Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:19][C:2]1[O:1][C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[CH:4][N:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: N#Cc1cccc(-c2cnco2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2cnc(Cl)o2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a round bottom flask was added 3-(oxazol-5-yl)benzonitrile (1.93 gm, 11.34 mmol) and THF (45 mL). The reaction was cooled to −78° C. and 2.5 M nBuLi (4.99 mL, 12.48 mmol) was added dropwise. The reaction turned deep red color. After 30 min, a solution of hexachloroethane (4.03 gm, 17.01 mmol) in THF (10 mL) was slowly added. The reaction was slowly warmed to rt over 30 min. After 1 h at rt the reaction was quenched by slow addition of sat. NH4Cl (20 mL). The mixture was concentrated to remove most of the THF. The mixture was then partitioned between EtOAc (40 mL) and water (20 mL). The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, 3-(2-chlorooxazol-5-yl)benzonitrile, (1.01 gm, 4.94 mmol, 44% yield) as a white solid. Anal. Calcd. for C10H5ClN2O m/z 204.0, found: 205.0 (M+H)+.
Reaction SMILES: CC1C=CC2C(=CC=CC=2N2CCN(CCC3C=C(C=CC=3)N)CC2)N=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH3:38])=[N:35]2)=[C:30]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-])=O)[CH:48]=3)[CH2:41][CH2:40]2)[CH:29]=1>>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH3:38])=[N:35]2)=[C:30]([N:39]2[CH2:40][CH2:41][N:42]([CH2:45][CH2:46][C:47]3[CH:48]=[C:49]([CH:50]=[CH:51][CH:52]=3)[NH2:53])[CH2:43][CH2:44]2)[CH:29]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cc(Cl)cc2n1
Agent: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(Cl)cc2n1
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield using a similar procedure to description D6 starting from 7-Chloro-2-methyl-5-{4-[2-(3nitrophenyl)ethyl]-1-piperazinyl}quinoline (D17).
Reaction SMILES: S(=O)(=O)(OC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](C(=O)NCCC)CC4)CCC=2C=1)N.[S:30](=[O:59])(=[O:58])([O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42]([C:51](=[O:57])[NH:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1)[NH2:31]>>[S:30](=[O:58])(=[O:59])([O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C@@H:42]([C:51](=[O:57])[NH:52][C:53]([CH3:54])([CH3:55])[CH3:56])[CH2:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1)[NH2:31]
Reactant: CC(C)(C)NC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: CCCNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C

Procedure:
In similar manners to those described for the synthesis of compound 7, compound 29e was prepared from compound 11e. FAB-MS m/z 435 (M+H)+; 1H NMR (270 MHz, DMSO-d6) δ 0.59 (s, 3H, CH3), 1.26 (s, 9H, C(CH3)3), 6.89 (s, 1H, NH),6.96 (d, 1H, J=2.3 Hz, ArH), 7.01 (dd, 1H, J=2.3, 8.6 Hz, ArH), 7.34 (d, 1H, J=8.6 Hz, ArH), 7.87 (s, 2H, NH2).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH3:11]>C(Cl)(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:1]
Reactant: Cc1ccc(F)cc1Cl
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Cl)c1
Yield: 80 %

Procedure:
A solution of bromine (7.10 ml) in carbon tetrachloride (70 ml) was added slowly over a period of 3 hours to a solution of 2-chloro-4-fluorotoluene (20.0 g) in carbon tetrachloride (80 ml) maintained at the reflux temperature and irradiated by light from a tungsten lamp (200 watt). After the addition was completed the mixture was heated at the reflux temperature with irradiation until the colour had been discharged (ca.1 hour). The solvent was then removed by evaporation under reduced pressure and the residual oil distilled to yield 2-chloro-4-fluorobenzyl bromide (80% pure, 18.0 g) b.p. 110°-120° C./15 mm Hg.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:38]1[N:39]=[CH:40][NH:41][CH:42]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:26])[CH3:27])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12]([C:38]3[N:39]=[CH:40][NH:41][CH:42]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(B2OC(C)(C)C(C)(C)O2)cn3S(=O)(=O)c2ccccc2)cc1
Reactant: Ic1c[nH]cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2cnc3c(c2)c(-c2c[nH]cn2)cn3S(=O)(=O)c2ccccc2)cc1
Yield: 84 %

