Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19]Br)(C)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCO>[C:23]1([NH:22][CH2:19][CH2:18][S:17][C:9]2[N:8]([CH2:7][C:6]([OH:5])=[O:21])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCBr)nc2ccccc21
Reactant: Nc1ccccc1
Solvent: CCO
Product: O=C(O)Cn1c(SCCNc2ccccc2)nc2ccccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To tert-butyl[2-(2-bromo-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Intermediate 4-I, 25 mg, 0.065 mmol) in EtOH (0.7 ml) is added aniline (31.3 mg, 0.34 mmol). The resulting mixture is heated up to 70° C. for 1 h. After cooling the solvent is evaporated in vacuo and the crude ester is dissolved in TFA/dichloromethane (3:2, 2 ml) and stirred at rt for 2 h. Evaporation of the solvents in vacuo affords a crude product that is purified by chromatography on silica-gel (dichlromethane/MeOH, 100:7.5), yielding the pure title compound: tR=2.11 min (LC-2), ESI-MS (pos.): m/z 328.33 [M+H]+, ESI-MS (neg.): m/z 326.34 [M−H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[Br:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH2:20][CH2:21][C:22]#[CH:23])[N:19]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH2:20][CH2:21][C:22]#[C:23][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cn2cccc(Br)c2n1
Product: FCc1cccc(C#CCCc2cn3cccc(Br)c3n2)n1
Yield: 10.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.97 mmol) and 8-bromo-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (242 mg, 0.97 mmol). The crude residue was purified over silicagel chromatography 25 g silicagel column Cyclohexane/AcOEt: from 100/0 to 60/40 as eluent) to afford 36 mg of 8-bromo-2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 10%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].[H-].[Na+].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20].O>CN(C)C=O>[S:19](=[O:22])(=[O:21])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:20]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
108 mg of 2′-nitrobiphenyl-4-ol was dissolved in 1.5 ml of N,N-dimethyformamide, and a suspension of 120 mg of sodium hydride in 1.5 ml of N,N-dimethyformamide was added thereto under cooling with ice, followed by stirring for 10 minutes under cooling with ice. 367 mg of sulfamoyl chloride was added to this mixture, followed by stirring at room temperature for 3 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium. sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 106 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH3:12])=[CH:4][CH:3]=1.C(O)C.C(=O)=O.FC(F)(C1C=C2C(=CC=1)N=CC=C2)C1N2N=C(C3C=CC(CCNC(=O)OC(C)(C)C)=CC=3)C=CC2=NN=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: CC(C(=O)NNc1ccc(Cl)nn1)c1ccc2ncccc2c1
Agent: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cc1
Agent: O=C=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12

