Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:31]1C=CC=C[CH:32]=1>C(OCC)(=O)C.CN>[N:1]1([C@@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12][NH:31][CH3:32])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC[C@@H](O)[C@H](c1cccs1)n1ccc2ccccc21
Reactant: c1ccncc1
Agent: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CNC[C@@H](O)[C@H](c1cccs1)n1ccc2ccccc21
Reaction time: 16 h
Yield: 71 %

Procedure:
(2S,3R)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol (102 mg, 0.37 mmol) was dissolved in pyridine (1.5 mL), para-toluenesulfonyl chloride (88 mg, 0.46 mmol) was added and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of copper sulfate, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0%-100% ethyl acetate in hexane) to afford 140 mg that was immediately dissolved in methylamine (8M solution in ethanol, 15 mL) and stirred for 3 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, gradient 2%-10% methanol saturated with ammonia in chloroform) to give 65 mg (71%) of (1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol as a colorless oil. The freebase was dissolved in diethyl ether (5 mL) and treated with a 1 N ethereal solution of hydrochloric acid (0.23 mL, 0.23 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give (1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol hydrochloride. HRMS: calcd for C16H18N2OS+H+, 287.12126; found (ESI, [M+H]+), 287.1209
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(c2ccccc2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=576.0 (M+H+), was prepared in accordance with the general method of example 62 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 4 phenylboronic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19][CH3:20])=[O:18])[CH2:8][NH:9]C(OC(C)(C)C)=O)=[O:5]>FC(F)(F)C(O)=O.ClCCl>[NH2:9][CH2:8][C@@H:7]([C:17]([O:19][CH3:20])=[O:18])[NH:6][C:4](=[O:5])[C:3]1[C:2]([CH3:1])=[CH:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])=[CH:22][C:21]=1[CH3:36]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1C

Procedure:
A solution of crude N-[2,6-dimethyl-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (144 mg, 0.235 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with saturated aqueous sodium hydrogen carbonate, and the aqueous layer was back-extracted seven times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, and evaporated to give crude 3-amino-N-[2,6-dimethyl-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (104 mg, 110% of the theoretical amount).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[I-].[Na+].[N:29]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([C:20]2[O:21][C:22]([CH2:25][NH:38][CH2:37][CH2:36][CH2:35][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: NCCCN1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cc(-c2nnc(CNCCCN3CCOCC3)o2)c2cn[nH]c2c1
Temperature: 70 °C
Yield: 117.8 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (300 mg, 0.661 mmol) and sodium iodide (99 mg, 0.661 mmol) were weighed into a round-bottomed flask and dissolved in acetonitrile (2 ml) before [3-(4-morpholinyl)propyl]amine (191 mg, 1.322 mmol, available from Sigma-Aldrich) and DIPEA (0.231 ml, 1.322 mmol) were added. The mixture was heated to 70° C. for 2 h, then cooled and the solvent removed under a stream of nitrogen. The crude residue was dissolved in DCM/MeOH (1:1) and preabsorbed onto silica which was then added to the top of a 20 g silica cartridge that was subsequently eluted with 0-15% MeOH (+1% triethylamine)/DCM over 20 mins. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a yellow oily solid (328 mg).
Reaction SMILES: [CH:1]([O-])=O.[NH4+].Cl[C:6]1[CH:7]=[C:8]([C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1)[C:9]([OH:11])=[O:10]>CO.[C].[Pd]>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[N:14][CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:1])=[O:10]
Reactant: O=C[O-]
Reactant: O=C(O)c1cc(Cl)ncc1C(F)(F)F
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 49 %

