Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:56][CH2:57][CH2:58][C:59]1[CH:76]=[CH:75][C:62]([O:63][CH2:64][CH2:65][CH2:66][P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])=[CH:61][CH:60]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[C:43]([O:42][CH2:41][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[C:38]([NH:56][CH2:57][CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:63][CH2:64][CH2:65][CH2:66][P:67]([O:68][CH2:69][CH3:70])([O:71][CH2:72][CH3:73])=[O:74])=[CH:75][CH:76]=1)=[O:39])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(CCCOc1ccc(CCN)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(OCCCP(=O)(OCC)OCC)cc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1 M) was added diethyl 3-(4-(2-aminoethyl)phenoxy)propylphosphonate (1.1 eq), DIEA (2.5 equiv) and HBTU (1.1 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, and washed with 5% citric acid three times, saturated NaHCO3 solution twice, water and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 60-100% EtOAc/Hex to give the product.
Reaction SMILES: COC[N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][CH:6]([NH2:22])[C:5]1=[O:23].[OH-].[Na+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>Br.C(O)(=O)C.O.O1CCCC1>[O:23]=[C:5]1[NH:4][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][CH:6]1[NH:22][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: COCN1C(=O)C(N)CN(c2ccccc2F)c2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NC1CN(c2ccccc2F)c2ccccc2NC1=O)OCc1ccccc1
Reaction time: 1 h
Yield: 40.7 %

Procedure:
1-Methoxymethyl-2-oxo-3-amino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.94 g) was dissolved in 25% hydrobromic acid-acetic acid solution (18 ml), the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was add, the solid so precipitated was collected by filtration to give pale brown crystals. This crystals were suspended in water (5 ml), 1N aqueous sodium hydroxide (4.5 ml) and a solution of benzyl chloroformate (301 mg) in tetrahydrofuran (7 ml) were added thereto, the resultant mixture was stirred for one hour. Water was added to the reaction mixture, extracted with methylene chloride, the organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 291 mg of the titled compound as amorphous.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].COC1C=CC=CC=1[Mg]Br.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=O)[C:31]=3[C:40]([O:42]CC)=[O:41])=[CH:24][C:23]=2[O:22]1>C1COCC1.C1COCC1.CCOCC>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=2)[CH:31]1[C:40]([OH:42])=[O:41]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1ccccc1Br
Agent: COc1ccccc1[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Reaction time: 0.25 h

Procedure:
To dry magnesium turnings (81 mg, 3,4 mmol) under an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2O (3 ml). A portion of the resulting 2-methoxyphenyl magnesium bromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound. (100 mg, 68%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH3:2])=[C:4]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1, 0.110 g, 0.445 mmol) is suspended in THF (3 mL) and cooled to 0° C. KHMDS (0.5M in toluene, 2 mL, 1 mmol) is added dropwise, the cooling bath is lowered and the mixture is stirred at room temperature for 15 min, whereupon it is lowered in the ice-water bath. Benzyl bromide (0.093 g, 0.534 mmol) is added dropwise. After 3 h, additional benzyl bromide (0.046 g, 0.267 mmol) is added, and upon reaction completion, the mixture is quenched with 1M aqueous HCl and diluted with ethyl acetate. The aqueous phase is extracted and the combined organic phase is dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (dichloromethane-methanol, 99:1) affords 1-benzyl-3-methyl-2-pyridin-3-yl-1H-indole as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 2.18 (s, 3H), 5.19 (s, 2H), 6.69-6.71 (m, 2H), 7.01-7.11 (m, 5H), 7.21 (d, J=8.1 Hz, 1H), 7.37-7.41 (m, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.67-7.70 (m, 1H), 8.36 (s, 1H), 8.43-8.45 (m, 1H). MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:7])=[CH:5][CH:6]=1.N1C=CC=CC=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1.[Cl:25][C:26]1[N:31]=[N:30][C:29]([O:32][C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=2[CH:40]2[CH2:42][CH2:41]2)=[C:28]([OH:43])[CH:27]=1>O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:14]([O:43][C:28]2[CH:27]=[C:26]([Cl:25])[N:31]=[N:30][C:29]=2[O:32][C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=2[CH:40]2[CH2:42][CH2:41]2)=[O:15])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: Cc1ccc(C)[nH]1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)n1c(C)ccc1C
Yield: 16.7 %

Procedure:
37.4 mg (0.393 mmol) of 2,5-dimethyl-1H-pyrrole was mixed with toluene (1 mL), 40.0 L (0.407 mmol) of pyridine, then 0.34 mL (0.367 mmol) of 1.08 mol/L phosgene-toluene solution were added to the mixture in an ice bath with stirring, and the resulting mixture was stirred for 1 hour. To the mixture were added 40.0 L (0.407 mmol) of pyridine, then 100 mg (0.361 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol, and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 24.0 mg (0.0603 mmol, Yield: 16.7%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,5-dimethyl-1H-pyrrole-1-carboxylate (Compound No. 3630).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].N1(CCCCCOC2C=CC(O)=CC=2)C=CN=C1.BrCCCCC(C)(C)C(OCC)=O>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCn2ccnc2)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: CCOC(=O)C(C)(C)CCCCBr
Agent: Oc1ccc(OCCCCCn2ccnc2)cc1
Product: CCOC(=O)C(C)(C)CCCCCOc1ccc(OCCCn2ccnc2)cc1

