Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]1([C@H:14]([CH3:17])[CH2:15][NH2:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(=O)C>[C:8]1([C@H:14]([CH3:17])[CH2:15][NH:16][C:1](/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5])=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H](CN)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: C[C@H](CNC(=O)/C=C/C(=O)O)c1ccccc1
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of maleic anhydride (765 mg, 7.8 mmol) in acetic acid (20 mL) at rt was added (S)-2-phenylpropylamine. The mixture was stirred overnight then was partially concentrated. Water (50 mL) was added causing precipitation of the product acid. The white solid was collected by suction filtration, washed with water, and dried to provide 1.44 g (79%) of the pure acid. 1H NMR (400 MHz, CDCl3): 7.38-7.32 (m, 2H), 7.29-7.24 (m, 1H), 7.24-7.20 (m, 2H), 6.68 (br m, 1H), 6.29 (d J=12.7, 1H), 6.18 (d, J=12.7, 1H), 3.78-3.69 (m, 1H), 3.47-3.38 (m, 1H), 3.11-3.00 (m, 1H), 1.33 (d, J=7.0, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=3[F:1])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1ccc(C(=O)O)c(F)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c(F)c1

Procedure:
From 2-fluoro-4-methoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.4° (c=1.02, CHCl3), ES-MS m/e (%): 419 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][O:15]COC)[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4]1)[CH3:2].Cl>CO>[CH2:1]([C:3]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1(COCOC)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: CO
Product: CCC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Yield: 40 %

Procedure:
2-Ethyl-2-methoxymethoxymethyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 21 (21.5 g, 83.7 mmol) was suspended in methanol (430 ml). Concentrated hydrochloric acid (2.15 ml) was added to this suspension followed by stirring under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the precipitates were filtered off to afford 2-ethyl-2-hydroxymethyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (7.14 g, yield 40%) as a light yellow powder.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=O)C.[OH-].[K+].CO>O>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[S:15][C:14]([C:11]3[CH:12]=[C:13]4[C:8]([CH2:7][CH2:6][CH2:5][NH:4]4)=[CH:9][CH:10]=3)=[N:18][C:17]=2[C:19]([OH:21])=[O:20])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1-c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2sc(-c3ccc4c(c3)NCCC4)nc2C(=O)O)cc1
Temperature: 55 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
To ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl)thiazole-4-carboxylate (1K) (0.483 g, 1.11 mmol) and KOH (1.24 g, 22.1 mmol) was added MeOH (10 mL) and water (45 mL). The reaction mixture was allowed to heat to 55° C. and stirred 48 hours. The reaction was monitored by LCMS. To the reaction mixture was added (0.5 g, 8.9 mmol). The reaction mixture was allowed to heat to 55° C. and stirred for 24 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude residue was added EtOAc and water. The layers were separated and the aqueous extract was acidified to ˜pH6 with 1N HCl and extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.350 g (86%) of the desired product 544-methoxyphenyl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (1L): LC/MS (APCI): m/z 367.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:21](=[O:22])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2c(Cl)c(NC(=O)Cc3ccc(Cl)cc3)ccc2s1
Yield: 76 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-chlorophenylacetyl chloride (65 mg, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(4-chloro-phenyl)-acetamide (65 mg, 0.19 mmol, 80% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([NH:23][C:37](=[O:39])[CH3:38])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(=O)OC(C)=O
Reactant: NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: c1ccncc1
Product: CC(=O)NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 95 %

