Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:15][NH:16][C@H:17]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:18][CH2:19][C:20]([NH:22][C@H:23]([CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[O:21])=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[C:45]#[N:46]>CCO>[NH2:46][C:45]1[N:16]([C@H:17]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:18][CH2:19][C:20]([NH:22][C@H:23]([CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[O:21])[CH2:15][C:3]2[CH:4]=[C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC[C@@H](NC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1N)C1CCCCC1)C(=O)N1CCOCC1
Reactant: N#CBr
Solvent: CCO
Product: CC(C)(C)OC[C@@H](NC(=O)CC[C@@H](C1CCCCC1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N)C(=O)N1CCOCC1

Procedure:
A solution of 4-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-N-(1-(R)-tert-butoxymethyl-2-morpholin-4-yl-2-oxo-ethyl)-4-(S)-cyclohexyl-butyramide (0.37 g, 0.6 mmol) and BrCN (3M in CH2Cl2, 0.25 mL) in EtOH (20 mL) was stirred at room temperature overnight. The EtOH was evaporated to yield an oil, which was purified by Gilson HPLC to yield 4-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-N-(1-(R)-tert-butoxymethyl-2-morpholin-4-yl-2-oxo-ethyl)-4-(S)-cyclohexyl-butyramide as a white solid, as its corresponding TFA salt.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:39]=[CH:38][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:39]=[CH:38][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)[nH]c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCNCC5)cc4)cnc3N)[nH]c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.5 %

Procedure:
tert-butyl 4-[4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]benzoyl]-1,4-diazepane-1-carboxylate (117 mg, 0.2218 mmol) was dissolved in DCM (3 mL) and the mixture was cooled to 0° C. TFA (3 mL, 38.94 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. Solvents were evaporated and the residue was dissolved in a mixture of MeCN and water (5 mL/5 mL) and submitted to Genevac evaporation to yield the product (119 mg, 99% Yield). 1H NMR (400.0 MHz, CD3OD) δ 2.18-2.04 (2H, m), 2.45 (3H, s), 3.33 (3H, m), 3.44 (2H, m), 3.63 (2H, m), 3.82 (1H, m), 3.96 (2H, m), 7.15 (1H, d), 7.45 (1H, s), 7.55 (2H, d), 7.58 (1H, s), 8.59 (2H, d), 8.59 (1H, s) ppm; MS (ES+) 428
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[O:14][CH3:15])[CH2:2][CH3:3].[Li]CCCC.[C:21](=[O:23])=[O:22].O>C1COCC1.CCCCCC>[CH2:1]([C:4]1[C:9]([O:10][CH3:11])=[C:8]([C:7]([O:12][CH3:13])=[CH:6][C:5]=1[O:14][CH3:15])[C:21]([OH:23])=[O:22])[CH2:2][CH3:3]
Reactant: CCCc1c(OC)cc(OC)cc1OC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OC)cc(OC)c(C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To the stirred solution of 2-propyl-1,3,5-trimethoxybenzene (3.00 g, 14.27 mmol) in dry THF (50 mL) at 0° C. in nitrogen atmosphere was added 6.28 mL (15.7 mmol) of 2.5 M n-BuLi in hexane dropwise via syringe. After the resulting solution was stirred at room temperature for 4 hr, 20 g of dry ice was added in portions over 20 min. After 30 min 50 mL of water was added. The mixture was evaporated under reduced pressure to remove THF and the aqueous phase was extracted with ether, acidified with hydrochloric acid to pH 3, and extracted again with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated. Purification of the solid residue by flash chromatography on silica column with 10% MeOH in dichloromethane provided 1.67 g of the title compound: mp 129.0-130.0° C. dec; 1H NMR (CDCl3): 6.30 (1 H, s), 3.93 (3 H, s), 3.87 (3 H, s), 3.83 (3 H, s), 2.54 (2 H, m), 1.49 (2 H, sex, J=7.5 Hz), 0.94 (3 H, t, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:25]=[N:26][C:27]([O:30]C)=[N:28][CH:29]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C>CC#N>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:25]=[N:26][C:27]([OH:30])=[N:28][CH:29]=5)[N:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cnc(O)nc1
Temperature: 75 °C

