Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[O:5]1[C:6](=[C:10]1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)C([O-])=O.[K+].C1(C)C=CC=CC=1>O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:6]=[O:5])=[CH:12][CH:13]=1
Reactant: COc1ccc(C2=C(C(=O)[O-])O2)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CC=O)cc1
Temperature: 25 °C

Procedure:
70 ml of an aqueous solution of 3.64 g of acetic acid are added dropwise to a mixture, heated to the boiling point, of 14 g (59 mmol) of potassium (E)-α,β-epoxy-p--methoxycinnamate, 112 ml of toluene and 28 ml of water. After 5 minutes the mixture is cooled to room temperature. The organic phase is washed with water and then with aqueous potassium carbonate solution. The aqueous washings are extracted with toluene. The organic phase is dried azeotropically. The yield of p-methoxyphenylacetaldehyde in the solution obtained amounts to 92-94%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[F:16][C:17]([F:51])([F:50])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]3[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=3)[CH:35]=2)[N:19]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:46]([C:42]2[CH:41]=[C:40]([C:36]3[CH:35]=[C:34]([C:20]4[N:19]=[C:18]([C:17]([F:16])([F:50])[F:51])[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[N:21]=4)[CH:39]=[CH:38][N:37]=3)[CH:45]=[CH:44][CH:43]=2)(=[O:47])=[O:48])[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2cccc(-c3cc(-c4nc(-c5ccc(C(F)(F)F)cc5)cc(C(F)(F)F)n4)ccn3)c2)CC1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methyl-piperazine (0.09 g, 0.9 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.18 g, 88%). MS (ISP) 607.6 [(M+H)+]; mp 205° C.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1([CH3:9])[CH2:7][CH2:6][O:5][C:4]1=O.[C:10](Cl)(=[O:14])[C:11](Cl)=O>CN(C=O)C>[Br:1][CH2:6][CH2:7][C:3]([CH3:9])([CH3:2])[C:4]([O:14][CH2:10][CH3:11])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Br
Reactant: CC1(C)CCOC1=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Hydrogen bromide was bubbled through 3,3-dimethyldihydro-2(3H)-furanone (1 g, 8.76 mmol) at room temperature for ca. 5 h and the resulting mixture was left at room temperature overnight. Nitrogen was then bubbled through the mixture. The crude acid was dissolved in DCM (10 ml) and treated with oxalyl chloride (2.3 ml, 26.3 mmol) and DMF (1 drop) and the resulting mixture was stirred at room temperature over the weekend then concentrated in vacuo. The residue was treated with ethanol (10 ml) and the resulting mixture stirred at room temperature for 1 hour then poured into water. The aqueous phase was extracted twice with diethyl ether and the ethereal solution was washed with brine, dried and concentrated in vacuo to give the title compound (949 mg, 49%) as a very pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.[N-:46]=[C:47]=[O:48].[K+]>O.C(O)(=O)C>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:47]([NH2:46])=[O:48])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NC(N)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 35 °C
Yield: 33.8 %

Procedure:
To a suspension of (S)-2-(1-((5-(3-amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in 403 μl water and 208 μl acetic acid was added potassium isocyanate (10 mg, 0.12 mmol) The mixture was heated 35° C. overnight. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 18 mg (33% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][O:14]1>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:12][CH:13]2[CH2:15][O:14]2)[CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(NCC2CO2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 6-bromopyridin-2-amine (1 g, 5.81 mmol) in DMF (15 mL) was added NaH (696 mg, 17.4 mmol), 2-(bromomethyl)oxirane (790 mg, 5.81 mmol) at 0° C. The mixture was stirred at 0° C. for 4 hours then quenched with water (50 mL), extracted with EA (30 mL×3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step. LCMS (m/z): 279.1/280.1 [M+H]+/[M+2H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1