Procedure:
A solution of N′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (2700 mg, 8238 μmol) in TFA (20 mL) was heated to 120° C. with microwaves (2 bar; 10 watts) for 40 min. The solution was concentrated under reduced pressure then partitioned between 9:1 CHCl3/IPA (75 mL) and 1 M NaOH (100 mL). The aqueous layer was further extracted with 9:1 CHCl3/IPA (2×20 mL). The combined organics were dried over MgSO4 then concentrated to an amber oil under reduced pressure. The product was isolated as off white crystalline solid from ACN. MS (ESI pos. ion) m/z: 310 (MH+). Calc'd exact mass for C16H12ClN5: 309. Enantiomer resolved with: Chiralpak AD-H (3×25 cm) column using 45% ethanol (0.1% DEA)/CO2 The following compounds were prepared using same method as tert-Butyl 2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate and resolved from racemic mixtures:
Reaction SMILES: C([Li])CCC.[NH3:6].[NH2-].[Li+].[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([C:24]2[S:28][C:27]([C:29]([O:31]C)=O)=[N:26][N:25]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:12])[CH3:11]>CCCCCC.O1CCCC1>[CH3:21][C:20]([C:17]1[CH:16]=[C:15]([C:24]2[S:28][C:27]([C:29]([NH2:6])=[O:31])=[N:26][N:25]=2)[CH:14]=[C:13]([C:10]([CH3:11])([CH3:12])[CH3:9])[C:18]=1[OH:19])([CH3:22])[CH3:23]
Reactant: COC(=O)c1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reactant: N
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(-c2nnc(C(N)=O)s2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.0 ml (3.20 mmol) of 1.6M n-butyllithium in hexane is added dropwise to liquid ammonia (3-5 ml) at -78° C. over 10 minutes under a nitrogen atmosphere. The resulting white slurry is treated slowly with 10 ml of tetrahydrofuran and the resulting mixture of lithium amide at -78° C. is treated dropwise with a solution of 1.08 g (3.10 mmol) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxylic acid, methyl ester in 3 ml of tetrahydrofuran. The reaction is allowed to warm slowly to room temperature and stirred for a total of 18 hours. The reaction is quenched with 100 ml of saturated aqueous NH4Cl and extracted with t-butylmethylether (3×). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a yellow solid. Chromatography (flash, SiO2, 70-230 mesh, 30% ethyl acetate-hexane) followed by recrystallization from toluene gives 0.68 g (1.03 g theor., 66%) of the desired product as a pale yellow solid, mp 200°-201° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:13][C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([CH2:27][CH2:28][C:29]4[CH:34]=CC(O)=[CH:31][CH:30]=4)=[CH:21][CH:22]=3)[CH2:17][C:16]=2[CH:15]=1)[CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1>O>[C:5]([O:4][C:1]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][C:20]2[CH:19]=[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][C:14]([O:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][C:16]=4[CH2:17]3)=[CH:22][CH:21]=2)=[CH:34][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(O)cc3)ccc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(OC(C)=O)cc3)ccc1-2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (5 mL) was slowly added to a mixture of 4-(2-(2-pentyloxyfluorene-7-yl)ethyl)phenol (5 g) produced according to the first to ninth steps in Example 1 and pyridine (100 mL) while maintaining 0° C., and the solution was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice and water (200 mL), and the product was extracted with toluene (50 mL). The toluene layer was dried on anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by means of column chromatography (silica gel, eluting solvent: toluene) to obtain 4-(2-(2-pentyloxyfluorene-7-yl)ethyl)phenyl acetate (5.1 g).
Reaction SMILES: [NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:15]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:16]([C@H:21]([CH2:23][C:24]([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])=[O:25])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>O>[NH:15]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C@H:16]([C@H:21]([CH2:23][C:24]([NH:26][C@H:27]([C:29]([NH:1][C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:30])[CH3:28])=[O:25])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)C[C@H](O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
In a manner analogous to that described in stage 13.1, using as starting materials 150 mg of H-Sta-OMe×HCl (from stage 13.4), 253 mg of Z-Sta-Ala-OH (from stage 13.2), 102 mg of HOBt×H2O, 67 mg of N-methylmorpholine and 178 mg of DCCI, Z-Sta-Ala-Sta-OMe is obtained; Rf (chloroform/methanol ]9:1])=0.37.
Reaction SMILES: C(C1C=C(N[C:10]2[N:15]=[C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:13](F)=[C:12](C)[C:11]=2F)C=CC=1)#N.IC.[H-].[Na+].[C:32](#[N:34])[CH3:33]>>[N:15]1[C:14]([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:13][CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[CH:19][C:33]([C:32]#[N:34])=[CH:23][CH:24]=1
Reactant: CC#N
Reactant: Cc1c(F)c(Nc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: N#Cc1ccc(Oc2cccc(Oc3cccc(C#N)c3)n2)cc1
Reaction time: 18 h

Procedure:
To 3-[(6-(3-cyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzonitrile (0.10 g, 0.28 mmol) in acetonitrile (10 mL) was added iodomethane (0.20 g, 1.4 mmol) and sodium hydride (0.055 g, 1.4 mmol). After stirring for 18 hours the reaction was partitioned with water and ethyl acetate. The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo. Chromatography of the residue on silica gel with ethyl acetate/hexane (1/3) as eluent gave 3-[(6-(3-cyanophenyl)-methylamino-3,5-difluoro-4-methylpyridin-2-y))oxy]-benzonitrile; NMR (CDCl3) 7.4 (m, 5), 7.25 (m, 1), 7.1 (m, 2), 3.25 (s, 3), 2.3 (s, 3) ppm.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:23][Si:24]([CH3:27])([CH3:26])[O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O