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxypyrimidin-5-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (88 mg, 0.20 mmol) in CH3CN (2 mL) was added TMSI (80 mg, 0.40 mmol). The mixture was heated at 75° C. for 4 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by preparative LC/MS to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(2-hydroxypyrimidin-5-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 427.3.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH2:42][CH2:43][CH2:44][N:45]=2)=[CH:37][CH:36]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:45]1[CH2:44][CH2:43][CH2:42][C:41]=1[C:38]1[CH:39]=[CH:40][C:35]([NH2:6])=[CH:36][CH:37]=1
Reactant: Brc1ccc(C2=NCCC2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1ccc(C2=NCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
LiHMDS (1.67 g, 10.0 mmol) is added to a 100 mL round bottom flask. Toluene (25 mL) is added followed by addition of Pd2(dba)3.CHCl3 (100 mg, 0.1 mmol) and P(tBu)3.HBF4 (78 mg, 0.27 mmol). 5-(4-Bromo-phenyl)-3,4-dihydro-2H-pyrrole (1.5 g, 6.7 mmol) is added to the flask. After degassing, the mixture is stirred at room temperature overnight. TLC is used to determine complete consumption of the starting bromide. The reaction mixture is diluted with ether and poured into dilute HCl (aq). The ether layer is discarded and the aqueous layer is basified with NH4OH and extracted with CH2Cl2. The CH2Cl2 layer is dried and concentrated to provide the desired product (820 mg, 76%). 1H NMR (300 MHz, CDCl3) ∂ 7.66 (2H, d, J=8.4 Hz), 6.67 (2H, d, J=8.1 Hz), 3.98-4.03(2H, m), 3.88 (2H, br), 2.85-2.92 (2H, m), 1.97-2.04 (2H, m). MS (ESI): 162 (M+1)+1.
Reaction SMILES: [OH:1][C:2]1([C:31](O)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[CH:34]1([NH:39][C:31]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[C:16]([NH:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=4[F:26])=[N:15][C:14]4[C:9]3=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=4)[CH2:4][CH2:3]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)O)CC3)c2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)NC4CCCC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-Hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylic acid (0.200 g, 0.4 mmol) was dissolved in 4 mL of dry THF. Cyclopentyl amine (0.079 mL, 0.8 mmol) was added neat followed by di-isopropyl amine (0.105 mL, 0.6 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) was added last, as a solid in one portion at room temperature (0.177 g, 0.4 mmol). The reaction was complete within 10 min as confirmed by LC-MS. DMF was removed under reduced pressure. The residue was triturated in saturated aqueous sodium bicarbonate. The resulting beige solid was collected by filtration and washed with water. The crude product was re-crystallized from hot methanol-water. The crystals were dried in vacuum oven. (141 mg, 66% yield) M+1: 532.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20]C(OC(C)(C)C)=O)=[CH:18][CH:19]=1)[CH:6]([S:9]C(=O)C)[CH2:7][CH3:8])C>Cl>[NH2:20][C:17]1[N:16]=[CH:15][C:14]([CH2:13][CH:5]([CH:6]([SH:9])[CH2:7][CH3:8])[C:4]([OH:28])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(CC)SC(C)=O
Agent: Cl
Product: CCC(S)C(Cc1ccc(N)nc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-pentanoic acid ethyl ester/D (19.2 mg; 0.05 mmol) in concentrated HCl (2 mL) was refluxed under argon for 1.5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford 12.9 m, of the title compound as the hydrochloride salt.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[N:19]=[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C(#N)CCC.C(OCC)(=O)C>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:19]=[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:5][CH2:4]1
Reactant: NCC1CCNCC1
Reactant: CCN(CC)c1nc(Cl)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1nc(N2CCC(CN)CC2)nc2ccccc12

