Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C@:32]([F:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C@:32]([F:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (S)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Light yellow oil (>98%). MS: m/e=505(M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([CH3:21])=[C:14](F)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:14]1[C:15]([CH3:21])=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:12]([Cl:11])[CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(O)c1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1cccc(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
3.81 g (27.9 mmol) of 3-isopropylphenol, 5.30 g (27.9 mmol) of 4-chloro-2-fluoro-5-nitrotoluene and 5.79 g (41.9 mmol) of potassium carbonate are stirred in 30 ml of N,N-dimethylformamide at 100° C. for 7 h and the mixture is poured onto ice, stirred at 0° C. for 15 min and then filtered. The solid is washed with water and hexane and dried under reduced pressure (4.03 g, 98.5% purity, 46.5% yield, log P (pH 2.3)=5.54).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.Br[C:12]1[CH:13]=[C:14]([NH:18][CH3:19])[CH:15]=[CH:16][CH:17]=1>>[N:9]1[O:8][N:7]=[C:6]2[C:10]([C:12]3[CH:13]=[C:14]([NH:18][CH3:19])[CH:15]=[CH:16][CH:17]=3)=[CH:2][CH:3]=[CH:4][C:5]=12
Reactant: CNc1cccc(Br)c1
Reactant: Clc1ccc2nonc2c1
Product: CNc1cccc(-c2cccc3nonc23)c1

Procedure:
Starting from 5-chloro-benzo[1,2,5]oxadiazole and (3-bromo-phenyl)-methyl-amine. Yellow powder. MS(ES+): 226 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16](=[S:18])[NH2:17])=[CH:12]2)[CH3:2].Br[CH:28]([CH:31]=O)[CH:29]=[O:30].CN(C)C(=O)C.[BH4-].[Na+]>C(OCC)(=O)C.O.O1CCCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]1[S:18][C:28]([CH2:29][OH:30])=[CH:31][N:17]=1)=[CH:12]2)[S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:21])[CH3:2]
Reactant: CCOCCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=CC(Br)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCOCCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.4 %

Procedure:
7-[(2-Ethoxyethyl) (2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (3.00 g), bromomalonaldehyde (2.32 g) and N,N-dimethylacetamide (50 mL) were stirred at 95° C. for 3 hr. The reaction mixture was diluted with ethyl acetate and water, and the ethyl acetate layer was washed successively with saturated brine and aqueous sodium bicarbonate, dried over magnesium sulfate and filtrated. The filtrate was concentrated, subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate-hexane (1:1) to give a solid. The solid was dissolved in tetrahydrofuran (50 mL) and methanol (20 mL), sodium borohydride (176 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtrated. The filtrate was concentrated, subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate-hexane (2:1) to give the title compound (1.00 g, yield 29%) as an amorphous form.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH3:28])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[N:35][NH:36]2)=[CH:32][CH:31]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:2]3[N:3]=[C:4]([NH:27][CH3:28])[C:5]4[C:10]([C:11]5[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=5)=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:38]=2)[CH:34]=[N:35]1
Reactant: CNc1nc(Cl)nc2c1c(-c1ccncc1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CNc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]cc(-c3ccncc3)c12
Temperature: 115 °C
Yield: 33.9 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.041 g, 0.091 mmol) in nBuOH (0.8 mL) was added 6-aminoindazole (0.024 g, 0.18 mmol) and TMSCl (0.03 mL, 0.23 mmol). After heating at 115° C. for 48 h, the mixture was purified by preparative HPLC to give N2-(1H-indazol-6-yl)-N4-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (0.011 g), MS (MH 357.1), λ=214.5, 247.5, 306.8.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([NH2:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2]>B.C1COCC1>[NH2:21][CH2:19][CH2:18][O:17][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:24])[F:25])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: NC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: B
Solvent: C1CCOC1
Product: NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Yield: 85 %

