Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1>O1CCCC1.[Ni]>[NH2:6][C:5]1[C:7]([NH2:9])=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1cc(F)cc(N)c1N

Procedure:
25 g (0.147 mol) of 4-fluoro-2-methyl-6-nitroaniline in 250 ml of tetrahydrofuran are hydrogenated at about 34° C. for 2 hours in the presence of 8 g of Raney nickel. The reaction mixture is then filtered off and concentrated. The title compound is obtained as a brown oil.
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:22]([O-:24])=[O:23].[CH3:25][C:26]([N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)([CH3:29])[C:27]#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>CS(C)=O.[Cu](Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[Cl:21][C:16]1[CH:15]=[C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([C:28]#[C:27][C:26]([CH3:29])([N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[CH3:25])=[C:4]([N+:22]([O-:24])=[O:23])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1Br
Reactant: C#CC(C)(C)N1CCN(C)CC1
Agent: Cl[Cu]Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(C)(C)C#Cc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 9 h
Yield: 49.9 %

Procedure:
A solution of (7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine hydrochloride (42.0 g, 96.8 mmol), 1-(1,1-dimethyl-2-propynyl)-4-methylpiperazine (4a) (19.3 g, 116 mmol) and triethylamine (47.2 mL, 339 mmol) in DMSO (400 mL) was subjected 3 times to the step of degassing under reduced pressure and then displacement with nitrogen. Copper iodide (I) (460.8 mg, 2.4 mmol), triphenylphosphine (2.53 g, 9.6 mmol) and palladium(II) acetate (543 mg, 2.4 mmol) were added. The mixture was stirred at 80° C. for 9 hrs and allowed to cool to room temperature. The mixture was poured into ethyl acetate (750 mL) and 1% aqueous ammonia solution (1.5 L), and Celite (50 g) was added, which was followed by stirring. Insoluble material was filtered off and the organic layer was washed with brine (500 mL×2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate-methanol mixed solvent (10:1, 130 mL) was added to the residue. The mixture was stirred and the precipitate was collected by filtration. The filtered product was suspension-washed with acetonitrile (100 mL) and dried to give a nitro compound 3a (23.3 g, 48.3 mmol, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][CH2:17][CH2:16][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc2cc(C(=O)OC)[nH]c2c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a light brown, homogeneous solution of methyl 6-hydroxy-1H-indole-2-carboxylate (1.4862 g, 7.77 mmol) and 1-bromo-2-methoxyethane (0.731 mL, 7.77 mmol) in DMF (38.9 mL) under nitrogen was added cesium carbonate (2.53 g, 7.77 mmol). The reaction was heated to 55° C. and stirred overnight. The reaction was cooled to room temperature, diluted with EtOAc (200 mL) and filtered through CELITE®. The filtrate was washed with water (4×50 mL) and brine (2×50 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 20-60% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give desired product (0.8592 g) as a white solid. Mixed fractions were combined and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 80 g column eluting with 20-60% EtOAc/hexanes to give another crop of desired product (0.1673 g) as a white solid.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN([CH:12]=[N:13][C:14]1[C:15]([C:24]([O-:26])=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)C.C(O)(=O)C>O1CCCC1.O>[O:26]=[C:24]1[C:15]2[C:14](=[CH:23][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:16]=2)[NH:13][CH:12]=[C:7]1[C:6]#[N:8]
Reactant: CN(C)C=Nc1cc2ccccc2cc1C(=O)[O-]
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c[nH]c2cc3ccccc3cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5.6 g (30 mmol) of 3-amino-2-napthoic acid in 30 mL of N,N-dimethylformamide dimethyl acetal is refluxed for 6 hours. Removal of the solvent yields 7.06 g (86.4%) of methyl 3-{[(dimethylamino)methylidene]amino}-2-naphthoate as a dark oil residue. To a solution of 20.8 mL (52 mmol) of n-butyllithium (2.5M in hexane) in 18 mL of tetrahydrofuran (THF) is added dropwise a solution of 5.97 mL (114 mmol) of acetonitrile in 100 mL of THF at −78° C. After completion of addition, the suspension is stirred for 15 minutes. To this is added 7.02 g (26 mmol) of 3-{[(dimethylamino)methylidene]amino}-2-naphthoate in 50 mL of THF dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour. Then 7.8 g (130 mmol) of acetic acid is added dropwise. The reaction mixture is warmed up to room temperature and diluted with water. The precipitate is collected by filtration and washed with water and ethyl acetate. After drying in vacuo, this yields 3.80 g (67%) of the product as a yellow solid, mp>260° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:21]([O-])=O)=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:6]=1[NH2:21])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(F)cc(Nc2ccc(I)cc2F)c1N
Temperature: 70 °C
Yield: 40 %

