Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:45][CH3:46])[C:41]=1[O:42][CH2:43][CH3:44])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:36](=[O:37])[C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH2:43][CH3:44])=[C:40]([O:45][CH3:46])[CH:39]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCNCC1)=C2
Reactant: CCOc1c(OC)cc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1c(OC)cc(C(=O)N2CCN(C(=O)C3=Cc4cc(OC)c(OC)cc4CCC3)CC2)cc1OC
Temperature: 0 °C
Yield: 45.2 %

Procedure:
To a mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine (1.2 g), triethylamine (0.5 g) and methylene chloride (20 ml) is added dropwise, with stirring under ice-cooling, a solution of 3,5-dimethoxy-4-ethoxybenzoyl chloride (1.0 g) in methylene chloride (20 ml). The reaction mixture is then stirred for one hour at room temperature, and then poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (hexane:ethyl acetate:acetone=1:2:1) to afford 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,5-dimethoxy-4-ethoxy-benzoyl)piperazine (0.9 g). This product is recrystallized from ethyl acetatehexane to give colorless needles, m.p. 171°-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:34]>CN(C)C=O.CO.O.NN>[NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:34]
Reactant: Nc1c(F)ccc2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Agent: NN
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: NCCCNc1ccc(-c2cc(=O)c3c(N)c(F)ccc3o2)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
4.78 g of Compound 15 was dissolved in 200 ml of a mixed solvent of dimethylformamide and methanol (1:1), 5.07 ml of hydrazine monohydrate was added and the mixture was stirred at 50-60° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol :aqueous ammonia=9:1:1) to give Compound 16 which was dissolved in ethanol, a 5.5N hydrochloric acid- isopropylalcohol solution was added, isopropyl ether was added, and the precipitated crystals were collected by filtration to give 2.69 g (64%) of hydrochloride of Compound 16.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=2)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 33.2 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (123 mg, 0.496 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 33%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].N1C2[C:25](=[CH:26]C=CC=2)[C:24]2(COC3C=C4C(=C[C:31]2=3)CCO4)[C:23]1=O.BrCCCCC.ClCC1C=NC(OC)=NC=1>>[C:24]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])([CH2:25][CH3:26])([CH3:31])[CH3:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Solvent: CCCCCBr
Product: CCC(C)(C)N1C(=O)[C@]2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-bromopentane to replace 5-(chloromethyl)-2-methoxypyrimidine, (3R)-t-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp 128-129° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33-7.26 (m, 1H), 7.17 (d, J=7.1 Hz, 1H), 7.07-7.02 (m, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.41 (s, 1H), 4.92 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 8.64 (t, J=4.5 Hz, 2H), 3.87-3.63 (m, 2H), 2.99 (t, J=4.5 Hz, 2H), 1.79-1.69 (m, 2H), 1.40-1.35 (m, 4H), 0.94-0.89 (m, 3H); 13C NMR (75 MHz, CDCl3) δ177.5, 161.6, 161.2, 142.4, 133.0, 128.6, 123.8, 123.0, 120.3, 119.7, 118.7, 108.4, 93.1, 80.5, 72.3, 57.6, 40.3, 29.0, 27.1, 22.3, 13.9; MS (ES+) m/z 349.9 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:13])=[C:9]([F:16])[CH:8]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)nc1C
Yield: 63.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (259 mg) described in Preparation Example 23 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (205 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (282 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[NH:33][NH2:34].[CH3:35]OC(OC)N(C)C.O>CCO>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[N:33]1[CH:35]=[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[N:16]=2)[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:34]1
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: NNc1c(Cl)cccc1Cl
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3cn(-c4c(Cl)cccc4Cl)nc3-c3ccc(F)cc3F)nn12
Temperature: 85 °C
Yield: 34.9 %