Procedure:
p-[3-(1-Imidazolyl)propoxy]phenol and ethyl 7-bromo-2,2-dimethylheptanoate were used as starting compounds in place of p-[5-(1-imidazolyl)pentyloxy]phenol and ethyl 6-bromo-2,2-dimethylhexanoate, respectively, in EXAMPLE 30. The starting compounds were heated and treated in a manner similar to EXAMPLE 30 to give the desired product, ethyl 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoate, as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O-:12])=[O:11])[CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16](S([O-])(=O)=O)=[CH:15][CH:14]=1.[NH+]1C=CC=CC=1.C(O)C1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH2:23][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:3]=1
Reactant: O=C([O-])c1cc(Cl)c(Cl)c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 142.5 °C

Procedure:
A 22 L round bottom flask was fitted with a thermocouple, mechanical stirrer and a Dean-Stark trap which was connected to a nitrogen bubbler. The vessel was purged with nitrogen and then 4,5,6-trichloropicolinate (2547 g, 10.07 mol), pyridinium p-toluene sulfonate (PPTS; 130 g, 0.52 mol), benzyl alcohol (2249 g, 20.8 mol) and xylenes (10278 g) were added. Stirring was started, and the pot was heated to 140 to 145° C. The xylenes/water azeotrope was collected in the Dean-Stark trap over about 5 h. The total amount of distillate collected was 4750 g (415 g was water). After the water stopped distilling overhead, a reactor sample was taken and analyzed by high-performance liquid chromatography (HPLC) to ensure less than 1.5 area % of starting carboxylic acid remained. The reaction was allowed to cool to room temperature and stirred overnight. Xylenes (4000 g) were removed by vacuum distillation. The solution was cooled to 85-100° C. and then vacuum transferred to a 30 L jacketed crystallization vessel that had been fitted with a mechanical stirrer and thermocouple. The vacuum was released with nitrogen and a nitrogen bubbler was placed on the crystallization vessel. To the xylene solution was added isopropyl alcohol (IPA; 6200 g) over about 15 minutes (min). The resulting slurry was allowed to cool slowly to room temperature and then cooled further to 5° C. The solid was collected by filtration, and the cake was washed with cold (5-10° C.) IPA (3731 g). The solid was dried in air to a constant weight providing white crystals (2765 g, gas chromatography (GC) internal standard purity 96.5%, 84.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11](Cl)(=[O:13])=[O:12])([O-:3])=[O:2].[NH3:15]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([NH2:15])(=[O:13])=[O:12])([O-:3])=[O:2]
Reactant: N
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Solvent: CCOCC
Product: NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a suspension of 29.4 g of the product of Example 2 in 250 ml of diethyl ether was added 6.5 ml of anhydrous ammonia at 5°-15°. After stirring at 15°-25° for 1 hour, the product was filtered off, washed with ether, and water and oven dried at 60° to give 20.5 g of 2-nitrophenylmethanesulfonamide, m.p.=134°-136°.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=O)[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[S:29])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN1c2ncccc2C(=O)N(C)c2cccnc21
Solvent: Cc1ccccc1
Product: CCN1c2ncccc2C(=S)N(C)c2cccnc21
Yield: 162.8 %

Procedure:
A mixture of 2.66 g (0.01 mol) of 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido-[3,2-b:2'3'-e][1,4]diazepin-6-one and 2.10 g (0.005 mol) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) in 50 ml of toluene was refluxed for 2 1/2 h. The solvent was then removed in vacuo and water was added to the residue. The product was extracted with ethyl acetate, dried (anhydrous sodium sulfate), and concentrated in vacuo. Purification was effected on a silica gel column using methylene chloride as the first eluent, followed by ethyl acetate/hexane (1:4). Removal of the solvent in vacuo gave 2.20 g (74% of theory) of 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-thione as a yellow powder, which was recrystallized from 10% hexane/ethyl acetate to provide 1.1 g of the title compound as yellow needles, m.p. 157°-158° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH:7]=1)C.[C:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[CH:31]=[C:30]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:21])[CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1cccc(COc2ccc(I)cc2)c1
Product: CC(=O)Nc1cccc(-c2ccc(OCc3cccc(CC(=O)O)c3)cc2)c1

Procedure:
[3-(3′-Acetylamino-biphenyl-4-yloxymethyl)-phenyl]-acetic acid was prepared using general procedure 5 from [3-(4-iodo-phenoxymethyl)-phenyl]-acetic acid ethyl ester (of intermediate 4) and 3-acetamidobenzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=376.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:21][P:22](=[O:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][P:22](=[O:25])([CH3:24])[CH3:23])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: CP(C)(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(ncn2CP(C)(C)=O)n(CCCC)c1=O
Temperature: 25 °C

