Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=3)=[N:14][C:12]=2[N:13]=1.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)CC)C>C1COCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:37][CH3:36])=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: COc1cc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid (1 equiv) was dissolved in THF (0.1 M) and HBTU (1.5 equiv) was added. Methylamine in THF (15 equiv) was added dropwise followed by triethylamine (1.5 equiv) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and CH2Cl2. The aqueous phase was extracted with CH2Cl2. Combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:12][CH2:11][N:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=3)[CH2:15][CH2:14]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CCOc1cccc(N2CCNCC2)n1
Product: CCOc1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-ethoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4](N)[CH:3]=1.N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4]([OH:13])[CH:3]=1
Reactant: Nc1cc(Cl)c2sccc2c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1cc(Cl)c2sccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A dispersion of 7-chloro-benzo[b]thiophen-5-ylamine (2.3 g, 0.012 mol) in dil. sulphuric acid (14 ml conc. H2SO4 in 400 ml water) was heated to obtain the clear solution and it was cooled to 0° C. A cold solution of NaNO2 (0.9 g in 5 mL of water, 0.013 mol) was added dropwise and the mixture was stirred at same temperature for 1 h and then warmed to 10° C. over 30 min. Excess nitrite was then quenched with urea. The reaction mixture was then added to dil. sulphuric acid (8 mL conc. Sulphuric acid in 115 mL water) maintained at 90° C. and the mixture was further refluxed for 1 h. The reaction mixture was filtered hot and the filtrate was stirred overnight at room temperature. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water, brine, dried and concentrated. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate/9:1) to give 0.4 g of 7-chloro-benzo[b]thiophene-5-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47].Cl>ClCCl.CO>[ClH:30].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 121.2 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)quinolin-3-yl)ethanone (6.0 g, 13.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.2 g, 15.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 200 mL) after which HCl (36 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to dryness and the resultant solid was triturated with dichloromethane. The mixture was filtered, washed with dichloromethane, and dried to obtain desired product (5.2 g, 66% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.30 (s, 1H), 8.15 (dd, J=8.8, 1.9 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.10 (s, 2H), 3.81 (s, 2H), 3.55-3.31 (m, 2H), 3.29-2.89 (m, 4H), 2.89 (s, 3H), 2.82 (s, 3H), 2.80-2.35 (m, 2H); APCI MS m/z 535 [C29H28Cl2N4O2+H]+; HPLC>99% (AUC), tR=7.89 min.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].I[C:19]1[C:27]2[C:22](=[N:23][CH:24]=[N:25][C:26]=2[NH2:28])[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=[C:19]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:2]3[S:1][CH2:5][CH2:4][N:3]=3)=[O:8])[C:27]=12
Reactant: O=C(NC1=NCCS1)c1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(C(=O)NC3=NCCS3)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 66.7 %

Procedure:
A solution of [3-((4,5-dihydrothiazol-2-yl)carbamoyl)phenyl]boronic acid (19 mg, 0.08 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA30 (17.8 mg, 67% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[CH:18]([OH:22])[CH2:19][C:20]#[CH:21]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]#[C:20][CH2:19][CH:18]([C:9]1[CH:10]=[N:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[OH:22]
Reactant: Ic1ccccn1
Reactant: C#CCC(O)c1cnc2ccccc2n1
Product: OC(CC#Cc1ccccn1)c1cnc2ccccc2n1
Yield: 62.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (72 mg, 0.35 mmol) and 1-quinoxalin-2-yl-but-3-yn-1-ol (70 mg, 0.35 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2 to DCM/MeOH 9:1) to yield 60 mg (0.22 mmol, 62%) of 4-pyridin-2-yl-1-quinoxalin-2-yl-but-3-yn-1-ol.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.[Pd]>[F:35][C:19]1[CH:20]=[C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:22]=[CH:23][C:18]=1[NH:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNCC3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
A suspension of 480 mg (1 mmol) 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-piperidine-1-carboxylic acid benzyl ester and Pd/C in 2 ml of a methanol/acetic acid 1/1 mixture was stirred under H2 for 4 h. The Pd/C was filtered and the filtrate was evaporated to dryness.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][NH2:15])[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([O-:3])=[O:2].[C:23](OCC)(OCC)(OCC)[CH3:24]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:23]([CH3:24])=[N:15][N:14]=[C:9]1[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([O-:3])=[O:2]
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc([N+](=O)[O-])ccc3n12