Procedure:
A suspension of N-(3-(allyloxy)-5-fluoro-2-nitrophenyl)-2-fluoro-4-iodobenzenamine (Intermediate 11, 1.56 g, 3.73 mmol) in ethanol (20 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution was added dropwise a freshly prepared solution of Na2S2O4 (1.94 g, 11.19 mmol) in water (3.5 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and concentrated to yield 3-(allyloxy)-5-fluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (600 mg). 1H-NMR (400 MHz, CDCl3): δ 3.65 (2H, bs), 4.57 (2H, d, J=5.6), 5.32 (1H, d), 5.40 (1H, s), 5.46 (1H, d), 6.03-6.10 (1H, m), 6.45 (1H, dd, J=10.4, 2.8), 6.52 (1H, dd), 6.59 (1H, t) 7.27 (1H, d, J=9.2), 7.38 (1H, dd, J=10.4, 2).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]2OC(=O)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1CS[C@@H]2[C@H](N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 3-acetoxy-7beta-aminocepham-4-carboxylic acid diphenylmethyl ester (4a) in dichloromethane cooling at -25° to -20° C. is added triethylamine (1 to 3 equivalents). The mixture is warmed slowly up to 0° to 5° C. and let stand overnight. To this is added ice-water (20 parts), stirred for 20 minutes, and extracted with dichloromethane. The extract is washed with hydrochloric acid, water, aqueous 7% sodium hydrogen carbonate, and aqueous 5% sodium chloride, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield 61.0% from (1). mp. 159°-160° C. (decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[Cl:62])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[Cl:62])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2Cl)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2Cl)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 95 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2-chloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 127 mg (90%) of a white solid. MS (ISP) 445.4 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[N:28]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH:54]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C@H:55]([C:57](O)=[O:58])[CH3:56].C(=O)([O-])O.[Na+]>C(#N)C.O.C(N(CC)CC)C>[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:60]([NH:54][C@H:55]([C:57]([NH2:28])=[O:58])[CH3:56])([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(N)=O

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile hydrochloride (1,053 mg, 2.65 mmols), 1,300 mg of a BOP reagent and 554 mg of Boc-L-Ala were dissolved in 50 ml of acetonitrile, and 0.8 ml of triethylamine were added thereto. The mixture was reacted at 60° C. for 17 hours. One-hundred milliliters of water and a small amount (about 10 g) of sodium hydrogencarbonate were added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using a silica-gel column (eluent, mixture of dichloromethane and ethyl acetate at a ratio of 20:1), and then concentrated to produce 1,085 mg (2.12 mmols) of the final product in a yield of 80%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2>>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[C@@H:12]([C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:11][O:10]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Clc1ncnc2nc[nH]c12
Product: C[C@@H](n1cnc2c(Cl)ncnc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 47.9 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol (607 mg) and 6-chloropurine (422 mg), (2S)-2-[(1R)-1-[6-chloro-9(9H) -purinyl]ethyl]-2-(2,4-difluorophenyl) oxirane (440 mg) was obtained as a white powder by the same way as in Reference Example 2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=2)[CH:28]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)nc1)CCC2
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)ccc(C)c43)c3ccc(C(C)C)nc3)cn2)c1
Yield: 74.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-chloromethyl-4-methylpyridine hydrochloride (0.36 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.45 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2[N:3]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=2)=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: CC(C)c1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Solvent: O
Product: CC(C)c1cc(N2CCOCC2)nc(-c2ccc(Cl)cc2)n1
Temperature: 130 °C