Procedure:
5 g (0.01 9 mol) of 1,3-dibutylxanthine were stirred at 80° C. for 6 hours with 2.88 g (0.0228 mol) of chloromethyldimethylphosphine oxide and 3.2 g (0.0228 mol) of potassium carbonate in 80 ml of DMF. The solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue which remained was crystallized in petroleum ether/ethyl acetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=3[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15](=[O:24])[NH:16][C:17]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Yield: 89.6 %

Procedure:
A solution of 4-(5-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 4.3 mmol) and H2O/TFA 5% (15 mL) in CH2Cl2 (20 ml) was stirred at room temperature for 1 h, after which the solvent was removed in vacuo. The residue was purified by gradient flash chromatography on silica gel (CH2Cl2 to EtOH), yielding an off-white/pinkish solid (0.97 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:30])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)cc1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.9 mg, 0.167 mmol) in CH2Cl2 (2 mL) was added 4-methylphenyl isocyanate (0.24 μL, 0.191 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 130 as a colorless solid (61.8 mg, 91%). LCMS m/z (%)=408 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (bs, 1H), 8.52 (bs, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.43 (dd, J=8.91, 2.73 Hz, 1H), 7.36 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.43 Hz, 2H), 7.08 (d, J=8.92 Hz, 1H), 7.06 (d, J=8.32 Hz, 2H), 6.23 (d, J=1.82 Hz, 1H), 3.96 (t, J=6.36 Hz, 2H), 3.65 (s, 3H), 2.23 (s, 3H), 2.19 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:28]2[CH:49]=[CH:48][CH:47]=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:45][CH2:46]5)=[O:43])[N:40]=4)[N:37]=3)[CH:29]=2)=[O:12])[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CCC1
Yield: 60.5 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalyl chloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.47 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (140 mg, 60%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:16]([O:15][C:8]1[CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=[CH:12][C:7]=1[CH:6]=[CH:5][CH2:4][OH:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C=Cc1ccc(CC)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCc1ccc(C=CCO)c(OCc2ccccc2)c1
Reaction time: 4 h
Yield: 71.3 %

Procedure:
A solution of 3-(2-benzyloxy-4-ethyl-phenyl)-acrylic acid ethyl ester (2.9 g, 9.3 mmol) dissolved in ether (7 mL) was added to a cooled 0° C. suspension of lithium aluminium hydride (0.89 g, 23.4 mmol) in ether (20 mL). The reaction mixture was stirred for 4 hours, quenched with H2O (3.6 mL) and 15% NaOH (0.9 mL) and then filtered through glass frit washing with ether. The filtrate was concentrated to a clear oil and purified by flash column chromatography (0% to 30% EtOAc in hexanes) to give the product (1.78 g, 71%). 1H NMR (400 MHz, CDCl3): δ 6 1.22 (t, J=7.6 Hz, 3 H), 2.62 (q, J=7.6 Hz, 2 H), 4.29 (m, 2 H), 5.10 (s, 2 H), 6.35 (dt, J=16.2, 7.6 Hz, 1 H), 6.78 (s, 1 H), 6.80 (d, J=7.1 Hz, 1 H), 6.95 (d, J=16.2 Hz, 1 H), 7.32–7.45 (m, 6 H).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:23])([CH3:24])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1)=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCNCC1
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCN(C)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. 1-methylpiperazine (0.32 mL, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent: MC/MeOH=10/1) to give the title compound (1.06 g, 95%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5]([CH3:10])[CH2:4]1.[CH:18]1[CH:19]=[CH:20][C:21]2[NH:26][CH:25]=[C:24]([CH2:27][CH2:28]O)[C:22]=2[CH:23]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.C(O)C.O>[CH3:17][N:2]([CH3:1])[C:3]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6]2([C:25]3[NH:26][C:21]4[C:22]([C:24]=3[CH2:27][CH2:28][O:9]2)=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH:5]([CH3:10])[CH2:4]1
Reactant: CC1CC(c2ccccc2)(N(C)C)CCC1=O
Reactant: OCCc1c[nH]c2ccccc12
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC1CC(c2ccccc2)(N(C)C)CCC12OCCc1c2[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(±)-4-dimethylamino-2-methyl-4-phenylcyclohexanone (461 mg, 2 mmol) together with tryptophol (322 mg, 2 mmol) was dissolved in DCM (100 ml) and mixed with trifluoromethane sulphonic acid (0.19 ml, 2.14 mmol). The mixture was stirred at RT for 20 h. The reaction mixture was mixed with 2N NaOH (2 ml) and H2O (2 ml) and stirred for 20 min. The organic residue was firstly washed with 2N NaOH (5 ml), then with H2O (5 ml) and dried over Na2SO4. The solvent was then removed in vacuum. The semisolid residue obtained was taken up in 10 ml of ethanol and cooled to 5° C. for 2 h. The solid precipitated out during this was discarded. The residue remaining in the mother liquor was purified by column chromatography on silica gel (50 g, EE/ethanol=4:1).