Procedure:
In the manner given in Example 2, 6-nitro-4-(o-chlorophenyl)-2-hydrazinoquinoline, and triethyl orthoacetate are refluxed in xylene to give 7-nitro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>CN(C=O)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:12]=2[N:20]=1
Reactant: OC1CCOCC1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (0.042 mL, 0.440 mmol) in DMF (1.60 mL) was added NaH (21.0 mg, 55% dispersion in mineral oil, 0.480 mmol) at 0° C. After stirring for 30 min at room temperature, 4,6-dichloropyrido[3,2-d]pyrimidine (80.0 mg, 0.400 mmol) was added to the mixture at 0° C. After stirring for 2 hours at room temperature, the reaction mixture was quenched with saturated aq. NH4Cl, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (60.0 mg, 57%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.18-2.23 (2H, m), 3.62-3.68 (2H, m), 4.08-4.13 (2H, m), 5.59-5.63 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (2H, d, J=8.8 Hz), 8.81 (1H, s).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[CH:8]1.[Li]CCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].[Cl-].[NH4+]>C1COCC1.C1CCCCC1>[CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[C:8]1[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C[Si](C)(C)CCOCn1ccc2cccnc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cccnc2n1COCC[Si](C)(C)C
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a solution of 1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 0.0020129 mol) in THF (5 mL) at −10° C. was added a 2.0 M of n-BuLi in cyclohexane (1.2 mL). After 10 min at −10° C., the mixture was cooled to −20° C. and tributyltin chloride (0.65 mL, 0.0024 mol) was added. The mixture was stirred at rt for 1 h, the poured into a 5% aqueous ammonium chloride (20 mL), extracted with EtOAc (3×20 mL) and the combined extracts dried over anhydrous MgSO4 and concentrated in vacuo. The material thus obtained was chromatographed over silica gel eluting with 1:9 EtOAc:hexane to afford 0.7 g of the title compound. 1H NMR (400 MHz DMSO-d6) δ 0.01 (s, 9H), 0.10 (s, 2H), 0.92-0.94 (m, 9M, 1.14-1.27 (m, 6H), 1.37-1.46 (m, 6H), 1.60-1.72 (m, 6H), 3.48-3.52 (m, 2H), 5.71 (s, 2H), 6.74 (s, 1H), 7.16-7.19 (m, 1H), 8.02 (dd, J=1.6, 7.6 Hz, 1H) and 8.31 (dd, J=1.6, 4.4 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([N:14]=[C:15]2[S:19][CH2:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[CH2:24]([N:16]1[C:17]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][S:19][C:15]1=[N:14][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CBr
Reactant: O=[N+]([O-])c1ccc(N=C2NC3(CCCC3)CS2)c2c1CCCC2
Product: CC(C)CN1C(=Nc2ccc([N+](=O)[O-])c3c2CCCC3)SCC12CCCC2

Procedure:
1-Amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8-tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthaline according according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method C1a to give 2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OCC)cc1OC
Yield: 68.9 %

Procedure:
A mixture of 50 g of 3-methoxy-4-hydroxybenzeneacetic acid ethyl ester, 66.1 g of powdered potassium carbonate, 70.57 g of 1-bromotetradecane and 500 ml of acetone is heated at reflux temperature for 76 hours. The reaction is cooled, filtered and the filtrate concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2% sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-10% ethyl acetate/hexane) to give 66.6 g of the desired product as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[OH:6].[H-].[Na+]>C1COCC1.[Ni]>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:5]2[CH2:4][CH2:3][CH2:2][O:6]2)=[CH:8][CH:9]=1
Reactant: O[C@@H](CCCCl)c1ccc(Br)cc1
Agent: [Ni]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc([C@@H]2CCCO2)cc1
Yield: 75 %