Procedure:
A mixture of 9.0 gm (0.03 mole) of 19-hydroxy-4-androstene-3,17-dione, 4.3 gm (0.04 mole) of trimethylchlorosilane and 3.2 gm (0.04 mole) of pyridine is refluxed in 100 ml of benzene for a period of 18 hours. The resulting suspension is filtered, the volatiles removed in vacuo and concentrated to a yellow oil. The oil is placed upon a silica gel chromatographic column packed in chloroform and eluted with chloroform. The chloroform eluate is evaporated to dryness in vacuo and the residue is recrystallized twice from hexane to yield the desired 19-(trimethylsiloxy)-4-androstene-3,17-dione having a m.p. of 87°-9° C., uv max (MeOH) 242 nm (ε14,700).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[S:35])[CH2:33][CH3:34])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH3:3].[CH:40]1(C(SCC)=S)CC1>C(N(CC)CC)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32]([CH:33]5[CH2:40][CH2:34]5)=[S:35])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:15][CH2:14]2)=[O:12])=[CH:38][CH:39]=1)[CH3:3]
Reactant: CCC(=S)NC[C@H]1CN(c2ccc(N3CCN(C(=O)COc4ccc(CN(C)C)cc4)CC3)c(F)c2)C(=O)O1
Reactant: CCSC(=S)C1CC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(OCC(=O)N2CCN(c3ccc(N4C[C@H](CNC(=S)C5CC5)OC4=O)cc3F)CC2)cc1

Procedure:
As described for the preparation of 27, the reaction of 26 (prepared from 357 mg of 25) with ethyl cyclopropanecarbodithioate and triethylamine gave the thioamide which was mixed with saturated NaHCO3 and extracted with CH2Cl2. The extract was dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.5% NH4OH—CH2Cl2 and crystallization of the product from Et2O—CH2Cl2-heptane gave 74 mg of 28: mp 169–170° C.; 1H NMR [300 MHz, (CD3)2SO] δ 0.84 (m, 2H), 1.01 (m, 2H), 2.12 (s, 7H), 2.93. 3.00 (s, s, 4H), 3.25 (s, 2H), 3.60 (s, 4H), 3.79 (dd, 1H), 3.94 (m, 2H), 4.12 (t, 1H), 4.83 (s, 2H), 4.92 (m, 1H), 6.86 (d, 2H), 7.07 (t, 1H), 7.17 (m, 3H), 7.49 (dd, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:35])=[C:9]([C:31]([Cl:34])=[CH:32][CH:33]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:6])=[O:4].[C:36]([NH:44][C:45]1[CH:55]=[CH:54][C:48]([CH:49]=[CH:50][C:51](O)=[O:52])=[CH:47][CH:46]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:35][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:51](=[O:52])[CH:50]=[CH:49][C:48]2[CH:47]=[CH:46][C:45]([NH:44][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)=[CH:55][CH:54]=2)=[CH:33][CH:32]=[C:31]([Cl:34])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=C(O)C=Cc1ccc(NC(=O)c2ccncc2)cc1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)c5ccncc5)cc4)c3Cl)c2n1
Reaction time: 24 h
Yield: 42.5 %

