Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]5[NH:40][C:39]([C@@H:41]6[CH2:46][C@@H:45]7[C@@H:43]([CH2:44]7)[N:42]6[C:47]([O:49][CH2:50][C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)=[O:48])=[N:38][CH:37]=5)=[CH:32][CH:31]=3)[CH:24]=[CH:23]4)=[CH:18][N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C@@H:10]12[CH2:11][C@@H:12]1[CH2:13][C@@H:14]([C:15]1[NH:16][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([C:36]5[NH:40][C:39]([C@@H:41]6[CH2:46][C@@H:45]7[C@@H:43]([CH2:44]7)[N:42]6[C:47]([O:49][CH2:50][C:51]6[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=6)=[O:48])=[N:38][CH:37]=5)=[CH:34][CH:35]=3)[CH:24]=[CH:23]4)=[CH:18][N:19]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OCc6ccccc6)[nH]5)cc4)ccc3c2)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6)[nH]5)ccc4c3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.4 %

Procedure:
A solution of 4.0 M HCl (1.167 mL, 4.67 mmol) in dioxane was added to a stirred solution of (1R,3S,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (228 mg, 0.311 mmol) in dioxane (3 mL) and the reaction was stirred vigorously at rt for 3 h. The reaction was concentrated to yield an HCl salt of (1R,3S,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (233 mg) as a yellow solid. LC-MS retention time 3.988 min; m/z 633.18 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.44 (s, 1 H), 8.28 (s, 1 H), 8.08-8.18 (m, 3 H), 7.92-8.02 (m, 4 H), 7.84 (br. s., 3 H), 7.31 (br. s., 5 H), 5.21 (d, J=12.1, 1 H), 4.95-5.05 (m, 2 H), 4.80-4.91 (m, 1 H), 3.70-3.77 (m, 1 H), 3.59-3.67 (m, 1 H), 2.77-2.93 (m, 2 H), 2.74 (dd, J=13.4, 9.2 Hz, 1 H), 2.46 (dt, J=13.5, 6.7 Hz, 1 H), 2.12-2.22 (m, 1 H), 1.83-1.96 (m, 1 H), 1.27-1.35 (m, 1 H), 1.09 (q, J=7.9 Hz, 1 H), 0.95 (ddd, J=8.7, 5.9, 5.8 Hz, 1 H), 0.75-0.83 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[C:19]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1[CH2:45][CH2:44]OCC1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([CH3:17])[C:18]2[C:19]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[N:20][C:21]([N:22]3[CH2:45][CH2:44][N:16]([CH3:14])[CH2:18][CH2:23]3)=[N:22][CH:23]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1COCCO1
Reactant: Cc1ccccc1Oc1nc(S(C)(=O)=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1Oc1nc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 97.2 %

Procedure:
To a solution of 0.22 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2-methanesulfonyl-4-o-tolyloxy-pyrimidin-5-yl)-N-methyl-isobutyramide in 10 ml dioxane 0.106 ml (0.96 mmol) I-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml sat. NaHCO3-solution. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.11 g (48%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyloxy-pyrimidin-5-yl]-isobutyramide as a white foam, MS (ISP): 596.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@@H:20]([O:35][CH2:36][CH3:37])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>CN1CCCC1>[Cl:32][C:31]1[C:30]([Cl:33])=[C:29]([CH3:34])[NH:28][C:27]=1[C:25]([NH:24][C@@H:21]1[CH2:22][CH2:23][N:18]([C:10]2[S:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:5]3[CH:4]=[N:3][C:2]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:7][N:6]=3)[N:9]=2)[CH2:19][C@@H:20]1[O:35][CH2:36][CH3:37])=[O:26]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OCC)C2)nc1-c1cnc(Cl)cn1
Reactant: C1CCNCC1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OCC)C2)nc1-c1cnc(N2CCCCC2)cn1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a stirred solution of ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 66, 120 mg, 0.204 mmol) and piperidine (87 mg 1.023 mmol) in N-methyl pyrrolidine was added N,N-diisopropyl ethylamine; the reaction mixture was then stirred over night at 80° C. The reaction mixture was cooled to room temperature and poured on to ice cold water. The precipitated product was collected by filtration and dried to afford 120 mg (92%) of ethyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28]>C(=O)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:28][CH2:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])([C:26]([O:30][CH2:31][CH3:32])=[O:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccc(Cl)cc1
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)CCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Temperature: 25 °C