Procedure:
A solution of [S]1--chloro-4-(4-bromophenyl)-4-butanol (50 mmol) in THF (25 ml) was added to a cooled suspension (0? C) of NaH (55 mmol) in THF (50 ml). After being stored for 2 h at 25C., the reaction mixture was quenched with water, brought to pH 6 with concentrated HCl, and extracted with ether (2×50 ml). The organic phase was dried over H2SO4, filtered and all volatiles removed under reduced pressure. The residue was distilled to provide the product in 75% yield, 98% ee as determined on a chiral capillary column of Ni(HFN-IR-Cam)2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:22].CS([C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1)=O.C(N(CC)C(C)C)(C)C.COCCO>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:22][C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1

Procedure:
A solution of 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (0.18 g, 0.00059 mol) with 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (85 mg, 0.30 mol) and N,N-diisopropylethylamine (0.057 g, 0.44 mmol) in 2-methoxyethanol (1.0 mL, 0.013 mol) in a microwave vessel was microwaved on 300 watts, 180° C. for 30 minutes. Repeated microwave for 30 minutes more to get to completion. Filtered through 0.45μ filter and purified by reverse phase HPLC. Concentrated and dissolved in DCM/MeOH and free-based with solid MP-carbonate. Filtered and concentrated {2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amineisolated as a brownish film (12 mg, 8%). 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.44 (t, J=8.0, 1H), 7.31 (s, 1H), 7.14 (t, J=7.5, 1H), 7.08 (d, J=8.0, 1H), 7.03 (d, J=4.7 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.57-6.45 (m, 1H), 6.46-6.43 (m, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.64 (broad d, J=12.3 Hz, 2H), 2.72-2.66 (m, 4H), 2.55-2.51 (broad m, 3H), 1.97 (broad d, J=12.4 Hz, 2H), 1.78-1.72 (m, 2H), 1.32-1.20 (m, 2H), 0.94-0.85 (m, 2H); LC/MS (ESI+): 528 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[C:12]([CH:16]=2)[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.Cl.[CH2:35]([NH2:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[C:12]([CH:16]=2)[C:13]([NH:37][CH2:35][CH3:36])=[O:14])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude acid chloride from Step A was dissolved in methylene chloride (1 mL) and treated with ethylamine hydrochloride (0.018 g; 0.217 mmol) and triethylamine (0.06 mL; 0.434 mmol) then stirred at room temperature for 1 h. The volatiles were removed in vacuo and purified by MPLC (silica gel; 0-50% ethyl acetate:hexane gradient) to afford the desired product: m/e=534 (M+2); Rt=4.57 min on LCMS.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2)=[O:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:29]2)=[O:25]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 20.3 %

Procedure:
142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 45 mg of the target compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: NCc1ccccn1
Solvent: CC#N
Product: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see Intermediate 18, 2.5 g, 7.5 mmol) and 2-aminomethylpyridine (2 eq, 1.41 g) in CH3CN (30 ml) was heated at 60° C. for 2 h. The mixture was extracted with DCM. The organic phase washed with saturated aqueous sodium hydrogen carbonate and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue taken up in diethyl ether. The precipitate was filtered off and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitro-N-(2-pyridinylmethyl)-4-quinolinamine (2.5 g) which was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.C1C[O:25][CH2:24]C1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]2[NH:14][C:24](=[O:25])[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=c1[nH]c2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Yield: 16.9 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 158 mg, 0.56 mmol) in THF (5 mL) Et3N (156 μL, 1.12 mmol) and carbonyldiimidazole (182 mg, 1.12 mmol) were added sequentially. The reaction mixture was heated to reflux for 4 h and then the solvent was removed under reduced pressure. Flash chromatography of the resulting crude oil (CH2Cl2/EtOH/aq NH3 60:8:1 to 40:8:1) followed by reverse phase chromatography (0% CH3CN in H2O to 25% CH3CN in H2O) gave the title compound as a white solid (29 mg, 17%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[CH:38]=[CH:37][C:31]2[C:32](=[O:36])[O:33][C:34](=O)[C:30]=2[CH:29]=1>>[CH3:27][C:28]1[CH:29]=[C:30]2[C:31](=[CH:37][CH:38]=1)[C:32](=[O:36])[N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[C:34]2=[O:33]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(c1)C(=O)N(c1cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c1)C2=O

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5-methyl-2-benzofuran-1,3-dione according to Method I.