Procedure:
To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (30 mg) and 4-(isonicotinamido)cinnamic acid (17 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg) and 1-hydroxybenzotriazole (11 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacua. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(isonicotinamido)cinnamoylglycyl]amino]-benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (19 mg) as an amorphous powder.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.CI.[C:27](OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(C)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH3:27])[N:13]=2)=[CH:19][CH:20]=1
Reactant: Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Solvent: CI
Product: Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.028 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using methyl iodide (0.21 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-methyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C14H16ClN3, 261.10; found, m/z 262.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.69-7.65 (m, 4H), 4.07 (s, 3H), 3.69-3.67 (m, 2H), 3.58-3.56 (m, 2H), 3.44-3.42 (m, 2H), 3.05-3.04 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.[CH3:21][C:22]([CH3:24])=[O:23]>>[OH:23][C:22]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)([CH3:24])[CH3:21]
Reactant: CC(C)=O
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)(O)c1cc2ccccc2o1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
1.00 g of benzofuran was dissolved in 20 ml of anhydrous tetrahdyrofuran. Thereto was dropwise added 6.2 ml of 1.5 M n-butyllithium hexane solution, in 5 minutes with stirring at -50° C. The mixture was stirred at 0° C. for 30 minutes and then cooled to -50° C. Thereto was added 0.94 ml of acetone. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed by distillation under reduced pressure. The residue was mixed with 30 ml of chloroform and 10 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.50 g of 2-(1-hydroxy-1-methylethyl)benzofuran as a colorless oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClCCl>C(OCC)(=O)C>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Temperature: 40 °C
Yield: 25.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3-amino-4-chloroquinoline (2.50 g, 1 eq), benzoyl chloride (3.0 g, 1.5 eq), and anhydrous dichloromethane (100 mL) was heated at 40° C. After 23 hours additional benzoyl chloride (3.0 g, 1.5 eq) was added and heating was continued for a total of 48 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with aqueous potassium carbonate (×2), water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (230 g of silica gel eluted initially with a gradient of 20-50% ethyl acetate in hexanes and then with 4/3/3 dichloromethane/ethyl acetate/hexanes) to provide 1.01 g of N-(4-chloroquinolin-3-yl)benzamide as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([O:25]C(C)(C)C)=O)[CH:21]=[CH:22][C:5]=2[NH:4]1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[CH2:40][NH:41][CH3:42].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([N:41]([CH3:42])[CH2:40][C:32]3[N:31]([CH3:30])[C:39]4[C:34]([CH:33]=3)=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:25])[CH:21]=[CH:22][C:5]=2[NH:4]1
Reactant: CNCc1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Yield: 88.9 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-hydroxymethyl-3-oxo-4-phenethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.49 g, 1.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.23 g, 1.4 mmole), Et3N (0.37 mL, 2.62 mmole), HOBt.H2O (0.19 g, 1.4 mmole), and EDC.HCl (0.27 g, 1.4 mmole), the title compound (0.53 g, 82%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 1-3% MeOH/CHCl3): MS (ES) m/e 497.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17]>>[NH2:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])=[O:20]
Reactant: N#CCC(N)=O
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Product: COc1cc(/C=C/C=C(\C#N)C(N)=O)cc(OC)c1O

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.1 g, 0.48 mmol) to 2-cyanoacetamide (0.04 g, 0.48 mmol). After refluxing for 3 h and recrystallization from ethanol an orange solid was obtained (0.083 g, 63%). The product gave the following analytical data:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].C(=O)([O-])O.[Na+].O>CO>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:14][CH2:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18])([O-:13])=[O:12]
Reactant: NCC(F)(F)C(=O)O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a solution of 2-chloro-1,3-dinitrobenzene (2.94 g, 14.54 mmol) in methanol (30.0 mL) were added 3-amino-2,2-difluoropropanoic acid (2.0 g, 15.99 mmol), sodium hydrogen carbonate (2.69 g, 31.98 mmol) and water (15 mL). The reaction mixture was stirred at 80° C. for 1 day. The starting material wasn't consumed completely. To the mixture was added sodium hydrogen carbonate (5.88 g, 63.96 mmol) and the mixture was stirred at 80° C. for 0.5 day. After cooling, the solvent was removed. The residue was neutralized with 1N hydrochloric acid (100 mL) and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (3.52 g, 12.09 mmol, 83%).
Reaction SMILES: FC1C=C(C2(C(OCC)=O)CCCC2)C=C(OCC2C=CC(N3C=CN=C3C)=CC=2)C=1.[F:32][C:33]1[CH:34]=[C:35]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([N:56]3[CH:60]=[CH:59][N:58]=[C:57]3[CH3:61])=[CH:52][CH:51]=2)[CH:36]=[C:37]([C:39]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43]O[CH2:41][CH2:40]2)[CH:38]=1>>[F:32][C:33]1[CH:34]=[C:35]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][C:53]([N:56]3[CH:60]=[CH:59][N:58]=[C:57]3[CH3:61])=[CH:54][CH:55]=2)[CH:36]=[C:37]([C:39]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][CH2:41][CH2:40]2)[CH:38]=1
Reactant: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Agent: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCCC1
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=O)CCCC3)c2)cc1

Procedure:
The desired compound was prepared from ethyl 1-[3-fluoro-5-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]cyclopentane-1-carboxylate according to the preparation of 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6- tetrahydro-2H-pyran-4-carboxamide (Example 5).