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (10 g) is dissolved in diethyl carbonate (150 ml) in a nitrogen stream, and 60% sodium hydride (2.0 g) is added with stirring at room temperature. The mixture is refluxed under heating for 2 hours and cooled to 50° C. with ice water. Ethyl acrylate (5.4 ml) is added. After stirring at 50° C. for 3 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) to give 3.2 g of (±)-ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)propionate as an oil. (±)-Ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionate (3.2 g) is dissolved in a mixture of ethanol (90 ml) and water (30 ml), and barium hydroxide 8 hydrate (7.8 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 6N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether to give 0.1 g of (±)-3-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionic acid as brown crystals, melting point 210°-212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)([O-])=O>C(OCC)(=O)C.CO>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[NH2:1])=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc2[nH]ncc2c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Under a hydrogen atmosphere at atmospheric pressure, a solution of the 5-(2-nitrophenoxy)-1H-indazole (56.7 mg, 0.222 mmol) obtained in Example 352 in a mixture of ethyl acetate (3 ml) and methanol (3 ml) was stirred at room temperature for 1.5 hours. The solution was filtered and then the filtrate was concentrated to obtain 2-(1H-indazol-5-yloxy)aniline (34.5 mg, 69%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:12](=[O:20])[C@@H:11]([NH:21]C(=O)OC(C)(C)C)[CH2:10]1.[ClH:29]>CCOC(C)=O>[ClH:29].[NH2:21][C@H:11]1[CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:14][N:13]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:12]1=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1C[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate (1.50 g, 3.67 mmol) in EtOAc (30 mL) at 0° C. was saturated with HCl (g) and aged for 30 min. The resulting mixture was concentrated in vacuo to give the title compound. MS: m/z=309.0 (M+1); 1H NMR (500 MHz, CD3OD) δ 7.29-7.17 (m, 3H), 4.36-4.25 (m, 2H), 4.12 (dq, 1H, J=15.1, 9.3 Hz), 3.84 (m, 1H), 3.75 (ddd, 1H, J=12.0, 5.4, 1.7 Hz), 3.64 (t, 1H, J=11.6 Hz), 2.46 (m, 1H), 2.37 (q, 1H, J=12.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[NH2:12][C@@H:13]1[C@@H:18]2[CH2:19][C@@H:15]([CH2:16][CH2:17]2)[C@@H:14]1[CH2:20][OH:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:12][C@H:13]2[C@@H:14]([CH2:20][OH:21])[C@H:15]3[CH2:19][C@@H:18]2[CH2:17][CH2:16]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Reactant: N#Cc1cnc(N)cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(N)cc1N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 280 mg, 2.04 mmol) and racemic ((1R*,2S*,3R*,4S*)-3-aminobicyclo[2.2.1]heptan-2-yl)methanol hydrochloride (435 mg, 2.45 mmol) in NMP (5 ml) was treated with DIPEA (1.07 ml, 6.13 mmol), stirred at 100° C. for 6 h and at 180° C. (MW) for 30 min. The reaction mixture was diluted in EtOAc and washed with water (2×) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. (UPLC-MS 3) tR 0.53 min; ESI-MS 259.2 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1.C(N(CC)CC)C>C(#N)C>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:5][CH2:4][C:3]([F:7])([F:6])[F:2])[CH:9]=1
Reactant: O=Cc1cccnc1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)CN=Cc1cccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of 2,2,2-Trifluoroethylamine hydrochloride (3.98 g, 29.4 mmol) in acetonitrile (9 mL) was added 3-pyridinecarboxaldehyde (Sigma-Aldrich) (2.1 g, 19.6 mmol) followed by triethylamine (4 ml, 29.43 mmol) at 0° C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered and the solids washed with acetonitrile. The filtrate was then concentrated in vacuo. The residue was taken up in ethyl ether, filtered and concentrated to afford 3.12 g (84%) of the tile compound as a white foam. 1H NMR (300 MHz, DMSO-d6) δ4.40 (m, 2H), 7.52 (m, 1H), 8.18 (m, 1H), 8.61 (s, 1H), 8.70 (dd, J=1.8, 4.8 Hz, 1H), 8.92 (d, J=1.8, 1H). MS (ESI, [M+H] +), 189.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][N:13]3[CH:19]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]3[C:17](=[O:18])[N:16]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:15][CH2:14][N:13]3[CH:19]=2)=[CH:21][CH:22]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(COc2cn3c(cc2=O)C(=O)NCC3)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cn3c(cc2=O)C(=O)N(CCN2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of 7-((4-methoxybenzyl)oxy)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (4.15 g, 13.82 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added sodium hydride (1.382 g, 34.5 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Then the mixture of 1-(2-chloroethyl)pyrrolidine, hydrochloride (Aldrich) (2.90 g, 17.03 mmol) and triethylamine (2.438 mL, 17.49 mmol) in N,N-dimethylformamide (DMF) (25.00 mL) was added. The reaction was stirred at 50° C. for 30 h. The solvent was evaporated and the residue was dissolved in water (50 mL) and extracted with dichloromethane (50 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to afford light yellow crude product, which was then purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with dichloromethane/methanol/ammonium hydroxide (v:v:v=80:20:2) over 16 min to afford 7-((4-methoxybenzyl)oxy)-2-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (3 g, 7.55 mmol, 54.6% yield) as light yellow solid. LCMS (M+H)+: 398.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[CH2:13]([Br:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br-:20].[CH2:13]([N:4]1[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][N+:2]([CH3:1])=[CH:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cnc(-c2ccccc2)c1
Reactant: BrCc1ccccc1
Solvent: Cc1ccccc1
Product: C[n+]1cc(-c2ccccc2)n(Cc2ccccc2)c1
Product: [Br-]
Yield: 75.1 %