Procedure:
Ammonium formate (500 mg) and 10% palladium carbon (270 mg) were added to a solution of 2-chloro-5-(trifluoromethyl)isonicotinic acid (1.04 g) in methanol (10 ml), followed by stirring at room temperature for 13 hours. An insoluble substance was removed by celite filtration and the filtrate was concentrated. Thionyl chloride (5 ml) was added to a solution of the resulting residue in methanol (30 ml), followed by heating to reflux for 15 hours. The reaction solution was concentrated, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain methyl 3-(trifluoromethyl)isonicotinate (463 mg) as an orange solid.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:13][O:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CO[C@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.207 g, 1.09 mmol), crude tert-butyl (3S)-3-methoxypyrrolidine-1-carboxylate (See Intermediate 60) (0.50 g, 1.09 mmol) and ethanol (2 mL) to give the title compound as a dark orange coloured oil (0.42 g): MS (m/e): 102 (M+1).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][CH2:6][C@@H:7]([CH3:28])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1.S(Cl)([Cl:32])(=O)=O.Cl>N1C=CC=CC=1>[C:1]([OH:4])(=[O:3])[CH3:2].[Cl:32][C:16]1[C:17](=[O:27])[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:15]=1[CH2:14][CH2:13][C@@H:12]1[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]1[CH2:10][CH2:9][C@@H:8]2[C@H:7]([CH3:28])[CH2:6][OH:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a stirred solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one acetate (10.2 g, 27.38 mmol) in pyridine (100 mL) cooled to 15° C. there was added sulfuryl chloride (4.4 mL, 54.76 mmol) dropwise. After 30 minutes, the reaction mixture was poured into 1N hydrochloric acid and extracted with ether. The combined organic extracts were successively washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. The solution was then dried over magnesium sulfate and concentrated to give an orange solid. Flash chromatography of this material [eluting with ethyl acetate-hexane (3:7)] gave (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate as a white solid (8.5 g, 72%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.Cl>CC(N(C)C)=O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCCc1ccccc1

Procedure:
A solution of 15.3 g of 2-chloro-5-nitrobenzoic acid and 49 g of 3-phenylpropylamine in 60 ml of dimethylacetamide is heated at 145° C. for 2 hours. After cooling, 300 ml of water are added, and the mixture is acidified (pH 2 to 1) with 2 N HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH2:15]3)[C:12]=2[C:6]2[O:7][CH:8]([CH2:10][NH2:11])[CH2:9][C:5]=2[CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].CC1C=CC(S(OC)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH2:15]3)[C:12]=2[C:6]2[O:7][CH:8]([CH2:10][NH:11][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:9][C:5]=2[CH:4]=1
Reactant: COc1cc2c(c3c1C1CCC3CC1)OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c3c1C1CCC3CC1)OC(CNC(=O)OCc1ccccc1)C2
Yield: 92.6 %

Procedure:
Treatment of (±)-1-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methanamine (2.5 g, 8.45 mmol) with diisopropylethylamine (2.73 g, 21.12 mmol) followed by benzyl chloroformate (1.73 g, 10.14 mmol) generally according to the procedure described for Intermediate 7 provided 3.08 g (93%) of (±)-benzyl (5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methylcarbamate as a colorless oil. Chiral HPLC separation of (±)-benzyl (5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methylcarbamate (Chiralcel OJ, methanol) provided two fractions. Fraction 1 (Rt=13.252 min, Chiralcel OJ, methanol); Fraction 2 (Rt=18.196 min, Chiralcel OJ, methanol). Treatment of 0.460 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methylcarbamate (Chiralcel OJ, methanol) with palladium on carbon (10 wt. %, 0.05 g) generally according to the procedure described for Example 2 provided 0.304 g (88%) of (+)-1-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. [α]D5=+40.03 (c 9.99 in methanol); mp>220° C.; Anal. calcd. for C16H21NO2HCl: C, 64.97; H, 7.5; N, 4.74. Found: C, 64.62; H, 7.79; N, 4.54.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])(=O)C.[Na+].C(O)(=O)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:21]([NH:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1

Procedure:
A four neck flask (1 liter) equipped with a thermometer and a stirrer was charged with 60.8 g (0.4 mol) of salicylohydrazide, 49.2 g (0.6 mol) of sodium acetate and 700 ml of acetic acid. Dropwise added thereto was 67.4 g (0.48 mol) of benzoyl chloride in one hour while stirring, and stirring was continued at room temperature (20° C.) for 3 hours. After finishing the reaction, 1.5 liter of deionized water was added and crystal was filtered off. After washing sufficiently the crystal with 500 ml of methanol, it was dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH2:38])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][N+:17]([O-:21])=[CH:16][C:15]=1[Cl:22])=[O:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([S:55](Cl)(=[O:57])=[O:56])[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH:38][S:55]([C:49]1[CH:50]=[CH:51][C:52]([O:53][CH3:54])=[C:47]([O:46][CH3:45])[CH:48]=1)(=[O:57])=[O:56])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:15]([Cl:22])=[CH:16][N+:17]([O-:21])=[CH:18][C:19]=1[Cl:20])=[O:10])(=[O:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(=O)OCCC[C@@H](N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@H](CCCOC(C)=O)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.2 %