Procedure:
The 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.200 g, 0.632 mmol, Preparation #K.1) in EtOH (2 mL) was treated with (2,6-dichlorophenyl)hydrazine hydrochloride (0.148 g, 0.696 mmol) then the mixture was heated at about 85° C. for about 10 min. The mixture was cooled then N,N-dimethylformamide dimethyl acetal (1.50 mL, 11.2 mmol) was added and the mixture was heated to about 85° C. for about 1 h. The mixture was cooled then water (2 mL) was added and the mixture was heated to about 60° C. for about 20 min. The mixture was then allowed to cool to ambient temperature then purified by RP-HPLC (Table 1, Method f) to give the title compound (0.107 g, 35%): LC/MS (Table 1, Method g) Rt=2.93 min; MS m/z: 485.2 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>>[O:15]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:19]3[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCS(=O)(=O)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCS(=O)(=O)CC3)ncn2)s1

Procedure:
6-(1,1-Dioxidothiomorpholin-4-yl)pyrimidin-4-amine 8-2 (0.237 g, 1.04 mmol), sodium hydride (0.083 g, 2.08 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.15 g, 1.04 mmol) were treated as in Scheme 4 above. The product was purified on a preparative hplc column and isolated via lyophilization to yield 8-3. Hi-Res MS: calc: 337.0536 found: 337.0530. 1NMR(DMSO): 8.51 ppm (s, 1H); 8.27 ppm (s, 1H); 6.36 ppm (s, 1H); 4.05 ppm (s, 4H); 3.21 ppm (s, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.CC(N([CH2:30][CH2:31][O:32]C1C=CC(N)=CC=1)C(N)=O)C.C(Cl)(=O)C>C(N(CC)CC)C>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[N:7]([CH:18]([CH3:19])[CH3:20])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:31](=[O:32])[CH3:30])=[CH:15][CH:16]=1
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(=O)NCCN(C)C
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(N)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc(OCCN(C(=O)NCCN(C)C)C(C)C)cc1

Procedure:
The title compound is prepared by reacting the compound of Example 64: N'-[2-dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(4-aminophenoxy)ethyl]urea with acetyl chloride in triethylamine.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: OCCCCCCCCCCCCBr
Reactant: NC(=O)C1CCNCC1
Product: NC(=O)C1CCN(CCCCCCCCCCCCO)CC1
Yield: 68.7 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 12-bromododecanol (4.15 g, 15.6 mmol) potassium carbonate and (2.16 g, 15.6 mmol) according to procedure used for Example 8 (Step A) to give 3.35 g of the title compound as a white solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:11].O=O>CO>[CH:8]1[CH:7]=[C:5]2[N:6]=[C:2]([S:1][S:1][C:2]3[S:3][C:4]4[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:11]=3)[S:3][C:4]2=[CH:10][CH:9]=1
Reactant: N
Reactant: Sc1nc2ccccc2s1
Agent: O=O
Solvent: CO
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1