Procedure:
A solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-amine (6 mg, 0.011 mmol, 1 eq.) in 1 mL of acetic anhydride and 1 mL of pyridine was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 6 mg (95%) of desired N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}acetamide. Compound was determined to be 95% pure by 1H NMR. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.95-2.11 (m, 3 H) 2.15-2.39 (m, 2 H) 2.60 (d, J=13.56 Hz, 2 H) 3.69 (br. s., 2 H) 5.23 (br. s., 2 H) 5.71 (br. s., 1 H) 7.10-7.60 (m, 13 H) 8.31-8.48 (m, 1 H), [M−H]− 554.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.[H-].[Na+].[OH-].[NH4+]>N1C(C)=CC(C)=CC=1C.[Cu]=O.C(OCC)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:5]=1)[O:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccnc1
Reactant: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Agent: O=[Cu]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(Br)cc(Oc3cccnc3)c2)cc1
Temperature: 210 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
A mixture of the 3,5-dibromo-1-p-methoxy-benzyloxybenzene (250 mg, 0.672 mmol) and 3-hydroxypyridine (128 mg, 1.34 mmol) and 96 mg (0.67 mmol) copper oxide in 3 mL of collidine was treated with sodium hydride (27 mg, 0.67 mmol) in a stirred tube. After 10 minutes to allow off-gassing, the tube was sealed and the reaction mixture was heated to 210° C. bath temperature overnight. It was then cooled and treated with ethyl acetate and aqueous ammonium hydroxide, and filtered through Celite®. The phases were separated, and the aqueous phase was extracted with additional ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The product was chromatographed (33% ethyl acetate/hexane) to give 66 mg of product 3-[3-bromo-5-(4-methoxy-benzyloxy)-phenoxy]-pyridine (25% yield). This material was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-yloxy)-phenol as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 11.22 (s, 1H), 9.77 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.36 (d, J=3.5 Hz, 1H), 7.53 (ddd, J=8.4, 2.7,1.3 Hz, 1H), 7.42 (dd, J=8.4, 4.7Hz, 1H), 7.36 (dd, J=5.4, 2.4Hz, 2H), 7.11 (t, J=7.7 Hz, 1H), 7.00 (d, J=7.0 Hz, 1H), 6.86 (s, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 6.40 (t, J=2.0 Hz, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18]3([CH2:20][CH2:19]3)[C:17]3[CH:16]=[C:15]4[O:21][CH2:22][O:23][C:14]4=[CH:13][C:12]=3[C:11]2=[O:24])[CH2:4][CH2:3]1.Br.Br[CH2:27][C:28]1[N:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]3[C:18]4([CH2:20][CH2:19]4)[C:17]4[CH:16]=[C:15]5[O:21][CH2:22][O:23][C:14]5=[CH:13][C:12]=4[C:11]3=[O:24])[CH2:4][CH2:3]2)[N:29]=1
Reactant: O=C1c2cc3c(cc2C2(CC2)N1CCC1CCNCC1)OCO3
Reactant: BrCc1cccnn1
Agent: Br
Agent: Cl
Product: O=C1c2cc3c(cc2C2(CC2)N1CCC1CCN(Cc2cccnn2)CC1)OCO3

Procedure:
Compound I-38 was prepared according to the method in example 42, using 6-[2-(4-piperidyl)ethyl]spiro[[1,3]dioxolo[4,5-f]isoindole-7,1′-cyclopropane]-5-one hydrochloride (compound II-5) and 3-bromomethylpyridazine hydrobromide as the raw materials: 1H NMR(CDCl3): δ 1.25-1.37 (m, 5H), 1.49-1.58 (m, 4H), 1.73 (d, 2H, J=11.2 Hz), 2.14 (t, 2H, J=10.7 Hz), 2.82 (d, 2H, J=11.6 Hz), 3.19 (t, 2H, J=7.8 Hz), 3.85 (s, 2H), 6.03 (s, 2H), 6.43 (s, 1H), 7.23 (s, 1H), 7.46 (dd, 1H, J=8.4, 4.9 Hz), 7.67 (d, 1H, J=8.0 Hz), 9.08 (dd, 1H, J=4.8, 1.4 Hz): m/z 407 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: COc1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (65 mg, 82%), MS (ISP) m/z=318.4 [(M+H)+], mp 278.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]=[CH:27][C:26]1=[O:31]>C1COCC1>[CH3:24][N:25]1[CH2:30][CH2:29][C:28]2=[CH:21][NH:22][CH:23]=[C:27]2[C:26]1=[O:31]
Reactant: CN1CCC=CC1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCc2c[nH]cc2C1=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 42.2 %