Procedure:
A mixture of 4-(aminomethyl)-piperidine (1.2 g, 11 mmol), 2-chloro-4-diethylaminoquinazoline (2.5 g, 11 mmol) and Hunig's base (2.8 ml, 16 mmol) in 5 ml of butyronitrile was reacted for 12 hours at 100° C. After cooling, ethyl acetate (50 ml) and 50 ml of sodium hydroxide (10%) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4), concentrated on a rotary evaporator and purified by chromatography on silica gel (eluent: methylene chloride/ethanol/ammonia, 50/10/1) to give the free base as a thick orange-brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ncn3)CC2)CC1
Reaction time: 0.08 h
Yield: 53.3 %

Procedure:
4-(4-Methylpiperazin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (81 mg) was dissolved in ethanol (1 ml), and then (S)-(+)-10-camphorsulfonic acid (44 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-phenylacetyl isothiocyanate in toluene (1.14 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml), brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:5 to 1:10, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (1.5 ml) and hexane (3.0 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (61.1 mg, 53.3%) as white powder.
Reaction SMILES: COC(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)N.C=O.FC(F)(F)C(O)=O.C[N:27]1[CH:39]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH2:28]1>[Pd].C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH:28]1[C:29]2[NH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]=2[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[N:27]=1
Reactant: COC(=O)C1Cc2c([nH]c3ccccc23)CN1C
Agent: [Pd]
Agent: C=O
Agent: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 1 h
Yield: 46 %

Procedure:
This compound was prepared by a modification of a known procedure (Couts et al., Heterocycles 1984, 22:131). To a mixture of the free base of L-tryptophan methyl ester (161 g, 0.738 mol) and paraformaldehyde (22 g, 0.733 mol) was added toluene (1 L). The mixture was refluxed with efficient mechanical stirring, and the water removed using a Barrett trap. After 1 hour, nearly the theoretical amount of water was collected (13 mL). Trifluoroacetic acid (5 mL, 0.065 mol, 8.8 mol %) was added through the top of the condenser (exothermic), and the mixture refluxed for another 1.5 hours. The solvent was evaporated and 10% palladium-on-carbon was added to the pot (44 g of moist material recovered from a previous run; dry wt=38 g based on water removed in subsequent step; ˜0.036 mol Pd, or 4.8 mol %). Xylene (800 mL) was added, and the mixture vigorously stirred (mechanical stirrer) and refluxed overnight with a Barrett trap to remove the water from the Pd/C. The reaction mixture was then cooled in an ice bath, then in a freezer at −20° C. overnight. The resulting sludge was filtered, affording mother liquors containing impurities, including a compound consistent with methyl 2-methyl-1,2,3,4-tetrahydro-9H-β-carboline-3-carboxylate, and a gray filter cake containing a mixture of the product and Pd/C. The filter cake was transferred to a paper thimble and extracted in a Soxhlet apparatus with methanol (800 mL in a 2-L recovery flask) in several batches. As the product crystallized in the pot, the slurry was filtered, the light yellow solid was washed with methanol and dried, and the filtrate was returned to the pot. Three batches of product were collected, affording a total of 76 g of product (46% yield from tryptophan methyl ester).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]#[C:14][OH:15]>>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[NH:13][C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: N#CO
Product: O=C1CN(Cc2ccccc2)C(=O)N1

Procedure:
The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].O>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (219 ml) was added to a solution of 4-bromophenol (259 g) and 4-dimethylaminopyridine (1.5 g) in dichloromethane (1000 ml) at 0° C. at such a rate that the temperature did not rise above 20° C. When the addition was complete propionyl chloride (137 ml) was added in portions over 1 hour such that the temperature did not rise above 20° C. Finally, the mixture was stirred at room temperature for 2 hours. Water (700 ml) was added and the layers were separated. The dichloromethane solution was washed with brine (500 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as an oil, 344 g.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]3[N:8]([N:9]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:16]=4)[C:11]=3[C:12]([NH2:14])=[O:13])[C:4]=2[CH:3]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>C(Cl)Cl>[C:30]([NH:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]3[N:8]([N:9]=[C:10]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:19][CH:20]=4)[C:11]=3[C:12]([NH2:14])=[O:13])[C:4]=2[CH:3]=1)(=[O:33])[CH:31]=[CH2:32]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1ccc(N)cc12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2c1
Yield: 8.3 %