Procedure:
A solution of 40 g (0.24 mol) of 2-mercaptobenzothiazole, 22.4 mg (0.1×10-3 mol) of Mn(OAc)2. 4H2O and 4.08 g (0.24 mol) of ammonia in 120 g of methanol is in the manner and reaction equipment described in Example 1 reacted with oxygen at an oxygen pressure of 4 bar and a reaction temperature of 55° C. After a reaction time of 3 hours, one obtains dibenzo thiazyl disulfide at a yield of 35.9 g, corresponding to 90.3% of theoretical. The conversion rate is determined to be 92.1%.
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(CC)=[C:8]([N:10]2[C:15](=[O:16])[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:9]=1)(=O)C.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2.[CH2:34]([OH:36])[CH3:35]>>[C:34]([C:13]1[C:12]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:24]=2)=[N:11][N:10]([CH2:8][CH3:9])[C:15](=[O:16])[C:14]=1[NH:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2)(=[O:36])[CH3:35]
Reactant: CCO
Reactant: Nc1ccc(F)c2ncccc12
Reactant: CCc1cc([N+](=O)[O-])c(C(C)=O)cc1-n1ncccc1=O
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(F)c3ncccc23)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
To a stirred solution of 150 mg (0.522 mmol) of 5-acetyl-2-ethyl-4-nitro-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (8 mL), 5-amino-8-fluoroquinoline (127 mg, 0.783 mmol) (Lee, Jae Keun et al., Bull. Korean Chem. Soc., 1996, 17(1), 90) was added. The resulting mixture was stirred at room temperature for five hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 3:1) to yield the title compound (140 mg, 66.7% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6](/[C:8](=[N:12]\[S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH:9]([F:11])[F:10])[CH:7]=1.Br[CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22](=[O:23])[C@H:21]([F:27])[C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:19])([NH:12][S@@:13]([C:15]([CH3:16])([CH3:18])[CH3:17])=[O:14])[CH:9]([F:11])[F:10])[CH3:26].[CH2:25]([O:24][C:22](=[O:23])[C@@H:21]([F:27])[C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:19])([NH:12][S@@:13]([C:15]([CH3:16])([CH3:18])[CH3:17])=[O:14])[CH:9]([F:11])[F:10])[CH3:26]
Reactant: CCOC(=O)C(F)Br
Reactant: CC(C)(C)[S@@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Product: CCOC(=O)[C@@H](F)[C@](N[S@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Product: CCOC(=O)[C@H](F)[C@](N[S@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-eth-(E)-ylidene]-amide (intermediate A2.3) and ethyl 2-bromo-2-fluoroacetate, a mixture (1 major component) of the 2 diastereoisomers (2R,3R)-3-(5-bromo-2-fluoro-phenyl)-2,4,4-trifluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester and (2S,3R)-3-(5-bromo-2-fluoro-phenyl)-2,4,4-trifluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester was obtained as a light yellow viscous oil after chromatography on silica gel (Telos Flash Silica) using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. MS (ISP): m/z=462.2 [M+H]+and 464.2 [M+2+H]+.
Reaction SMILES: CNC(NC1SC(C2C=CN=CC=2)=C(C)N=1)=O.[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2[S:29][C:28]([NH:30][C:31]([N:33]3[CH:37]=[CH:36]N=C3)=[O:32])=[N:27][C:26]=2[CH3:38])[CH:22]=[C:21]([CH3:39])[N:20]=1.[CH2:40]([C:42]1[O:46][C:45](CCN)=[N:44][CH:43]=1)[CH3:41]>>[CH3:39][C:21]1[CH:22]=[C:23]([C:25]2[S:29][C:28]([NH:30][C:31]([NH:33][CH2:37][CH2:36][C:45]3[O:46][C:42]([CH2:40][CH3:41])=[CH:43][N:44]=3)=[O:32])=[N:27][C:26]=2[CH3:38])[CH:24]=[C:19]([CH3:18])[N:20]=1
Reactant: Cc1cc(-c2sc(NC(=O)n3ccnc3)nc2C)cc(C)n1
Reactant: CCc1cnc(CCN)o1
Agent: CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(C)c3)s2)o1

Procedure:
The titled compound is prepared by an analogous procedure to 1-methyl-3-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-urea (example 18b) by replacing imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) with imidazole-1-carboxylic acid [5-(2,6-dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide and by replacing methylamine with 2-(5-ethyl-oxazol-2-yl)-ethylamine. The preparation of 2-(5-ethyl-oxazol-2-yl)-ethylamine is described previously.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:67][CH2:68][C:69](O)=[O:70]>CN(C)C=O>[Br:67][CH2:68][C:69]([NH:15][CH:13]1[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:10])[CH2:12]1)=[O:70]
Reactant: O=C(O)CBr
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 81.6 %

Procedure:
A solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (100 mg, 0.22 mmol), PyBOP (131 mg, 0.25 mmol), N,N-diisopropylethylamine (80 μL, 0.44 mol) and bromoacetic acid (35 mg, 0.25 mmol) in dimethylformamide (1 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography eluting with 80% ethyl acetate in hexanes to afford 2-bromo-N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide (102 mg, 82% yield) as a white foam. MS (EI) for C18H14BrF3IN3O2: 568.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[NH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29]([NH:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:35])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCCC4)c(C)c3C)c2cc1OC
Yield: 57.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (40 mg, yield 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:14]1([CH3:20])C=CC=C[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].B1(C2CC2)OC(=O)CN(C)CC(=O)O1>O>[CH:20]1([C:2]2[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Reactant: Cc1ccccc1
Agent: CN1CC(=O)OB(C2CC2)OC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=[N+]([O-])c1cc(C2CC2)cc([N+](=O)[O-])c1
Yield: 64 %