Procedure:
A solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetamide (220 mg, 0.61 mmol) in borane/THF (1M, 10 ml) was stirred for 10 minutes at 70° C. in an oil bath. The solution was quenched by the addition of aqueous hydrogen chloride (2 ml of a 1M solution), diluted with water (15 ml), and extracted with ethyl acetate (3×15 ml). The aqueous layer was adjusted to pH˜8 with saturated aqueous sodium bicarbonate and extracted further with dichloromethane (3×20 ml). The organic layers were combined and concentrated under vacuum to afford N-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl)aniline as yellow oil (180 mg, 85%). (ES, m/z) [M+H]+ 348; 1H NMR (300 MHz, DMSO): δ 8.06 (d, J=Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 6.84 (dd, J=2.7 Hz, 7.8 Hz, 1H), 3.39-3.55 (m, 6H), 2.65-2.70 (t, J=5.7 Hz, 2H), 1.90-2.10 (m, 4H), 1.15-1.40 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])[CH2:9]2)[N:5]=[C:4]([CH3:21])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([NH:37][CH3:38])=[O:36]>C(O)(C)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[N:5]=[C:4]([CH3:21])[N:3]=[C:2]([NH:31][C:32]4[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=4)[C:35]([NH:37][CH3:38])=[O:36])[N:7]=3)[CH2:9]2)=[C:14]([F:20])[CH:15]=1
Reactant: Cc1nc(Cl)nc(N2CC(Oc3ccc(Cl)cc3F)C2)n1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2nc(C)nc(N3CC(Oc4ccc(Cl)cc4F)C3)n2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 4.2 %

Procedure:
To a solution of 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-6-methyl-1,3,5-triazine (1.0 g, 3.04 mmol) in Isopropanol (10 mL) was added DIPEA (0.8 mL) and 3-amino-N-methylbenzamide (0.460 g, 3.04 mmol) and the reaction mixture was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL) and water (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-(3-(4-chloro-2-fluorophenoxy) azetidin-1-yl)-6-methyl-1,3,5-triazin-2-yl)amino)-N-methylbenzamide (0.057 g, 6%) as a solid. Observed mass (M+1): 443.1.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3=[N:17][N:18]([C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH:23]=[O:24])[C:19](=[O:20])[C:9]3=[CH:8]2)=[CH:4][CH:3]=1.[BH4-].[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3=[N:17][N:18]([C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH2:23][OH:24])[C:19](=[O:20])[C:9]3=[CH:8]2)=[CH:29][CH:30]=1
Reactant: O=Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(F)cc3)cc-2c1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2cn(Cc3ccc(F)cc3)c3ccccc3c-2nn1-c1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[5-(4-Fluorobenzyl)-3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl]benzaldehyde (Example 786) (60 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), treated with sodium borohydride (7.4 mg, 0.20 mmol, 1.3 equiv) and stirred at ambient temperature for 24 hours. The mixture was washed with brine (5 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL), treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (56 mg, 0.25 mmol, 1.6 equiv) and stirred at ambient temperature for 3 hours. The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound: 1H-NMR (400 MHz, CD3OD) δ 9.12 (1H, s), 8.19 (1H, d, J=7.9 Hz), 7.75 (1H, d, J=8.6 Hz), 7.66-7.60 (2H, m), 7.55-7.51 (1H, m), 7.44-7.38 (5H, m), 7.20 (2H, d, J=8.8 Hz), 5.73 (2H, s), 4.45 (2H, s), ppm; low resolution mass spectrometry (ES+) m/z 399.9 [(M+H)+; calculated for C24H18FN3O2: 400.1].
Reaction SMILES: [OH-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:21]=[CH:22]/[C:23]2[N:37]=[C:26]3[CH:27]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH2:28][CH2:29][CH2:30][N:25]3[N:24]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:21]=[CH:22]/[C:23]2[N:37]=[C:26]3[CH:27]([CH:31]4[CH2:32][CH2:33][N:34]([C:3](=[O:5])[CH3:4])[CH2:35][CH2:36]4)[CH2:28][CH2:29][CH2:30][N:25]3[N:24]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: CC(=O)Cl
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(C(C)=O)CC2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A 1 N sodium hydroxide solution (0.5 ml) and acetyl chloride (14 ul) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (25 mg) in methylene chloride (0.5 ml), and the reaction solution was stirred at room temperature for 40 minutes. Chloroform was added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with chloroform twice. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 25 mg of racemic 1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]ethanone. Then, the racemate was separated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title optically active compound with a retention time of 27 minutes and positive optical rotation (7.4 mg; 100% ee) and the title optically active compound with a retention time of 34 minutes and negative optical rotation (6.7 mg; 97% ee)
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.C(N(CC)C(C)C)(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:51]1([CH2:61][N:62]2[CH2:82][CH2:81][C:65]3([N:69]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH2:68][N:67]([CH2:76][C:77](O)=[O:78])[C:66]3=[O:80])[CH2:64][CH2:63]2)[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53][CH:52]=1>CN(C)C=O.ClCCCl>[CH2:29]([NH:36][C:77](=[O:78])[CH2:76][N:67]1[C:66](=[O:80])[C:65]2([CH2:81][CH2:82][N:62]([CH2:61][C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:63][CH2:64]2)[N:69]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH2:68]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of the the commercially available aminomethylated polystyrene resin (Novabiochem) (20 g, 16 mmol) in dimethylformamide (70 ml) was added a solution of the commercially available BAL-Linker (PerSeptive Biosystems GMBH) (12.88 g, 48.0 mmol) and 1-hydroxybenzotriazole (7.26 g, 48.0 mmol) in 70 ml of dimethylformamide. To this was added N,N′-diisopropylcarbodiimide (6.06 g, 48.0 mmol) followed by N,N-diisopropylethylamine (6.19 g, 48.0 mmol). The reaction was allowed to stir 20 h at room temperature. The resin was filtered and washed as follows: 3×dimethylformamide (50 ml), 3×tetrahydrofuran (50 ml), 3×dichloromethane (50 ml), 3×ether (50 ml). The resin was dried in vacuo and isolated: 23.92 g. IR spectroscopy showed an aldehyde stretching band at 1674 cm−1. To a part of this resin (0.200 g, 0.160 mmol) in 1,2-dichloroethane (8 ml) at room temperature, was added benzyl amine (0.171 g, 1.60 mmol) followed by sodium triacetoxyborohydride (0.339 g, 1.60 mmol). The reaction was allowed to shake 20 h at room temperature, filtered and washed as follows: 3×dimethylformamide/water (90/10) (8 ml); 3×dimethylformamide (8 ml); 3×dichloromethane (8 ml). The resin was suspended in dimethylformamide, treated with (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid (0.274 g, 0.640 mmol), 1-hydroxybenzotrazole (0.099 9, 0.640 mmol) and N,N′-diisopropylcarbodiimide (0.081 g, 0.640 mmol). The reaction was allowed to shake for 20 h at room temperature. The resin was filtered, suspended in dimethylsulfoxide and heated to 40° C. for 1 h. The resin was again filtered, suspended in dimethylsulfoxide (8 ml) and heated to 40° C. for 1 h. The resin was filtered and washed as follows: 3×dimethylformamide/water (90/10) (8 ml); 3×dimethylformamide (8 ml); 3×dichloromethane (8 ml) and air-dried. The resin was treated with trifluoroacetic acid/water (95/5) (8 ml) for 1 h at room temperature. The filtrate was collected and concentrated in vacuo to give the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1
Reactant: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCn2nc(N)cc2C1
Reaction time: 2 h
Yield: 95 %

