Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[Na].C[O:6][C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:26])[NH:15][C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(O)(=O)C>CO.O.C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1>[OH:3][NH:2][C:7](=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:15][C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:26]
Reactant: NO
Reactant: COC(=O)CCCCCCC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCCCCCC(=O)NC12CC3CC(CC(C3)C1)C2)NO
Reaction time: 24 h
Yield: 68 %

Procedure:
To a first solution of hydroxylamine hydrochloride (66 mg, 0.950 mmol) and phenolphthalein (0.5 mg) in methanol (3 mL), was added dropwise a second solution of sodium metal (33 mg, 1.435 mmol) in methanol (3 mL) via additional funnel until a pink endpoint was reached and precipitate appeared. To the reaction mixture was added a solution of 7-(adamantan-1-yl-carbamoyl)-heptanoic acid methyl ester (152 mg, 0.474 mmol) in methanol (4 mL) was added, followed by the remainder of the second solution of sodium metal in methanol. The resulting reaction was allowed to stir for 24 hours, then the reaction mixture was diluted with water (15 mL), followed by glacial acetic acid (0.2 mL) with stirring. The resulting precipitate was suction filtered and rinsed using water, then dried at room temperature under vacuum to provide a crude residue which was purified by recrystallization from dichloromethane/hexane to provide Compound 17 (104 mg, 68% yield). 1H NMR (300 MHz, CD3OD) δ 7.31 (br s, 1H), 2.09 (t, J=7.5 Hz, 2H), 2.08-1.98 (m, 11H), 1.71 (m, 6H), 1.59 (m, 4H), 1.33 (m, 4H). 13C NMR (75 MHz, CD3OD) δ 175.7, 173.1, 52.8, 42.5, 38.0, 37.7, 33.9, 31.1, 30.00, 29.96, 27.2, 26.8.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[S:13][C:6]=12.[OH-].[K+]>C1COCC1>[F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([OH:16])=[O:15])[S:13][C:6]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 95.8 %

Procedure:
To a stirred solution of 38 (2.5 g, 7.18 mmol) in THF (50 ml) was added KOH (14.3 ml, 1.0 N in H2O, 14.3 mmol). After 4 hours the reaction mixture was concentrated and the resultant residue was dissolved in H2O (50 ml). The aqueous layer was then washed with ethyl acetate and acidified with 1N HCl (pH=1). The precipitate that formed upon acidification was collected by filtration, washed with water and dried under high vacuum to afford title compound 39 (2.3 g, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.6 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.8 and 10.4 Hz, 1H), 8.20 (m, 1H), 8.17 (s, 1), 7.76 (dd, J=8.0 and 8.8 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Oc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-difluorophenol (10 g, 76.9 mmol) in CH2Cl2 at 0° Celsius was added 4.9 mL of 70% nitric acid dropwise. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was poured into a separatory funnel and washed once with 750 mL water. The organic layer was dried with Na2SO4, filtered and concentrated to dryness. The resulting residue was purified via FCC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 6.81-6.67 (m, 2H), 3.40 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[NH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])[CH2:21][CH:22]1[CH2:24][CH2:23]1)(=[O:19])[NH2:20]
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(Br)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=382.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH3:2]
Reactant: CCOC(=O)Cc1cccs1
Reactant: ClCCCCCCl
Product: CCOC(=O)C1(c2cccs2)CCCCC1