Procedure:
In a 25 ml one-necked flask, there is dissolved 0.320 g (2.023 mmol) of 1-methyl-4-phenylimidazole, which was obtained according to P. Benjes et al., Heterocycles (1994), 37(2), 735-38, in 10 ml of toluene and then 0.36 ml (3.035 mmol) of benzyl bromide is added. After 5 days of heating under reflux, the reaction medium is concentrated under reduced pressure. The residue is taken up in 50 ml of diisopropyl ether. The precipitate formed is drained, washed twice with 5 ml of diisopropyl ether, and then dried under reduced pressure. 0.500 g (90%) of 3-benzyl-1-methyl-4-phenylimidazolium bromide is thus obtained in the form of a beige-grey solid whose characteristics are the following:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5Br)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Nc1ccc2[nH]cc(-c3ccccc3)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 130 °C

Procedure:
Phenyl boronic acid (24.6 mg, 0.204 mmol) was added to a solution of 1-(benzo[d][1,3]-dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (39.9 mg, 0.100 mmol) in ethanol (1 mL) containing FibreCat 1001 (6 mg) and 1M aqueous potassium carbonate (0.260 mL). The reaction mixture was then heated at 130° C. in a microwave reactor for 20 minutes. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-phenyl-1H-indol-5-yl)cyclopropane carboxamide. ESI-MS m/z calc. 396.2, found 397.3 (M+1)+. Retention time of 3.52 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.27 (d, J=1.9 Hz, 1H), 8.66 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.65-7.61 (m, 3H), 7.46-7.40 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 7.25-7.17 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.06-1.02 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][CH:13](Br)C.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: N#CCc1ccccc1Cl
Reactant: CC(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccccc2Cl)CC1