Procedure:
A 500-mL Parr hydrogenation bottle was charged with 125e (2.3 g, 10.9 mmol), 10% palladium on carbon (50% wet, 570 mg dry weight) and ethanol (100 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 2 h on a Parr hydrogenation apparatus. The catalyst was removed by filtration through a pad of CELITE® 521 washing with 1:1 CH2Cl2:MeOH (500 mL). The resulting solution was concentrated under reduced pressure to afford a 95% yield (1.9 g) of crude 125f.
Reaction SMILES: C(N1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[C:11]([O:38][CH3:39])[CH:10]=2)[CH2:5]1)(=O)C.C(NC1C=CC(N)=C(OC)C=1)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=3)[C:19]([C:34]([F:37])([F:35])[F:36])=[CH:18][N:17]=2)=[C:11]([O:38][CH3:39])[CH:10]=1)([CH3:5])[CH3:7]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(C(C)=O)C4)cc3OC)ncc2C(F)(F)F)c1
Agent: COc1cc(NC(C)C)ccc1N
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC(C)C)cc3OC)ncc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
As shown in Scheme 2, a mixture of intermediate 1 of Scheme 2 (16 mg) and N1-isopropyl-3-methoxybenzene-1,4-diamine (15 mg, prepared from WO 2006/021548) in dioxane (1.0 mL) with catalytic trifluoroacetic acid was stirred overnight at 50° C. The crude was concentrated under reduced pressure and purified using HPLC (TFA modifier) to give the title compound (8 mg) as a TFA salt. 1H-NMR (DMSO-d6, 400 MHz) δ 10.12 (s, 1H), 8.49 (br, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.71 (br, 1H), 7.47 (d, J=6.4 Hz, 1H), 7.23 (m, 3H), 6.44 (dd, J=10.0, 16.8 Hz, 1H), 6.23 (m, 2H), 5.91 (m, 1H), 5.75 (dd, J=1.6, 10.0 Hz, 1H), 5.21 (m, 1H), 3.68 (s, 3H), 1.10 (d, J=6.0 Hz, 1H); calculated mass for C24H25F3N6O2: 486.2. found: 486.9 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)CC>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:10]([CH2:13][CH2:14][CH2:15][C:16]3=[O:18])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccc(-c2ccccc2)cc1
Solvent: CCC(=O)O
Product: O=C1CCCc2ccc(-c3ccccc3)cc21
Yield: 30 %