Procedure:
The dialkylation of (1) was performed as described in Example 1, Step 1 using 1,5-dichloropentane to obtain the title compound (15).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:39]([CH2:40][CH3:41])[CH2:37][CH3:38])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CCNCC
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(CC)CC)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 29) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloro-methane and subsequent treatment of the corresponding chloride with diethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (123 mg, 50%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:19]=[C:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH:12]=[O:11]
Reactant: O=C1CCCN1CCO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCN1CCCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.87 mL, 10 mmol) was added dropwise to a solution of DMSO (0.71 mL, 10 mmol) in CH2Cl2 (7 mL) cooled to −78° C. After stirring 15 min at this temperature, 1-(2-hydroxyethyl)-2-pyrrolidinone (1 g, 7.7 mmol) was added dropwise. The mixture was stirred 30 min at −78° C. and Et3N (2.8 mL, 20 mmol) was added dropwise. After allowing the reaction to warm to rt, a solution of NaHCO3 was added and the mixture was extracted with CH2Cl2 (6×). The combined organic layers were dried and concentrated to give the product as an oil: 1H NMR (CDCl3) δ 9.60 (1H, s), 4.16 (2H, s), 3.46 (2H, t, J=7 Hz), 2.45 (2H, t, J=8 Hz), 2.11 (2H, m).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].ClB([C@H]1C[C@H]2C[C@H](C2(C)C)[C@@H]1C)[C@H]1C[C@H]2C[C@H](C2(C)C)[C@@H]1C.[F:28][C:29]([F:58])([F:57])[C:30]1[CH:31]=[C:32]([C@H:40]([O:42][C@@H:43]2[C@@H:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@H:47]([CH:55]=[O:56])[CH2:46][CH2:45][O:44]2)[CH3:41])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C([O-])(=O)C.[Na+].OO>C(OCC)C>[CH2:3]([C@H:55]([C@@H:47]1[CH2:46][CH2:45][O:44][C@H:43]([O:42][C@@H:40]([C:32]2[CH:31]=[C:30]([C:29]([F:57])([F:28])[F:58])[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=2)[CH3:41])[C@H:48]1[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[OH:56])[CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Agent: OO
Solvent: CCOCC
Product: C=CC[C@@H](O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Allylmagnesium bromide (15.4 mL, 15.4 mmol) was slowly added to a stirred, cooled −40° C. solution of chlorobis[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]borane (5.91 g, 18 mmol) in diethyl ether (20 mL). The mixture was warmed to room temperature and stirred for 1 hour before cooling to −78° C. (2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde (WO 00/56727A1; 5.5 g, 12.3 mmol) in diethyl ether (10 mL) was slowly added and the mixture was stirred at −78° C. for 1.5 hours. The mixture was warmed to room temperature and stirred for a further 1.5 hours. The mixture was cooled to −78° C. and aqueous sodium acetate (3M, 20 mL) then aqueous hydrogen peroxide (31% wt, 10 mL) were added. The mixture was allowed to warm to room temperature and stirred overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (90:10), to give the title compound as a yellow oil (4.7 g, 78%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:18]2[CH:19]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH3:10]
Reactant: CCOc1ccnc(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOc1ccnc(-c2cccc([N+](=O)[O-])c2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a suspension of 2-bromo-4-ethoxypyridine (879 mg), 3-nitrophenylboronic acid (944 mg) and tetrakis(triphenylphosphine)-palladium (251 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (5.66 ml). The mixture was stirred at 90° C. for 8 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g, 25% ethyl acetate in n-hexane) to give 3-(4-ethoxypyridin-2-yl)nitrobenzene (887 mg).
Reaction SMILES: C(OP(=O)(OCC)O[CH2:6]/[CH:7]=[CH:8]/[C:9](=[O:16])[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)C.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=1[CH:25]=O.CC(C)([O-])C.[K+]>C1COCC1>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=1/[CH:25]=[CH:6]/[CH:7]=[CH:8]/[C:9]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:16]
Reactant: CCOP(=O)(OCC)OC/C=C/C(=O)N1CCCCC1
Reactant: COc1ccc(OC)c(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(/C=C/C=C/C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
(E)-diethyl 4-oxo-4-(piperidin-1-yl)but-2-enylphosphoric acid (50 mg, 0.17 mmol) and 2,5-dimethoxybenzaldehyde (28.4 mg, 0.17 mmol) were dissolved in THF (1.5 mL) at −10° C., and then potassium tert-butoxide (0.51 mL, 0.51 mmol) was added thereto, followed by stirring at the same temperature for 20 minutes under anhydrous reaction conditions. The temperature of the mixture was raised to room temperature, and the reaction was terminated by the addition of distilled water. After EtOAc was added, the oil layer was separated, followed by washing with distilled water and a saturated solution of NaCl, drying over anhydrous Na2SO4, and then filtering. The filtrate was distilled under reduced pressure, and the thus obtained residue was purified by column chromatography (hexane:EtOAc (2:1)) to give a target compound (40.7 mg, yield: 78.6%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:21]=[CH:20][C:19]3[C:10](=[C:11]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:12]4[C:17]([C:18]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)=[CH:4][CH:3]=1.[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[S:39][C:38]=2[C:37]([C:47]2[CH:48]=[CH:49][C:50]3[NH:51][C:52]4[C:57]([C:58]=3[CH:59]=2)=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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].CCCCCC.C1(C)C=CC=CC=1>[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[S:39][C:38]=2[C:37]([C:47]2[CH:48]=[CH:49][C:50]3[N:51]([C:2]4[CH:3]=[CH:4][C:5]([C:8]5[CH:21]=[CH:20][C:19]6[C:10](=[C:11]([C:28]7[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=7)[C:12]7[C:17]([C:18]=6[C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)=[CH:16][CH:15]=[CH:14][CH:13]=7)[CH:9]=5)=[CH:6][CH:7]=4)[C:52]4[C:57]([C:58]=3[CH:59]=2)=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:36][CH:35]=1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3sc3ccccc34)cc12
Reactant: Brc1ccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4ccc(-n5c6ccccc6c6cc(-c7cccc8c7sc7ccccc78)ccc65)cc4)ccc23)cc1
Yield: 61 %