Procedure:
A mixture of 267 mg of 4-chloro-2-(4-chlorophenyl)-6-isopropylpyrimidine and 522 mg of morpholine was heated at 130° C. for 2 hours. After cooling, 20 ml of water were added, the mixture was stirred, and the solid was filtered off with suction and dried at 50° C. in vacuo. Yield: 0.28 g.
Reaction SMILES: [CH:1]1([NH:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:21][O:22][CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C(Cl)(Cl)Cl.CO>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]1([NH:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N+:13]([O-:33])=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:21][O:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccccc3c2n1NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
N-Cyclohexyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-amine (0.51 g, 1.57 mmol) was placed in a 200 mL round bottom flask, purged with N2 and dissolved in dichloromethane (25 mL). MCPBA (0.484 g, 1.96 mmol, 77% max) was added over a S min period. The reaction was stirred at room temperature under N2. After 2 h, analysis by thin layer chromatography (TLC) (SiO2, 95:5 chloroform:methanol) showed complete conversion. The solution was diluted with dichloromethane (15 mL) and 2% sodium carbonate solution (15 mL). The mixture was transferred to a separatory funnel, and the phases were separated. The organic portion was washed sequentially with 2% sodium carbonate solution (15 mL), water (15 mL) and brine (15 mL), dried (Na2SO4), filtered and then concentrated to yield 0.431 g of N-cyclohexyl-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-amine as a tan foam.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>O1CCCC1>[OH:11][C@@H:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc21
Solvent: C1CCOC1
Product: O[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-diphenylethanol (59 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and trimethylborate (27.2 μL, 0.24 mmol) were added to a dry flask and stirred under an atmosphere of nitrogen for 1.5 hours to form a solution of (R)-4-cyclohexyl-5,5-diphenyl-2-methoxy-1,3,2-oxazaborolidine. To this solution was added borane dimethylsulfide complex (100 μL, 1.0 mmol) and the mixture was stirred at room temperature for a further 30 minutes. A solution of 1-tetralone (133 μL, 1.0 mmol) in tetrahydrofuran (5 mL) was added by means of a syringe pump at a rate of 16 mL/min and the reaction was then stirred for a further 1 hour. Thin layer chromatography (silica gel/hexane/ethyl acetate 4:1) showed no starting material. The reaction was quenched by addition of methanol. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate and washed 3 times with IN HCl. The ethyl acetate solution was dried over magnesium sulfate, filtered through a plug of silica gel and concentrated to give (S)-1-hydroxy-1,2,3,4-tetrahydronaphthalene with an ee of 96.5%. The enantiomer ratio was determined by HPLC using a Chiralcel OB 25 cm×4.6 mm column with hexane/2-propanol (9:1) mobile phase at 0.5 mL/min at 25° C. Detection with UV was at 254 nm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](O)=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][CH2:10][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.2 %

Procedure:
3,4-Difluorophenylacetic acid (0.095 g) was dissolved in tetrahydrofuran (5.0 ml). After adding 1,1-carbonyldiimidazole (0.089 g) to the resultant solution, the resultant mixture was stirred at room temperature for 15 min followedbytheadditionof 1-(piperidin-4-yl)indoline (0.1 g). After stirring at room temperature overnight, the resultant mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give a colorless oil. Then this product was dissolved in tetrahydrofuran (2.5 ml) and lithium aluminum hydride (0.046 g) was added thereto under ice cooling followed by heating under reflux for 2 hr. After cooling the reaction solution, water (0.05 ml), a 5 N aqueous solution (0.05 ml) of sodium hydroxide and further water (0.15 ml) were added thereto. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.190 g) as a colorless oil (yield: quantitative).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([NH:40][CH:41]3[CH2:44][CH2:43][CH2:42]3)[N:37]=[C:36]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:35]=2)[CH:31]=[N:32][CH:33]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]([C:28]3[CH:29]=[C:30]([C:34]4[CH:39]=[C:38]([NH:40][CH:41]5[CH2:44][CH2:43][CH2:42]5)[N:37]=[C:36]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=5)[CH:35]=4)[CH:31]=[N:32][CH:33]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cncc(-c2cc(NC3CCC3)nc(-c3ccccn3)c2)c1
Reactant: CC(C)(C)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)N1CCN(Cc2cccc(-c3cncc(-c4cc(NC5CCC5)nc(-c5ccccn5)c4)c3)c2)CC1

Procedure:
To a solution of 3-(4-tert-Butyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B11) (1.5 eq, 0.197 mmol, 54 mg) and 2M Na2CO3 (2.0 eq, 0.262 mmol, 0.13 ml) in DME (1 ml) are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclobutyl-amine (Example 2.152, step1) (1 eq, 0.131 mmol, 50 mg) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.0131 mmol, 9.6 mg). The reaction mixture is heated using microwave radiation at 90° C. for 3 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The residue is purified by reverse phase chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 533.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].[CH2:12](Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>C(O)C>[C:13]([C:12]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=1)(=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1O
Reactant: O=C(CCl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
24.4 g of salicylaldehyde and 300 ml of ethanol are mixed with 11.6 g of potassium hydroxide. The resulting suspension is agitated at room temperature until the potassium hydroxide is completely dissolved. Subsequently, 31 g of phenacyl chloride are added in portions to the solution, and the batch is heated under stirring in a reflux condenser for 2 hours. The crystals precipitated while cooling down to room temperature are filtered by suction, washed with water, and recrystallized from methanol. Another fraction may be obtained by evaporating the mother liquor. Yield: 70%, colourless crystals.