Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35](=[O:48])OC3C(F)=C(F)C(F)=C(F)C=3F)[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:57][O:58][C@@H:59]([C@@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1)[C@@H:60]([CH3:64])[C:61]([OH:63])=[O:62].C(N(C(C)C)CC)(C)C>ClCCl>[CH:5]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35]([N:66]3[CH2:67][CH2:68][CH2:69][C@H:65]3[C@H:59]([O:58][CH3:57])[C@H:60]([C:61]([OH:63])=[O:62])[CH3:64])=[O:48])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Yield: 92 %

Procedure:
The above reaction and purification were repeated in a similar fashion using #104 (2.60 g, <3.35 mmol, 1 eq.), #103 (750 mg, 3.35 mmol, 1 eq.), dichloromethane (10 mL, 0.3 M) and diisopropylethylamine (1.35 mL, 7.73 mmol, 2.3 eq.) to give #105 (2.4 g, 92%) as a tan foam. Fractions containing impure product (1.7 g) were combined with the previous impure fractions and purified as described above to afford additional #105 (1.30 g, quantitative yield for both reactions over two steps). LC-MS: m/z 779.3 [M+H+], 802.3 [M+Na+], retention time=1.05 minutes.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][CH2:21][C:22]([OH:24])=[O:23]>C(O)C>[Cl-:20].[C:22]([CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([OH:24])=[O:23]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCl
Solvent: CCO
Product: O=C(O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
Triphenyl phosphine (26 g; 0.1 mole) was heated under reflux with chloroacetic acid (9.5 g; 0.1 mole) in ethanol (150 ml) for four hours. Evaporation of the solvent yielded carboxymethyl triphenyl phosphonium chloride. ##STR32##
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([N+:15]([O-])=O)[CH2:12][N:11]([CH3:18])[CH2:10][CH:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21]>C(O)C.[Ni]>[C:20]([NH:15][CH:13]1[CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]([CH3:19])[CH2:10][N:11]([CH3:18])[CH2:12]1)(=[O:22])[CH3:21]
Reactant: CC1CN(C)CC([N+](=O)[O-])CN1Cc1ccccc1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: CCO
Product: CC(=O)NC1CN(C)CC(C)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Benzyl-2,4-dimethyl-6-nitrohexahydro-1H-1,4-diazepine (5.1 g) is dissolved in ethanol (100 ml) and acetic acid (5 ml) and hydrogenated over Raney-nickel (about 1 g) at 25° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure. The residue is dissolved in chloroform (100 ml), and acetic anhydride (4.0 g) is added to the solution. The reaction mixture is stirred for 2 hours at 25° C., diluted with aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer is washed successively with water, aqueous sodium hydroxide solution, and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, the residue is chromatographed on silica gel with elution of chloroform-methanol (9:1). Fractions containing the object compound are pooled and evaporated under reduced pressure to give 6-acetylamino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine (1.8 g) as an oil. The above compound is dissolved in 10% hydrochloric acid (20 ml) and is refluxed for 2 hours. After cooling, the reaction mixture is basified with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give the title compound (1.5 g).
Reaction SMILES: [N:1]1([CH2:12][CH2:13][OH:14])[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[CH2:8][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][N:1]1[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[CH2:8][C:4]=2[CH:3]=[N:2]1)(=[O:25])=[O:24]
Reactant: OCCn1ncc2c1-c1ccsc1C2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1ncc2c1-c1ccsc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0.50 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethanol was dissolved in 15 ml of methylene chloride, 1.00 ml of triethylamine and 0.28 ml of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with chloroform. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the resulting filtrate was concentrated under a reduced pressure to give 0.75 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethyl methanesulfonate.
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[C:3]1=[O:14].[C:15]([O-:18])([O-])=O.[K+].[K+].BrC[CH2:23][CH2:24][Cl:25]>CC(C)=O>[Cl:25][CH2:24][CH2:23][CH2:15][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:12][CH3:13])[C:3](=[O:14])[CH2:2][CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)C(=O)C(O)CC2
Reactant: ClCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCCCCl)CCCC2=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.4 %