Procedure:
To a stirred solution of lithium bis(trimethylsilyl)amide (11 mL of 1 M solution in THF) cooled to −78° C. under nitrogen was added dropwise a solution of tosylmethyl isocyanide (1.9 g, 10 mmol) in THF (45 mL). After stirring for 40 minutes at −78° C., a solution of 1-methyl-5,6-dihydro-1H-pyridin-2-one (1.1 g, 10 mmol) in THF (10 mL) was added and the mixture was stirred at room temperature for overnight. The reaction was concentrated and the residue was partitioned between water (150 mL) and dichloromethane (150 mL). The aqueous was extracted with dichloromethane (3×). The combined organic layers were concentrated and dried under high vacuum. The resulting foam was recrystallized from dichloromethane to give 633 mg (42%) of 5-methyl-2,5,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-4-one as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:3].[OH-].[Na+].O>C(O)(=O)C>[CH3:3][N:2]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N(C)C)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1ccc(Nc2ncc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
Ethyl 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylate (7.5 g) and sodium hydroxide (3.0 g) are added to water (150 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylic acid (5 g). M.p. 261°-263° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][C:15](=O)[CH3:16])=[CH:12][CH:11]=[N:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[CH:12][CH:11]=[N:10]1
Reactant: CC(=O)Nc1ccnn1-c1ccc(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1ccnn1-c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
At 0° C., a solution of N-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)acetamide (2.58 g, 10.88 mmol) in 35 mL of THF was treated with lithium aluminum hydride (22 mL of the 1.0 M solution in THF, 22 mmol). The reaction mixture was stirred at 0° C. for 90 min then quenched with Rochelle's salt. It was extracted with EtOAc (3×100 mL) followed by DCM (2×50 mL). The combined organic solution was dried over MgSO4, filtered and concentrated. Purification of the crude material on an ISCO 80 g column (30-80% EtOAc in hexanes) afforded 1-(2,4-difluorophenyl)-N-ethyl-1H-pyrazol-5-amine (1.21 g, 50% yield) as a light yellow viscous oil. MS (ES+): 224.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][NH:32][CH3:33])=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:32]([CH3:33])[CH2:31][CH2:30][O:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:34])[CH3:21])=[CH:24][CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCOc1ccc(N(C)C)cc1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[2-(4-dimethylaminophenyloxy)-ethyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[C:5]([F:29])=[CH:4][CH:3]=1.[Cl:30][C:31]1[C:32]([C:39]([NH2:41])=[O:40])=[N:33][N:34]([CH:36]([F:38])[F:37])[CH:35]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:15])([F:17])[F:16])[CH2:13][C@:8]([C:6]2[N:7]=[C:2]([NH:41][C:39]([C:32]3[C:31]([Cl:30])=[CH:35][N:34]([CH:36]([F:37])[F:38])[N:33]=3)=[O:40])[CH:3]=[CH:4][C:5]=2[F:29])([CH2:27][F:28])[N:9]=1
Reactant: NC(=O)c1nn(C(F)F)cc1Cl
Reactant: O=C(NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Product: NC1=N[C@](CF)(c2nc(NC(=O)c3nn(C(F)F)cc3Cl)ccc2F)C[C@@H](C(F)(F)F)O1

