH2:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[C:11]=1[Cl:16].[CH3:17][C:18]([CH3:36])([CH3:35])[CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:34])[C:30](OC)=[O:31])=[CH:25][C:23]=2[N:24]=1>O1CCCC1>[Cl:16][C:11]1[C:12]([CH3:15])=[N:13][S:14][C:10]=1[NH:9][C:30](=[O:31])[CH:29]([C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([CH2:19][C:18]([CH3:35])([CH3:17])[CH3:36])=[N:24][C:23]=2[CH:25]=1)[CH3:34]
Reactant: COC(=O)C(C)c1ccc2oc(CC(C)(C)C)nc2c1
Reactant: Cc1nsc(N)c1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)C(C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (2.0 molar solution in tetrahydrofuran/ethylbenzene/heptane, 1.46 ml, 0.0029 mole) was added dropwise to a chilled solution of 5-amino-4-chloro-3-methylisothiazole (0.44 g, 0.0029 mole) [preparation as in Example 1, Step 1] in tetrahydrofuran (20 ml) and the solution was stirred at 0° C. for 1 hour. A solution of methyl 2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propionate (0.80 g, 0.0029 mole) [from previous step] in tetrahydrofuran (5 ml) was added dropwise and once the addition was complete the mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The mixture was quenched with water, acidified with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Further purification by flash column chromatography, eluting with ethyl acetate:hexane at 1:4 by volume gave N-(4-chloro-3-methylisothiazol-5-yl)-2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propionamide as a colourless solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].CN(C)C=O.Cl[CH2:13][C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>O>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CC(C)CCO
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Into a mixture of 500 ml (4.59 mol) of 3-methyl-1-butanol and 140 ml of dimethylformamide, 158.1 g (0.92 mol) of 3-chloromethylnitrobenzene was dissolved, and 78 g (1.39 mol) of potassium hydroxide pellets was added to the thus formed solution while cooling with water under a vigorous stirring. The temperature of the reaction mixture rised to 43° C. and then dropped slowly to room temperature. Thereafter, the reaction mixture was stirred for 7 hours at room temperature to complete the reaction.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][O:10][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])(OC(C)(C)C)=O.Cl>CO.O1CCOCC1>[N+:11]([C:5]1[C:6]2[O:10][N:9]=[CH:8][C:7]=2[C:2]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])=[N:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc(Cl)c2cnoc12
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCCCNc1ncc([N+](=O)[O-])c2oncc12
Reaction time: 8 h

Procedure:
4-Chloro-7-nitro-[1,2,5]benzoxadiazole (100 mg, 0.501 mmol) was dissolved in methanol (5 ml). N-Boc-1,3-propanediamine (44 mg, 0.25 mmol) was then added and the reaction mixture stirred overnight. The solvent was evaporated and the residue was purified using silica gel chromatography with ethyl acetate:hexane (1:1) to afford dark brown solid. This material was then treated with a solution of 4.0 M HCl in dioxane (excess) overnight to remove the Boc group. The solution was evaporated to afford N1-(7-nitro-[1,2,5]benzoxadiazol-4-yl)propane-1,3-diamine as the hydrochloride salt, which was used without further purification. Yield: 60 mg (51%). MS (m/z): (M+H)=237.22.
Reaction SMILES: FC1C=CC(N2C(C=O)=CN=C2S)=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]([C:28](N(OC)C)=[O:29])=[CH:26][N:25]=[C:24]2[S:34][CH2:35][C:36]2[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:37]=2[F:44])=[CH:19][CH:18]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]([CH:28]=[O:29])=[CH:26][N:25]=[C:24]2[S:34][CH2:35][C:36]2[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:37]=2[F:44])=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=Cc1cnc(S)n1-c1ccc(F)cc1
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carbaldehyde (32) was prepared in a similar manner as that described for the synthesis of compound 12 using 1-(4-fluorophenyl)-N-methoxy-N-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (9) (1.15 g, 2.7 mmol), diisobutyl aluminum hydride (DiBAL) (1M in THF, 5.5 mL, 5.5 mmol), and THF (5 mL).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+].O>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CCCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 25.7 %

Procedure:
A mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (10 mmol, 1.99 mmol), azepane (10 mmol, 990 mg) and titanium isopropoxide (12.5 mmol, 3.7 mL) was stirred at room temperature for 50 mins. A solution of sodium cyanoborohydride (7 mmol, 440 mg) in anhydrous ethanol (10 mL) was added and the solution was stirred under nitrogen at ambient temperature for 24 hr. Water (2 mL) was added and the precipitate was removed by filtration through Celite®, rinsing through with ethanol. The solvent was removed under vacuum and the residue purified by chromatography on silica gel eluting with a 5%-10% methanol-dichloromethane gradient to give 4-azepan-1-yl-piperidine-1-carboxylic acid tert-butyl ester (726 mg, 26%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:20]=[CH2:21])[CH:16]=3)[NH:11][C:10]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1CO.[C].[Pd]>[CH2:20]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:22])[N:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:18]2=[O:19])[CH3:21]
Reactant: C=Cc1ccc2[nH]c(=O)n(CCc3ccccc3)c(=O)c2c1
Agent: [Pd]
Solvent: OCC1CCCO1
Product: CCc1ccc2[nH]c(=O)n(CCc3ccccc3)c(=O)c2c1
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a solution (20 mL) of 3-(2-phenylethyl)-6-vinylquinazoline-2,4(1H,3H)-dione (0.6 g) in tetrahydrofuran-methanol (1:1) was added palladium carbon (10%, 0.06 g), and the mixture was stirred under hydrogen atmosphere for 4 hr. Insoluble material was filtered off, and the filtrate was concentrated to give the title compound as a brown solid (0.47 g, 78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:28]=[O:29]>C1COCC1>[CH:28]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)cc2)C1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(C=O)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(4-bromophenyl)morpholine-4-carboxylate (684 mg, 2 mmol, CAS 1131220-82-0) in THF (6 ml) was cooled to −78° C., treated dropwise with n-butyllithium (1.88 ml, 3 mmol, 1.6 M solution in hexane) and stirred 30 min at −78° C. Dimethylformamide (1 ml, 2 mmol) was added dropwise and the mixture was stirred for 2 h at −78° C., and then allowed to warm up to −10° C. The reaction mixture was quenched by addition of saturated ammonium chloride solution (4 ml) and water (4 ml) and the resulting mixture was partitioned between water and ethyl acetate.