Procedure:
A solution of 13.1 g of 2-chlorophenylacetonitrile and 20.3 g of 1,2-dibromopropane in 142 ml of DMF is mixed with 9 g of sodium hydride [55-65% in oil] at room temperature. It is stirred for several hours and carefully added to water. After extraction with ethyl acetate and filtration by silica gel, the desired product is obtained: 13.1 g
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]([N+:12]([O-:14])=O)=[C:8]([CH:11]=2)[CH:9]=O)[CH2:3][CH2:2]1.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.[C-:26]#[N:27].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:9]([C:26]#[N:27])=[C:8]3[C:7]([CH:6]=[C:5]([N+:15]([O-:17])=[O:16])[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:11]3)=[N+:12]2[O-:14])=[CH:21][CH:20]=1
Reactant: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [C-]#N
Reactant: Nc1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a stirred suspension of compound (iv) (6.2 g, 0.026 mol) in acetic acid (120 mL) was added 4-bromoaniline (9.28 g, 0.054 mol) and the reaction mixture was heated to 60° C. to get a clear solution. To this was added sodium cyanide portionwise (6.2 g, 0.127 mol) and the reaction mixture was stirred at 60° C. for 5 min. Acetic anhydride (1.9 mL, 0.020 mol) was added and the reaction mixture was stirred for 5 min at the same temperature. Sodium cyanide (6.2 g, 0.127 mol) was then added at the same temperature at which time the product precipitated out. The reaction mixture was stirred for 30 min at this temperature and diluted with water (50 mL), filtered and washed with ethanol to give 2-(4-bromophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile 1-oxide (v) (4.1 g, 39%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:7]2[CH2:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[F:16][C:13]([F:14])([F:15])[CH2:12][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([NH2:1])[CH:17]=[C:7]2[CH2:8]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)(F)F)C2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCN(CC(F)(F)F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 134a (390 mg, 1.56 mmol) in ethanol (20 mL) was added Pd/C (about 200 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated under reduced pressure to afford 134b as a yellow solid (308 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 221.1
Reaction SMILES: C1C=CC(/C=C/C[O:10][C@@H:11]2[O:16][C@H](CO)[C@@H:14]([OH:19])[C@H:13](O)[C@H:12]2O)=CC=1.C1(=O)OC(=[O:26])C=C1.[S:29]([O-:32])([O-:31])=[O:30].[Na+].[Na+]>>[S:29]([CH:13]([CH2:12][C:11]([OH:10])=[O:16])[C:14]([OH:19])=[O:26])([OH:32])(=[O:31])=[O:30]
Reactant: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=S([O-])[O-]
Reactant: O=C1C=CC(=O)O1
Agent: [Na+]
Product: O=C(O)CC(C(=O)O)S(=O)(=O)O

Procedure:
926 Parts of the above rosin addition product are reacted according to Example A (b) with 98 parts of maleic anhydride and 132.3 to 138.6 parts of sodium sulfite to give the sulfosuccinic acid semiester.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:5](=[O:7])[CH3:6])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)cc(Cl)c1
Product: CC(=O)Nc1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Acetic anhydride (6.7 mL) and 3-chloro-5-methyl-phenylamine (5.0 g, 35 mmol) was mixed and stand for 2.0 h. The reaction mixture was cooled to room temperature to give N-(3-chloro-5-methyl-phenyl)acetamide (5.1 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 6.91 (s, 1H), 2.31 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9](N(OC)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:24]1>>[CH2:1]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:9](=[O:10])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Product: CC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 26.7 g of tert-butyl (1R)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate in 534 cm3 of tetrahydrofuran dried over 4 Å sieves is cooled, under an inert atmosphere, to a temperature in the region of 0° C. 87 cm3 of a 3 M solution of methylmagnesium bromide in diethyl ether are then added over 45 minutes and the resulting mixture is then stirred for 1 hour at 0° C. and for 18 hours at room temperature. The reaction medium is re-cooled to a temperature in the region of 0° C., 55 cm3 of 1N hydrochloric acid are then added dropwise and the mixture is stirred for 30 minutes at this temperature. After filtration through Celite, 200 cm3 of water are added to the filtrate, which is then extracted with twice 200 cm3 of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 21.2 g of tert-butyl (1R)-1-benzyl-2-oxopropylcarbamate are obtained in the form of yellow crystals melting at 59° C. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.34 (s: 9H); 2.13 (s: 3H); 2.71 (dd, J=14 and 10 Hz: 1H); 3.01 (dd, J=14 and 5 Hz: 1H); 4.13 (mt: 1H); from 7.10 to 7.35 (mt: 6H).