Procedure:
A solution of 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.598 ml, 9.70 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.00 g, 9.70 mmol), Pd(dppf)-CH2Cl2 adduct (0.396 g, 0.485 mmol), and potassium carbonate (2.329 g, 38.8 mmol) in 1,4-dioxane (36.4 ml) and water (12.13 ml) was stirred at 70° C. for 18 hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (Redi-Sep Gold 80 g silica gel column (Teledyne Isco, Lincoln, Nebr.), gradient elution 0 to 100% Et2O:Heptane) to afford tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a light yellow oil. m/z (ESI) 428.1 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([O:48][CH2:49][CH3:50])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:49]([O:48][C@H:45]1[CH2:44][CH2:43][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:21]3[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][C:12]=4[O:28][CH3:29])[N:22]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:47][CH2:46]1)[CH3:50]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCO[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (40.0 mg, 0.0944 mmol) and 7-amino-4-(trans-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166B). 1H NMR (CDCl3, 400 MHz): δ=1.19-1.32 (m, 9H), 1.34-1.46 (m, 2H), 1.58-1.69 (m, 2H), 1.92 (d, J=12.88 Hz, 2H), 2.23 (d, J=10.11 Hz, 2H), 2.51 (t, J=12.00 Hz, 1H), 3.14-3.21 (m, 2H), 3.22 (s, 3H), 3.31-3.43 (m, 1H), 3.59 (q, J=6.99 Hz, 2H), 3.93 (s, 3H), 3.99-4.12 (m, 4H), 4.40 (s, 2H), 6.89 (d, J=8.08 Hz, 1H), 6.94 (s, 1H), 7.34 (d, J=8.59 Hz, 1H), 7.70 (br. s., 1H), 8.28 (d, J=7.58 Hz, 1H), 8.39 (br. s., 1H), 8.62 (d, J=8.59 Hz, 1H), 10.54 (br. s., 1H). MS (ES+): m/z 706.26 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][CH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[C:21](OC)=[O:22].[Cl-].[NH4+]>C1COCC1.O>[CH3:19][CH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)C(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl methylphosphonate (60 g, 485 mmol) in 600 ml THF was cooled to −78° C. and treated with a 2.5 M solution n-butyl lithium in hexane (194 mL, 485 mmol). After 30 min, the reaction was treated with a solution of methyl 2-methylhexanoate (14 g, 97 mmol) in THF (40 mL). The reaction was stirred for 1 h at −78° C. The reaction was treated with a saturated aqueous ammonium chloride solution (200 mL) and allowed to warm to ambient temperature. The solution was diluted with water and extracted with ether. The combined organic layers were washed with brine, dried, and concentrated. Purification by normal phase chromatography using a gradient of ethyl acetate in hexane gave dimethyl (3-methyl-2-oxoheptyl)phosphonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][NH2:6].[N:19]1[CH:24]=[C:23]([C:25]([NH:27][C:28]2([C:31](O)=[O:32])[CH2:30][CH2:29]2)=[O:26])[CH:22]=[N:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][NH:6][C:31]([C:28]1([NH:27][C:25]([C:23]2[CH:22]=[N:21][CH:20]=[N:19][CH:24]=2)=[O:26])[CH2:30][CH2:29]1)=[O:32]
Reactant: COc1ccc(Oc2ccc(CN)cc2F)cc1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.7 mg (0.1 mmol) of 3-fluoro-4-(4-methoxy-phenoxy)-benzylamine were dissolved in 1 ml DMF. 20.7 mg (0.1 mmol) of 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (prepared in 1b) were also dissolved in DMF and 35.3 mg (0.11 mmol) and 21 μl triethylamine (0.15 mmol) were added. Shaken overnight at ambient temperature and purified by reversed-phase chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([N:24]5[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25]5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[ClH:32].[CH3:29][C:27]1[CH:26]=[N:25][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[C@H:15]([N:13]2[CH2:14][C:11]4([CH2:30][CH2:31][NH:8][CH2:9][CH2:10]4)[CH2:12]2)[CH2:16][CH2:17]3)[CH:28]=1
Reactant: Cc1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)c1
Reaction time: 3 h