Procedure:
In a 50-mL three-neck flask were put 1.3 g (2.7 mmol) of 2-(4-bromophenyl)-9,10-diphenylanthracene, 0.93 g (2.7 mmol) of 3-(dibenzothiophen-4-yl)-9H-carbazole, and 0.76 g (8.0 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 20 mL of toluene and 0.2 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 76 mg (0.13 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 4 hours under a nitrogen stream. After the stirring, the obtained mixture was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and the filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (a developing solvent in which the hexane/toluene ratio was 5:1). A suspension was formed by addition of toluene/hexane to the obtained solid, and the suspension was irradiated with ultrasonic wave. Then, a solid was collected by suction filtration, so that 1.2 g of a yellow solid which was the object of the synthesis was obtained in a yield of 61%. The synthesis scheme of Step 2 is illustrated in (b-14).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CN1CCCC1=O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:9]=[C:10]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:4]3[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Reactant: Oc1ccc(Br)cc1
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc(Br)cc2)cc2nc(-c3ccco3)nn12

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. p-bromo-phenol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 371 M+ (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12].[BH4-].[Na+]>CO>[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH:20][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[Cl:1])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-4-fluoro-benzaldehyde (742 mg, 4.68 mmol) in MeOH (16 mL), add N-(2-aminoethyl)carbamic acid tert-butyl ester (500 mg, 3.12 mmol) and stir at RT for 4 hours. Cool reaction to 0° C. and slowly add NaBH4 (1.42 g, 37.4 mmol). Allow reaction to slowly warm to RT and stir for 12 hours. Quench reaction with 1N NaOH (80 mL) and extract with CH2Cl2 (40 mL). Dry organic layer over Na2SO4 and concentrate to afford the title compound. Quantitative yield. MS (IS) 303.1 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:18][CH3:19]>>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Product: COc1cc(C(=O)O)ccc1OC(C)=O
Temperature: 25 °C