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Method R, Example 134 above, except N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (11i) underwent the conditions described in step 10 with 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide (intermediate 32) followed by the conditions described in step 9. MS m/z=488.9 [M+H]+. Calculated for C16H12ClF7N6O2: 488.1.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCS(C)(=O)=O)c4ccc(OC(F)F)cc34)nc12
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (105 mg, 0.138 mmol) in dichloromethane (4 mL) was added drop-wise trifluoroacetic acid (2 mL) at room temperature and the reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was purified by preparative-TLC (silica gel, EtOAc as eluent) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (50 mg, 72%) as a white solid. MS: (M+H)+=521.1; 1H NMR (300 MHz, DMSO): δ 12.85 (brs, 1H), 9.13 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.93 (t, 1H, J=7.8 Hz), 7.47 (d, 1H, J=9.0 Hz), 7.24 (s, 1H), 4.72 (d, 2H, J=6.6 Hz), 3.28-3.18 (m, 2H), 3.02 (s, 3H), 2.40-2.38 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:32]>C(O)(C)C.O1CCOCC1>[ClH:1].[ClH:32].[N:26]1([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:2]3[N:11]=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Clc1nc(Nc2ccccc2)c2ccccc2n1
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: c1ccc(Nc2nc(Nc3ccc(N4CCCCC4)cc3)nc3ccccc23)cc1

Procedure:
A mixture of 2-chloro-4-phenylamino-quinazoline (0.18 g) and N-(4-aminophenyl)-piperidine (0.164 g) is heated for 3 min to produce a melt which is dissolved in isopropanol (4 ml). 4 N HCl in dioxane (1 ml) is added. Recrystallization from ethanol and diethylether yields 2-[4-(piperidin-1-yl) -phenylamino]-4-phenylamino-quinazoline dihydrochloride, Rf (A1) 0.64, FAB-MS: (M+H)+ =396. m.p.: (decomposition).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25](Br)=[CH:24][C:23]=2[CH2:37][CH3:38])[C:12]=1[CH2:39][CH2:40][CH3:41].[O:43]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44]1.C(=O)([O-])[O-].[Na+:55].[Na+]>O1CCCC1.O.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>[OH2:2].[Na+:55].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[Na+:55]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(Br)cc2CC)cccc1Oc1ccccc1C(=O)OC
Reactant: OB(O)c1ccoc1
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: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCOc2cc(O)c(C3CCOC3)cc2CC)cccc1Oc1ccccc1C(=O)[O-]
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl ester (3.00 g, 4.73 mmol), furan-3-boronic acid (1.06 g, 9.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47 mmol), and 2 M aqueous sodium carbonate solution (20 mL) in tetrahydrofuran (40 mL) was heated at 100° C. for 48 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 1.9 g (65%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J=9 Hz, 1H), 6.76 (d, J=2 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 6.60 (s, 1H), 6.43 (d, J=9 Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H), 2.66 (t, J=8 Hz, 2H), 2.62 (q, J=7 Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.57 (hextet, J=8 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 0.92 (t, J=7 Hz, 3H); MS ES+ m/z=621 (p+1); IR (CHCl3, cm−1) 3000, 1727, 1603, 1461.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CS(C)=O.[OH-].[Na+].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CCCCCC.O.CCOCC>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 155.4 %

Procedure:
A 3 L flask fitted with a mechanical stirrer was charged with 2-bromofluorene (45 g, 183.6 mmole) and 150 mL DMSO. Under a N2 atmosphere was added 80 mL of a 50% aqueous NaOH solution and 2.72 g of benzyltriethylammonium chloride (2.72 g, 11.98 mmole). This was stirred for 2 h at RT. With vigorous mechanical stirring, n-octylbromide (84.96 g, 440 mmole) was added via a dropping funnel (exotherm). Stirring was continued for 2 hours. To the reaction mixture was added 500 mL of a 1:1 mixture of water/ether, and the organic layer separated and was washed successively with brine and then water. Drying over magnesium sulfate and evaporation of the solvent gave an oil. Purification by column chromatography (silica gel; hexane as the mobile phase) gave 67 g (78% yield) of 2-bromo-9,9-dioctylfluorene as a pale oil.