Procedure:
A mixture of 16 (150 mg, 0.298 mmol), 4-iodoimidazole (86.7 mg, 0.447 mmol), dichlorobis(triphenylphosphine)palladium (II) (20.9 mg, 0.0298 mmol), LiCl (37.9 mg, 0.894 mmol), 1M aq. Na2CO3 (0.75 mL, 0.75 mmol) in toluene (1.8 mL) and EtOH (1.8 mL) was microwaved at 120° C. for 15 min. The reaction mixture was cooled, brine (3 mL) was added and the aqueous layer extracted with ethyl acetate (3×5 mL). Sorbent (HM-N, Jones Chromatography) was added, the solvent evaporated and the product purified by silicagel chromatography using MeOH:CH2Cl2 (3:97) (gradient elution) to give product 17 as a brown foam (111 mg, 84%); 1H NMR (400 MHz, CDCl3) δ 2.96 (s, 6H), 6.77 (d, J=8.8 Hz, 2H), 7.48-7.35 (m, 5H), 7.52 (t, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.99 (s, 1H), 8.11 (d, J=7.5 Hz, 2H), 8.27 (d, J=2.0 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([CH2:13][O:12][C:9]3[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=3)=[C:18]([CH3:19])[O:17][N:16]=2)=[N:21][CH:22]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)noc2C)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (379 mg, 1.1 mmol) in THF (2.6 mL), water (2.6 mL) and methanol (0.5 mL) was added lithium hydroxide monohydrate (88.8 mg, 2.1 mmol) and the resulting mixture stirred at room temperature overnight and then acidified with HCl (4 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title product (329 mg, 94%) which was obtained as white solid. MS: m/e=329.1 [M−H]−.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)([CH3:12])[CH3:11].[ClH:25]>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:25].[CH:10]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=1)([CH3:12])[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)NCCCOc1cccc(Br)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)NCCCOc1cccc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of phenyl boronic acid (0.36 g) in ethanol (3.0 ml) was added to a stirred suspension of N-isopropyl-3-(3-bromophenoxy)propylamine (1.0 gm) and tetrakis(triphenylphosphine)-palladium (100 mg) in aqueous 2M sodium carbonate (4.0 ml) and toluene (6.5 ml) under an atmosphere of argon. The mixture was heated at reflux for 18 hours and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with aqueous 2M sodium hydroxide and the organic phase was evaporated to give a solid. The solid was dissolved in hot ethanol, the solution was filtered, and the filtrate evaporated to give a residue which was purified by dry-flash column chromatography on silica gel (Merck 60H, Art No 7736) using ethyl acetate initially followed by ethyl acetate/1% triethylamine as eluent. There was thus obtained an oil which was treated with ethereal hydrogen chloride to give a solid which was recrystallised from isopropyl alcohol to give N-isopropyl-3-(3-phenylphenoxy)propylamine hydrogen chloride (0.26 g) as a solid, m.p. 147°-149° C.; microanalysis, found: C, 70.7; H, 7.9; N, 4.7; Cl, 11.5%; C18H23NO. HCl requires: C, 70.7; H, 7.91; N, 4.58; Cl, 11.6%; NMR(CD3 !2SO): 1.27(6H,d), 2.16(2H,m), 3.05(2H,br.m), 3.30(1H,m), 4.18(2H,t), 6.96(1H,d of d), 7.24(2H,d of d), 7.31-7.52(4H,m), 7.67(2H,d of d) and 9.07(1H,br.s); m/z 270(M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=O.[C:25]([O:29][C:30]([C:32]1([CH2:39][NH2:40])[CH2:37][CH2:36][S:35](=[O:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:25]([O:29][C:30]([C:32]1([CH2:39][NH:40][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:2])[CH2:33][CH2:34][S:35](=[O:38])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)C1(CN)CCS(=O)CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCS(=O)CC1
Yield: 39.3 %