Procedure:
To a solution of 2-[(R)-5-(4-methyl-pyrazol-1-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (8-1a, 239 mg, 0.57 mmol) in MeOH (5 mL) was added 9 mL of 4N HCl in dioxane solution. The reaction was stirred for 3 hours. The reaction was concentrated and the residue was coevaporated with diethylether (3×) to afford 2-((R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride as a white solid (8-1b, 135 mg, 61%). This material was used without further purification in the next reaction. MS (ES+) 322.9 (M+H)+. 1H NMR (DMSO-d6) δ 1.89-2.20 (m, 7H), 2.28-2.48 (m, 2H), 2.84-3.14 (m, 4H), 3.28-3.46 (m, 1H), 3.84-4.03 (m, 3H), 4.19-4.33 (m, 2H), 4.83-4.98 (m, 1H), 7.54 (s, 1H), 7.66 (s, 2H), 7.74-7.79 (m, 1H), 8.28 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]([NH2:16])([CH3:15])[C:10]([F:14])([F:13])[CH2:11][OH:12])=[O:5])[CH3:2].[N:17]#[C:18]Br.C(#N)C>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]1([CH3:15])[C:10]([F:14])([F:13])[CH2:11][O:12][C:18]([NH2:17])=[N:16]1)=[O:5])[CH3:2]
Reactant: N#CBr
Reactant: CCOC(=O)[C@H]1C[C@@H]1[C@@](C)(N)C(F)(F)CO
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)[C@H]1C[C@@H]1[C@@]1(C)N=C(N)OCC1(F)F
Temperature: 75 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of (1S,2S)-rel-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (542 mg, 2.28 mmol) and cyanogen bromide in acetonitrile (5M; 685 μl, 3.43 mmol) in ethanol (14 ml) was heated at 75° C. for 7 hours. In order to complete the reaction another volume of cyanogen bromide in acetonitrile (5M; 228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 6 hours, and again cyanogen bromide in acetonitrile (228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 24 hours. For the workup, the solution was evaporated, the residual oil was washed once with a solution of sodium carbonate (2M) and twice with ethyl acetate, then dried over sodium sulphate, filtered and concentrated at reduced pressure. The light yellow oil (731 mg) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (1S,2S)-rel-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid ethyl ester (404 mg, 67% yield) was obtained as a colorless oil. MS (ISP): m/z=263.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH2:10]([N:17]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=[C:18]1[S:19][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccncc1
Reactant: NNC(=O)c1cccs1
Reactant: S=C=NCc1ccccc1
Product: c1ccc(Cn2c(SCc3ccncc3)nnc2-c2cccs2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-thiophencarboxylic acid hydrazide, benzyl isothiocyanate and 4-bromomethylpyridine as the starting materials. (M+H)+−365.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([Cl:21])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Cl
Temperature: 40 °C
Yield: 41.6 %

Procedure:
6-(4-Fluorophenyl)-2-methyl-3-pyridinecarboxylic acid (0.2 g, 0.866 mol) was suspended in DCM (14 mL) and DMF (1 drop) was added. The mixture was cooled in an ice-bath and oxalyl chloride (0.226 mL, 2.598 mmol) was added portion wise over 5 minutes. The mixture was heated to 40° C. for 90 minutes. The mixture was allowed to cool and the solvent removed under vacuum to give 6-(4-fluorophenyl)-2-methyl-3-pyridinecarbonyl chloride as a yellow solid (0.270 g) which was used directly in step 2. Step 2: The acid chloride from step 1 was taken up in DCM (3 mL) and added to a solution of 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D9) (0.23 g, 0.693 mmol) in DCM (2 mL). Triethylamine (0.193 mL, 1.386 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated. The crude product was purified by column chromatography. Elution with 0-50% EtOAc/petroleum yielded the title compound as a white foam (0.331 g). δH (CDCl3, 400 MHz) 7.89 (2H, m), 7.36 (1H, m), 7.26 (1H, m), 7.19 (2H, m), 7.10 (2H, t), 6.99 (2H, m), 4.00 (2H, m), 3.53 (3H, s), 3.34 (2H, s), 2.58 (3H, s), 2.44 (2H, d), 2.05 (2H, m), 1.44 (9H, s), 1.18 (6H, d). MS (ES): MH+ 547.3. Description 16
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[N:19]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1