Procedure:
To a solution of 4-((S)-2-((R)-5-acetoxy-2-aminopentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (205 mg, 0.354 mmol) dissolved in DCM (2.5 mL), pyridine (58 μl, 0.710 mmol) and 3,4-dimethoxybenzene-1-sulfonyl chloride (168 mg, 0.710 mmol) were added. The mixture was stirred at RT for 48 hours. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1M and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated, to yield 284 mg of a yellow solid which was purified by preparative reverse-phase HPLC to yield 42 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:33])[F:32])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][OH:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:37][O:38][CH2:39]Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:32])[F:33])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][O:13][CH2:37][O:38][CH3:39])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COCCl
Reactant: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NO)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCON=C(/C=C(/c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc2c(c1)CCC2NC(=O)CC(C)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
0.5 g of N-[5-{(Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-hydroxyimino-2-butenyl}-indane-1-yl]-3-methoxybutyric acid amide was dissolved in 10 ml of tetrahydrofuran, and 0.08 g of 60% sodium hydride was added to the resulting solution under ice-cold conditions, followed by stirring for 30 minutes at room temperature. The temperature was cooled again, and 0.1 g of chloromethyl methyl ether was added to the resulting solution, followed by stirring for one night at room temperature. The reaction solution was poured into ice-water, extracted with ethyl acetate, washed with saturated brine, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=7/3 (volume ratio)) to obtain 0.3 g of the target compound. Yield was 54%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:14]=2[N:15]=[CH:16][N:17]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:4][C:3]4[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=4[F:1])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=Cc1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnc2c1c(C(=O)c1cccc(NCc3cc(F)ccc3F)c1)cn2C1CCCC1
Yield: 57.7 %

Procedure:
2,5-difluorobenzaldehyde (88.1 mg, 0.62 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (100 mg, 0.31 mmol) and AcOH (18.6 mg, 0.31 mmol) in MeOH (10 mL). After 5 min NaCNBH3 was added. After 3 h the reaction was quenched with 1N NaOH. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over MgSO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) afforded the title compound as a white solid (80 mg, 58%). MS: 448.1 (MH+); HPLC Rf: 6.59 min. (HPLC method 4).
Reaction SMILES: Br[C:2]1[C:3]([Cl:31])=[CH:4][C:5]([O:29]C)=[C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:31][C:3]1[C:2]([CH:32]2[CH2:34][CH2:33]2)=[CH:7][C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([OH:29])[CH:4]=1
Reactant: COc1cc(Cl)c(Br)cc1CCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)CCc3cc(C4CC4)c(Cl)cc3O)CC2)C1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A mixture of tert-butyl 3-(4-(3-(5-bromo-4-chloro-2-methoxyphenyl)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (280 mg, 0.54 mmol), cyclopropylboronic acid (185 mg, 2.2 mmol), K3PO4.3H2O (444 mg, 1.9 mmol), tricyclohexylphosphine (30 mg, 0.1 mmol), Pd(OAc)2 (24 mg, 0.11 mmol) in toluene (10 mL) and water (1 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=60:1) to afford the desired product (194 mg, 75% yield). ESI-MS m/z: 477.3[M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.Br[CH2:18][CH2:19][OH:20].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([NH:12][CH2:18][CH2:19][OH:20])[CH:13]=[CH:14][CH:15]=2)[O:5]1
Reactant: OCCBr
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cccc(NCCO)c2)OC1(C)C
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (219 mg, 1.00 mmol), 2-bromoethanol (82.7 μL, 1.10 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) in toluene (2 mL) was refluxed for 22 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=2:1→1:1) to afford desired product (76.3 mg, 29.0%) as colorless oil.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])([O-:3])=[O:2]
Reactant: C=CC(=O)OCCCCCCCC
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.22 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Octyl acrylate (10.2 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 4 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid octyl 4,4-dinitropentanoate (5.0 g, yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH:37]([N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH:37]([CH3:39])[CH3:38])[CH3:50])=[O:49])[CH2:48][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin 1-yl)-N-isopropyl-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 16c) in an analogous manner as described in example 25. LR-MS: 703.4 [(M+H)+]