Procedure:
A mixture of 4-cyano-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (193 mg) and Raney Ni (0.5 mL in water) in MeOH (30 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product 4-aminomethyl-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (195 mg), which was used in the next step. A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (35 mg) and 4-aminomethyl-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (52 mg) in EtOH (1.5 mL) was refluxed overnight. The mixture was cooled, concentrated and the residue was column purified to give the desired product (23 mg). LC MS ESI+: 536 (M+1)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](COCC[Si](C)(C)C)[N:11]=[C:10]2[N:24]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH3:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[N:24]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH3:25]
Reactant: COCCCN(C)c1nn(COCC[Si](C)(C)C)c2ccc(C3OCCCO3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: COCCCN(C)c1n[nH]c2ccc(C3OCCCO3)cc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 187 mg (0.429 mmol) 5-(1,3-dioxan-2-yl)-N-(3-methoxypropyl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-amine (Example 49A) in anhydrous THF (12 ml) were added 6.2 ml (6.2 mmol) tetrabutylammonium fluoride solution (1 M in THF) and ethane-1,2-diamine (145 μl). The solution was stirred at 50° C. for 3 h. After addition of further 6.2 ml tetrabutylammonium fluoride solution (1 M in THF), stirring at 50° C. was continued for 24 h. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution and with water. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining solid (131 mg, 99% of th.) was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([CH:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 332. NMR: CDCl3: 1.56 (3 H, d, J 7.1, Me), 2.62-2.80 (4 H, m, CH2), 2.81 (3 H, s, Me), 3.26-3.31 (4 H, m, CH2), 3.95-3.99 (4 H, m, CH2), 4.02-4.11 (5 H, m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 528.31
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[NH:12][C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O.C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[N:12]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1c(Br)[nH]c2cc(Br)c(OC)c(Br)c12)NC(C)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1c(Br)n(Cc2ccccc2)c2cc(Br)c(OC)c(Br)c12)NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 19.6 mg (0.04 mmol) of (S)-(+)-N-acetyl-2,4,6-tribromo-5-methoxytryptophan methyl ester (4) dissolved in 1.5 mL of N,N-dimethylformamide was charged with 18.0 mg (0.13 mmol) of potassium carbonate and subsequently with 0.09 mL (d =1.44,0.7 mmol) of benzyl bromide. The mixture was stirred at room temperature for 30 minutes. The reaction solution was charged with water and subjected to extraction with an ethyl acetate-methanol (95:5, v/v) mixed solvent. The organic phase was washed with a saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain yellow oil. Thin-layer chromatography using silica gel as a carrier and a chloroform-methanol (99:1, v/v) mixed solvent as a developing solvent was performed. A band having an Rf value of 0.18 to 0.29 was extracted with a chloroform-methanol (95:5, v/v) mixed solvent to obtain the substance of interest (8) at a yield of 22.0 mg (96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13].N[C:20]1[CH:25]=CC=CN=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:25]=[CH:20][CH:18]=[CH:17][N:16]=1)=[S:13]
Reactant: COc1ccccc1CCNC(=S)n1ccnc1
Reactant: Nc1ccccn1
Solvent: CN(C)C=O
Product: COc1ccccc1CCNC(=S)Nc1ccccn1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 1-(2-[2-methoxyphenyl]ethyl)thiocarbamoyl imidazole (0.52 g, 2 mmol) and 2-aminopyridine (0.19 g, 2 mmol) in N,N-dimethylformamide (5 mL) was stirred at 90° C. for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.25 g (44%) of the titled product: IR (KBr, cm-1) 3219, 3048, 1607, 1557, 1236, 1036, 756;
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:41])[CH2:21][NH:22][C:23]2([CH2:26][CH2:27][N:28]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([CH3:39])([CH3:38])[O:30][C:29]3=[O:40])[CH2:25][CH2:24]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:41][CH:20]([C:12]1[C:13]2[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=2[C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:21][NH:22][C:23]1([CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH3:39])([CH3:38])[O:30][C:29]2=[O:40])[CH2:24][CH2:25]1
Reactant: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(OCc4ccccc4)c4c3OCC(=O)N4)CC2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
650 mg (1.17 mmol) of 1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one is dissolved in 30 mL of methanol, combined with palladium on charcoal (10%), and hydrogenated at ambient temperature and 3 bar hydrogen pressure. Yield: 240 mg (44%); mass spectroscopy: [M+H]+=468.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12](O)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O.CN(C=O)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([Cl:22])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (500 mg, 1.90 mmol) in methylene chloride (15 mL) was added oxalyl chloride (0.34 mL, 3.80 mmol) dropwise at 0° C. This was followed by a drop of DMF. The reaction was warmed to room temperature and stirred at room temperature for 1.5 hr. The mixture was concentrated to dryness to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl chloride as a light yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a stirred solution of 88 mg (0.26 mmol) of (S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (6 mL) was added NaH (19 mg, 0.40 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 6-chloro-nicotinonitrile (45 mg, 0.32 mmol) in DMF (2 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 100 mg (87%) of the title compound as a colorless oil. ES-MS m/e: 436.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.[Na]>CC(C)=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Yield: 64.9 %

Procedure:
A suspension of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (1.23 g, 4 mmol) and sodium hydrosuffite (7.0 g, 85% pure from Aldrich, 40 mmol) in acetone and water (1:1, 20 mL) was refluxed for 3 h. Upon cooling, the volatile components (mainly acetone) were removed on rotavap, and the resulting mixture was subjected to filtration. The solid was thoroughly washed with EtOAc. The combined filtrate was extracted with n-BuOH (4×), and the combined organic layer was washed with saturated aq. NaHCO3, dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas) to provide 0.71 g of product as a pale yellow solid.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6](=[O:35])([O:10][CH:11]([O:13][C:14](=[O:34])[CH2:15][CH2:16][CH:17]([P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[CH3:12])SCC>C(Cl)Cl>[CH2:21]([O:20][P:18]([CH:17]([P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[CH2:16][CH2:15][C:14]([O:13][CH:11]([O:10][C:6]([Cl:4])=[O:35])[CH3:12])=[O:34])([O:23][CH2:24][CH3:25])=[O:19])[CH3:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOP(=O)(OCC)C(CCC(=O)OC(C)OC(=O)SCC)P(=O)(OCC)OCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCC(=O)OC(C)OC(=O)Cl)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (78 μL, 0.96 mmol) was added drop-wise to a solution of 23 (237 mg, 0.48 mmol) in 10 mL of CH2Cl2 cooled to 0° C. The solution was stirred for 2 h. The solvent was removed under reduced pressure to afford chloroformate 24 and which was used for the next reaction without further purification.