Procedure:
A mixture of 6-.hydroxy-7-methoxy-1-tetralone (J. Org. Chem., 1985, 50, 4937) (1.5 g, 7.8 mmol), K2CO3 (1.7 g, 12.3 mmol), and acetone (30 ml) was stirred at reflux under nitrogen for 45 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (1.9 g, 12.1 mmol) dissolved in 8 ml acetone was dripped into the mixture. After total addition, the reaction was heated to reflux and stirred under nitrogen for 21 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed well with acetone and the filtrate was concentrated to yield 2.0 g 6-(3-chloropropoxy)-7-methoxy-1-tetralone as an amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:31][N:32]=[C:33]=[S:34]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:33]([NH:32][CH3:31])=[S:34])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNC(=S)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 20 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 73 mg (1 mmol) of methyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. Purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) resulted in 90 mg (20%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:12]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[S:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:18]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(N(CC)CC)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:17][CH2:16][CH2:15][O:14][CH2:13][CH:12]2[C:6]3[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:2][CH3:1])=[CH:18][C:7]=3[CH2:8][CH2:9][CH2:10][S:11]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)C(COCCO)SCCC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(COCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1)SCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethanol and triethylamine is added p-nitrobenzenesulfonyl chloride. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is then extracted with aqueous sodium bicarbonate and brine. The organic layer is filtered through sodium sulfate and taken to dryness. The residue is chromatographed on silica gel to give 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethyl 4-nitrobenzenesulfonate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:14][NH:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1C(=O)CCC1>[N:1]1([C:11]2[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=2[Cl:27])[CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@@H](NCc1ccc(Cl)c(Br)c1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@@H](NCc1ccc(Cl)c(-n2cnc3ccccc32)c1)c1ccccc1
Temperature: 150 °C
Yield: 19.3 %

Procedure:
To a mixture of 1H-benzo[d]imidazole (0.106 g, 0.90 mmol) and (R)—N-(3-bromo-4-chlorobenzyl)-1-phenylethanamine 75 (0.247 g, 0.76 mmol) was added potassium carbonate (0.141 g, 1.0 mmol), copper(I) iodide (0.023 g, 0.12 mmol), and NMP (0.8 mL). The reaction mixture was degassed and heated to 150° C. for 3 d, diluted with EtOAc, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 40% to 100% EtOAc in hexanes) gave (1R)—N-(3-(1H-benzo[d]imidazol-1-yl)-4-chlorobenzyl)-1-phenylethanamine 76 (0.053 g, 19% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.38 (d, J=6.7 Hz, 3H), 3.69 (s, 2H), 3.82 (q, J=6.7 Hz, 1H), 7.20-7.43 (m, 11H), 7.55 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.2 Hz, 1H), 8.04 (s, 1H). Mass spectrum: calculated for C22H20ClN3 361.1. found 362.2 (M++1).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=O)=O)(C)(C)C.Cl[CH2:17][CH2:18][CH2:19][CH2:20]CCC.F[C:25](F)(F)[C:26]([OH:28])=[O:27]>[Pd]>[NH:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[CH2:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCCCCCl
Reactant: O=C(O)C(F)(F)F
Agent: [Pd]
Product: O=C(O)CCCCCCC1CCCN1

Procedure:
2-Pyrrolidineheptanoic acid is prepared from N-t-butoxycarbonylproline following steps A and B of Example 4 and step C of the procedure of Example 15. In step C, benzyl ω -chlorohexanoate is substituted for the 1-chloroheptane. The product thus obtained is hydrogenated in the presence of 10% palladium on charcoal and is then treated with trifluoroacetic acid, as in step E of the same procedure.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:6](Cl)=[O:7])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][OH:7])([CH3:15])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1C(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1CO
Temperature: 25 °C

Procedure:
A solution of 2,6-diisopropylbenzoyl chloride (11.65 g, 0.052 mol), in ethyl ether (100 mL) was added over 20 minutes to a suspension of lithium aluminum hydride (1.9 g, 0.050 mol) in ethyl ether (200 mL) keeping the temperature below -15° C. The reaction mixture was allowed to slowly warm to room temperature and was then cooled to zero. The reaction was quenched by careful addition of sodium bisulfate solution until no further reaction was evident. The mixture was diluted with ether (200 mL), the ether washed with brine. The grey goo (lithium/aluminum salts) was washed several times with ether, the ether washes were combined, dried (magnesium sulfate), filtered, and concentrated to an oil which solidified, 10.67 g.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:31])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=3)[NH:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: CN(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1
Solvent: Cc1ccccc1
Product: CN(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(C(N)=O)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
3-{3-[2-(Dimethylamino)acetylamino]phenyl}-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide was suspended in toluene (10 mL) and HCl gas was bubbled through the suspension for 15 min. The reaction was then stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparatory HPLC. (0.027 g, 13.5% yield over 2 steps): 1H NMR (CD3OD) δ 8.66 (s, 1H), 8.22 (t, 1H), 7.97 (dd, 1H), 7.75 (t, 2H), 7.63 (d, 2H), 7.51 (t, 1H), 3.21 (s, 2H), 2.41 (s, 6H); ES-MS (m/z) 338 [M+H]+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[N:17]1C2C(=CC=CC=2)[CH:20]=[CH:19][CH:18]=1>P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:17])[CH2:19][CH3:20]
Reactant: c1ccc2ncccc2c1
Reactant: Oc1ccnc2cccnc12
Agent: CS(=O)(=O)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCN
Product: Nc1ccnc2cccnc12