Procedure:
Acetic anhydride (72.9 g, 67.4 mL) is added under nitrogen at room temperature to 4-hydroxy-3-methoxybenzoic acid (97.7 g) in xylenes (817 g, 950 mL) while stirring. The stirred mixture is heated to 115°-125° C. and heated at 120°-125° C. for 4 to 20 hours under nitrogen. Part of the liquid is then removed by distillation at about 150° bath temperature to a volume of about 700 ml and the mixture is cooled to room temperature to obtain a slurry of 4-acetoxy-3-methoxybenzoic acid which is again diluted with additional xylenes (224 g, 226 mL). N,N-dimethylformamide (DMF, 1.9 g, 2.0 mL) is added followed by dropwise addition, over 2.5 hours, of oxalyl chloride (90.6 g, 62.2 mL). The reaction mixture is stirred at room temperature for 24 hours to obtain a solution of 4-acetoxy-3-methoxybenzoyl chloride which is used as such in the next step. The xylenes solution is cooled to -14° to -20° C. with a brine solution and diisopropylamine (169 g, 234 mL) is added dropwise over a 45 minute period, at a rate so that the temperature does not exceed 0° C. The reaction mixture is allowed to warm to room temperature and is stirred at room temperature (17°-20° C.) for 21 hours. The resulting slurry is filtered under vacuum, and the filter cake is further slurred with xylenes (430 mL) and filtered.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:12]([NH:19][C:20]1[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[S:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>O.C1C=CC=CC=1>[CH2:1]([N:19]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:20]1[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[S:23][C:24]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: c1ccc(CNc2c(-c3ccccc3)sc3ccccc23)cc1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1
Yield: 62.9 %

Procedure:
40.2 g (0.33 mol) of benzoic acid are added to 100 milliliters of absolute benzene and, by cooling and stirring, 3.78 g (0.1 mol) of NaBH4 are added in portions sufficiently slowly for the temperature not to exceed 20° C. After the addition of 6.3 g (20 mmol) of 3-benzylamino-2-phenyl-benzo(b)thiophene the mixture is refluxed for 60 minutes. The still hot reaction mixture has added to it by stirring half a liter of water and is neutralised by ammonia. By evaporating the organic phase dried over K2CO3 and recrystallising the residue in ethanol, 5.1 g (41% of theory) of 3-dibenzylamino-2-phenyl-benzo(b)thiophene are obtained, colourless crystals, mp 98°-100° C.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[CH:14]1([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:19][N:18]=2)[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH:14]1([C:17]2[N:18]=[CH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][N:28]([S:10]([CH2:9][C@@:2]3([CH3:1])[NH:3][C:4](=[O:8])[NH:5][C:6]3=[O:7])(=[O:12])=[O:11])[CH2:27][CH2:26]4)=[CH:21][N:22]=2)[CH2:16][CH2:15]1
Reactant: c1cc2c(cc1-c1cnc(C3CC3)nc1)CCNC2
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4cnc(C5CC5)nc4)ccc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.020 g, 0.087 mmol) in anhydrous THF (0.40 mL) was added dropwise to a stirred solution of 6-[2-(cyclopropyl)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline (0.023 g, 0.091 mmol), DIPEA (0.022 mL, 0.13 mmol) and dry THF (0.50 mL) at RT. After the addition was complete, the solution was stirred at RT for 2 h and then taken up in water-brine and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give a crude product. Purification by preparative HPLC afforded 0.021 g (50%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][C:26]([NH:29][S:38]([CH3:37])(=[O:40])=[O:39])([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NS(C)(=O)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 64.3 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (1 eq, 36.5 mg, 0.068 mmol), methanesulfonyl chloride (2 eq, 0.01 mL, 0.135 mmol), and triethylamine (3 eq, 0.03 mL, 0.203 mmol) was stirred in tetrahydrofuran for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)methanesulfonamide (27 mg, 65%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.18 (d, J=4.52 Hz, 6H) 2.21-2.37 (m, 2H) 2.39-2.61 (m, 2H) 3.65 (t, J=10.69 Hz, 1H) 3.86 (t, J=10.93 Hz, 1H) 4.07-4.20 (m, 2H) 4.29 (d, J=13.75 Hz, 1H) 5.30 (s, 1H) 7.03-7.11 (m, 2H) 7.15-7.21 (m, 1H) 7.21-7.38 (m, 4H) 7.38-7.47 (m, 2H) 7.47-7.55 (m, 2H).