Procedure:
40.0 g of 4-nitrobenzyl bromide are dissolved in 500 ml of methylene chloride, 51.5 ml of triethylamine are added and 18.3 ml of piperidine are carefully added dropwise. After the end of the exothermic reaction the mixture is refluxed for another 30 minutes. After cooling it is washed with water and the organic phase is dried over sodium sulphate. Finally, the organic phase is evaporated down.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]5[O:26][CH2:25][CH2:24][C:23]=5[CH:27]=4)[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:32]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](C(C)C)C(C)C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]5[O:26][CH2:25][CH2:24][C:23]=5[CH:27]=4)[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(-c3ccc4c(c3)CCO4)cnc21
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(-c3ccc4c(c3)CCO4)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a solution of 48 (187 mg, 0.270 mmol) in CH2Cl2 (2 mL) was added triisopropylsilane (0.14 mL), TFA (0.73 mL) and distilled water (6 drops). The mixture was stirred at room temperature for 1 h 30 min. The reaction was quenched and made neutral by addition of aqueous saturated NaHCO3 and diluted with EtOAc (200 mL) and water (100 mL). The aqueous layer was extracted further with CH2Cl2 (150 mL), the organic solutions were combined, dried (MgSO4) and concentrated to afford a light brown oily solid. Purification by preparative TLC (EtOAc) afforded 49 (45 mg, 38%) as an off white solid; 1H NMR (400 MHz, CDCl3+1 drop CD3OD) δ 2.62 (t, J=17.7, 8.6 Hz, 2H), 3.96 (t, J=17.3, 8.6 Hz, 2H), 6.22 (d, J=8.2 Hz, 1H), 6.65 (t, J=8.0, 2.4 Hz, 2H), 6.76 (s, 1H), 6.84-6.88 (m, 2H), 6.93-6.96 (m, 1H), 7.19 (s, 1H), 7.27 (s, 1H), 7.41 (s, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.97 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5](=[N:15]S(C2C=CC(C)=CC=2)(=O)=O)[N:6]([CH:8]([CH3:14])[C:9]([CH:11]2[CH2:13][CH2:12]2)=O)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:15]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2cnc(Br)cn2C(C)C(=O)C2CC2)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2cnc(Br)cn12
Temperature: 60 °C
Yield: 80.5 %

Procedure:
To a solution of N-(5-bromo-1-(1-cyclopropyl-1-oxopropan-2-yl)pyrazin-2(1H)-ylidene)-4-methylbenzenesulfonamide (1.24 g) in THF (10 ml) was added trifluoroacetic anhydride (1.23 g) at 0° C., and the mixture was heated at 60° C. for 3 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (593 mg) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1
Reactant: CC(=O)N1CCCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCCCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
A mixture of 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (1.3 g, 5.4 mmol) and Pd—C (10%, 100 mg) in EtOH (200 mL) was stirred under H2 (1 atm) at room temperature for 1.5 h. The mixture was filtered through a layer of Celite and the filtrate was concentrated to give 1-(8-amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (DC-9) as a white solid (1 g, 90%). 1H NMR (CDCl3) δ 7.01 (d,J=6.0 Hz, 1 H), 6.56 (dd,J=6.0, 1.8 Hz, 1 H), 6.50 (d,J=1.8 Hz, 1 H), 4.66-4.61 (m, 1 H), 3.50 (br s, 2 H), 2.64-2.55 (m, 3 H), 1.94-1.91 (m, 5 H), 1.77-1.72 (m, 1 H), 1.32-1.30 (m, 1 H); ESI-MS 204.1 m/z (MH+).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:28]([OH:30])=[O:29])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[C:28]([O:30][CH2:2][C:1]#[N:4])=[O:29])=[O:22])=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Reaction time: 3.5 h
Yield: 100 %

Procedure:
N,N-Diisopropylethylamine (205 μL, 1.176 mmol) and subsequently bromoacetonitrile (373 μL, 5.34 mmol) were added to a solution of (S)-5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk61) (435.5 mg, 1.069 mmol) in acetonitrile (1 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 3.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk62) (477.2 mg, quant.).