Procedure:
In a 250 mL round bottom flask to a solution of 3-bromo 1,5-dinitrobenzene (2.1 g, 8.50 mmol) in toluene (90 mL) tricyclohexylphosphine (0.72 g, 2.55 mmol), Cs2CO3 (16.58 g, 51 mmol), cyclopropylboronic acid MIDA ester (2.35 g, 11.90 mmol) and 10 ml de-ionized water were added and the solution was degassed with nitrogen for 30 minutes. To the above solution Pd (OAc)2 (0.29 g, 1.28 mmol) was added under nitrogen and the reaction mixture was refluxed for 12 hours. LC MS analysis of the crude reaction indicated the completion of the reaction. The crude reaction mixture was filtered on celite pad and the volatiles were removed under reduced pressure. The dark brown oil was worked-up with 2×100 mL ethyl acetate and water (100 mL), dried on MgSO4 and ethyl acetate was evaporated under reduced pressure. The crude reaction mixture was separated by column chromatography to give Compound 8 in 64% yield.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[C:7]1=[O:26])=O)C.[CH3:27][NH2:28].O>CN(C)C=O.C(O)C>[CH3:27][NH:28][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[C:7]1=[O:26])=[O:3]
Reactant: CCOC(=O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Reactant: CN
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Temperature: 120 °C
Yield: 14 %

Procedure:
300 mg (0.84 mmol) 1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester is dissolved in 2 ml N,N-dimethylformamide. 0.17 ml (4.2 mmol) of a 33% solution of methylamine in ethanol is added. The reaction vessel is tightly stoppered and heated to 120° C. for 24 hours. Addition of water precipitates the crude material. Chromatography (silica gel, dichloromethane/methanol) yields 41 mg (14%) of a yellowish solid. MS: m/e=343.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]2Cl.[O:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]2[NH:22][CH:19]1[CH2:20][CH2:21][O:16][CH2:17][CH2:18]1
Reactant: NC1CCOCC1
Reactant: NC(=O)c1cnc2ccc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of 6-bromo-4-chloroquinoline-3-carboxamide (50 g, 175.4 mmol), tetrahydro-2H-pyran-4-amine (26.2 g, 193 mmol) and DIPEA (56.13 mL, 438.5 mmol) in DMA (500 mL) was stirred at 90° C. overnight. The mixture was allowed to cool and poured into water (1500 mL). The precipitate was filtered, washed with water (2×200 mL) and dried under reduced pressure to afford the desired material (57.3 g, 93%) as a white solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.88-1.92 (2H, m), 2.59-2.78 (2H, m), 3.50-3.62 (3H, m), 3.96-4.08 (2H, m), 4.92-4.98 (1H, m), 7.80 (1H, m), 7.99 (1H, dd), 8.46 (1H, d), 8.74 (1H, s).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.[CH:33]1([C:37](O)=[O:38])CCC1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:37](=[O:38])[CH3:33])[CH2:30][CH2:31]3)=[CH:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2ncc(N3CCNCC3)n2cc1-c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(=O)N1CCN(c2cnc3cc(CN)c(-c4ccc(Cl)cc4Cl)cn23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.3 %

Procedure:
To a mixture of [6-(2,4-dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol, prepared according to Example 38, Step 23.1), cyclobutanecarboxylic acid (0.007 mL, 0.07 mmol) and NMM (0.035 mL, 0.32 mmol) in DMF (0.5 mL) was added HATU (35.9 mg, 0.095 mmol). The reaction mixture was stirred at RT for 14 h, then poured into AcOEt (20 mL) and washed with a 2.0 M aqueous Na2CO3 solution (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred at RT for 30 min. The reaction mixture was concentrated to dryness and the remaining residue purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 20 mg, 0.029 mmol, 46% for 2 steps). MS: 459 [M+1]+; HPLC: AtRet=1.29.