Procedure:
To a solution of 7-amino-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide (45 mg, 0.11 mmol) in 10 mL of DCM at 0° C. was added TEA (36 mg, 0.35 mmol). Acryloyl chloride (11 mg, 0.12 mmol) in 2 mL of DCM was added dropwise over a period of 20 min. The mixture was stirred until TLC and LCMS analysis showed that most of starting material was consumed. The mixture was then partitioned between water (50 mL) and DCM (20 mL), extracted with additional 20 mL of DCM. The combined organic layer was washed with brine, dried over Na2SO4, concentrated and purified by Pre-TLC (DCM/MeOH=20/1) to get 4 mg (7.8%) of 7-acrylamido-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide as a grey solid. 1H NMR (400 MHz, CD3OD-d4) δ 8.25 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 7.05-6.90 (m, 4H), 6.42-6.25 (m, 2H), 5.69 (dd, J=9.6, 1.9 Hz, 1H). MS (ESI) m/e [M+1]+ 438.
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[C:7]([NH:10][C:11]1[S:12][C:13]([S:16](Cl)(=[O:18])=[O:17])=[N:14][N:15]=1)(=[O:9])[CH3:8].Cl>O>[C:7]([NH:10][C:11]1[S:12][C:13]([S:16]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])(=[O:17])=[O:18])=[N:14][N:15]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1nnc(S(=O)(=O)Cl)s1
Reactant: CCC(N)CC
Agent: Cl
Solvent: O
Product: CCC(CC)NS(=O)(=O)c1nnc(NC(C)=O)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1-Ethylpropylamine (0.1 mole) and water (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer. The solution is cooled to 20° C. and stirred while 2-acetamido-5-chlorosulfonyl-1,3,4-thiadiazole (0.1 mole) is added slowly while holding the reaction temperature between 0° C. and 20° C. At the conclusion of the addition, stirring is continued for a period of about 2 hours at room temperature. The reaction mixture is then neutralized with 6 N hydrochloric acid. Solids are filtered out, water washed and dried to yield the desired product 2-acetamido-5-[N-(1-ethylpropyl)aminosulfonyl]-1,3,4-thiadiazole.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][C:16]#[N:17]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:15](/[C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH3:10])[CH:13]=2)\[C:16]#[N:17])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(Br)cc2)cc1OC
Yield: 78.6 %

Procedure:
4-Bromobenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.9 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.9 g, yield: 78%).
Reaction SMILES: COC([C@H]1C[C@@H](O)CN1C(OC(C)(C)C)=O)=O.[CH3:18][O:19][C:20]([C@@H:22]1[CH2:26][C@H:25]([NH2:27])[CH2:24][N:23]1[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:21]>>[CH3:18][O:19][C:20]([C@H:22]1[CH2:26][C@H:25]([NH2:27])[CH2:24][N:23]1[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:21]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Agent: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Product: COC(=O)[C@H]1C[C@H](N)CN1CC1CCCCC1

Procedure:
(2R,4S)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C13H25N2O2 [(M+H)+] 241, obsd. 241.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([O:10][C:11](/[CH:13]=[CH:14]/[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=O)C>O1CCCC1>[CH3:4][O:3][P:2]([CH2:1][C:11](=[O:10])/[CH:13]=[CH:14]/[CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]1)([O:5][CH3:6])=[O:7]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)OC
Reaction time: 0.17 h

Procedure:
To a solution of 13.1 g (106 mM) of dimethyl methylphosphonate in 100 ml of tetrahydrofuran was added 69.2 ml (111 mM) of 1.6M n-butyllithium-hexane dropwise at −78° C. and the mixture was stirred at the prevailing temperature for 10 minutes. To this reaction mixture was added a solution of 14.271 g (50.362 mM) of tert-butyl (E)-4-(2-ethoxycarbonylvinyl)piperidine-1-carboxylate in 100 ml of tetrahydrofuran at −78° C. and the mixture was stirred until the temperature had recovered to room temperature. This reaction mixture was poured in aqueous solution of ammonium chloride and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate:1/1 to ethyl acetate) to provide the title compound.