Procedure:
4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridine derivatives by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxy-3-carboxylic acid ester derivative with subsequent hydrolysis to the acid, followed by thermal decarboxylation in quinoline (as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylic acid, 3. T. Adams et al., J.Amer.Chem.Soc., 1946, 68, 1317). A 4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivative by heating in phosphorus oxychloride, or to the 4-methanesulphonyloxy or 4-trifluoromethanesulphonyloxy derivative by reaction with methanesulphonyl chloride or trriluoromethanesulphonic anhydride, respectively, in the presence of an organic base. A 4-amino 1,5-naphthyridine can be obtained from the 4-chloro, 4-methanesulphonyloxy or 4-trifluoromethanesulphonyloxy derivative by reaction with n-propylamine in pyridine.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Cl:9][C:10]1[CH:11]=[C:12]([C:17](=[O:28])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:13]=[CH:14][C:15]=1[Cl:16]>CCCCCC.C1COCC1.O>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([OH:28])([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:2][C:1]#[N:3])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CC#N
Reactant: COc1ccc(OCC(=O)c2ccc(Cl)c(Cl)c2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCC(O)(CC#N)c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of acetonitrile (3.54 mL) and THF (30 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 42.1 ml), and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added dropwise a solution of 1-(3,4-dichlorophenyl)-2-(4-methoxyphenoxy)ethanone (14 g) in THF (45 mL), and the mixture was stirred at −78° C. for 10 min, and then stirred for 1 hr while warming to room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.73 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][C:9]2[C:10]([N:15]([CH3:22])[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.CC(C)([O-:32])C.[K+]>CS(C)=O.CC(O)(C)C>[CH3:22][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[C:9]([CH2:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[OH:32])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)[O-]
Reactant: CN(c1cccnc1)c1ncccc1CC(c1cccnc1)c1cccnc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: CN(c1cccnc1)c1ncccc1CC(O)(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 3-(2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine (34 mg) in 1.2 mL of DMSO:t-BuOH (80:20) was added potassium tert-butoxide (21 mg). The reaction was stirred under an oxygen balloon at room temperature for 2 h, then quenched by adding 2 drops of water. Purification by reverse phase HPLC gave 26 mg of 2-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-1,1-dipyridin-3-ylethanol as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.54 (d, J=1.9 Hz, 2H), 8.47 (dd, J=4.6, 1.7 Hz, 2H), 8.35 (dd, J=4.6, 1.7 Hz, 1H), 8.21 (dd, J=4.6, 1.2 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.59-7.57 (m, 2H), 7.24-7.15 (m, 4H), 7.08-7.05 (m, 1H), 6.99-6.95 (m, 1H), 4.57 (s, 1H), 3.55 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [CH2:1]([C:15]1[CH:26]=[CH:25][C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOCC>N1C=CC=CC=1>[CH2:1]([C:15]1[CH:26]=[CH:25][C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 72 h

Procedure:
An about 364 mg portion of 3-(4-tetradecylphenoxy)-1,2-propanediol was dissolved in about 1.5 ml of dry pyridine and about 501 mg of tritylchloride was added. The mixture was stirred under argon for about 72 hours, ether was added and the mixture was washed with ice-cold dilute (about 1N) hydrochloric acid, sodium bicarbonate solution, brine, then dried and the solvent evaporated. The residue was recrystallized from ethanol, giving about 700 mg of the desired title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:36]3[CH:35]=[C:34]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:39]=[CH:38][CH:37]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1coc(-c2cccc(-c3ccccc3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 54.1 %

Procedure:
In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol), 3-biphenyl boronic acid (104 mg, 0.53 mmol), Cs2CO3 (257 mg, 0.79 mmol), Pd(PPh3)2Cl2 (15 mg, 0.021 mmol), DME (0.8 mL), ethanol (0.2 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 140° C. for 20 min. The mixture was diluted with EtOAc and washed with 1N HCl and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (70 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:11][OH:12])[NH2:6])[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1cccc(Cl)c1
Temperature: 90 °C
Yield: 22.1 %

Procedure:
A solution of 3.35 mL (30.0 mmol) 3-chlorobenzonitrile in ethanol (40 mL) was added to a solution of 2.47 g (35.5 mmol) hydroxylamine hydrochloride and 1.42 g (35.5 mmol) NaOH in water (20 mL) at r.t. and then heated at 90° C. for 24 h. After cooling, the reaction mixture was concentrated, the residue diluted with water, followed by filtration and drying to afford 1.13 g (93%) of the title compound. 1H NMR: 8.11 (s, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.36 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:32]([CH:28]4[CH2:31][CH2:30][CH2:29]4)=[O:33])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCC1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)C1CCC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and cyclobutanecarbonyl chloride (18 mg, 150 μmol). Yield 18 mg (82%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:20][C:21]([NH:27]C)([CH2:25][CH3:26])[C:22]([NH2:24])=[O:23]>>[C:22]([C:21]([NH:27][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:20])[CH2:25][CH3:26])(=[O:23])[NH2:24]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CCC(C)(NC)C(N)=O
Agent: Cl
Product: CCC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Methyl-2-methylamino-butyramide hydrochloride (CAN 18305-22-1) as starting materials and isolated (19.6 mg, 16%) as a white solid; MS (ESI, m/z): 360.5 (M+H+).