Procedure:
4- (4'-Biphenylyl) butanoic acid (80g, 0.333 mole m.p. 116° C prepared by the Clemmensen reduction of 3-(4'-biphenylycarbonyl) propanoic acid) was cyclised with 85% polyphosphoric acid as described in example 8(a) to give 20.98g (30%) of the tetralone m.p. 67° C after recrystallisation from 40-60 petrol. (Found; C, 86.30; H, 6.53; C16H14O requires; C, 86.45; H, 6.35%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([OH:9])[CH:8]=1)#[N:2].[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[OH:9]
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(N)c(O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of 5-cyano-2-nitrophenol (250 mg, 1.5 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (175 mg, 86 %). 1H NMR (CD3OD): d 7.00 (d, 1H), 6.88 (s, 1H), 6.69 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[C:3]=1[CH2:17][OH:18].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:13])([CH3:14])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[C:3]=1[CH:17]=[O:18]
Reactant: Cc1cc2c(c(CO)c1C)C(C)(C)CCC2(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: Cc1cc2c(c(C=O)c1C)C(C)(C)CCC2(C)C
Yield: 61 %

Procedure:
Treatment of 5,6,7,8-tetrahydro-2,3,5,5,8,8-hexamethyl-1-naphthalenemethanol (1.30 g) with PCC, in an analogous way to that described above, afforded 456.0 m cg of 5,6,7,8-tetrahydro-2,3,5,5,8,8-hexamethyl-1-naphthalenecarbaldehyde (M.p. 74°-80°) and mother liquors (476.0 g, 80% pure), with an estimated yield of 61%. The analytical data from this product is also described hereinafter.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24]>CN(C=O)C>[CH2:7]([O:22][C:20]1[CH:19]=[CH:18][C:17]([C:23](=[O:25])[CH3:24])=[C:16]([OH:15])[CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Potassium carbonate (27.2 g, 0.2 mol) followed by benzyl bromide (7.04 mL, 59.2 mmol) were added to a solution of 1-(2,4-dihydroxy-phenyl)-ethanone (10 g, 66 mmol) in DMF (90 mL). The mixture was stirred for 2 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) followed by recrystallization gave the title compound as a white solid (8.7 g, 55%). 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 5.09 (s, 2H), 6.50 (s, 1H), 6.51 (dd, J=9.1, 3.9 Hz, 1H), 7.34-7.43 (m, 5H), 7.64 (d, J=9.1 Hz, 1H), 12.73 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5].[BH3-]C#N.[Na+].[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>CO.[Cl-].[Cl-].[Zn+2]>[CH2:21]([NH:2][C@@H:3]([CH:4]([CH3:6])[CH3:5])[C:7]([O:9][CH3:10])=[O:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: C=CCCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: C=CCCCCCN[C@H](C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution (0.3M) of L-valine, methyl ester, hydrochloride in dry MeOH was added ZnCl2 (1.0 eq.), NaCNBH3 (1.2 eq.), hept-6-enal 66 (1.2 eq.), and the reaction mixture was stirred at RT overnight. Then the volatiles were evaporated at reduced pressure and the residue taken-up in CH2Cl2 and washed with a saturated aq. solution of NaHCO3. The organic layer was dried over Na2SO4 and evaporated at reduced pressure affording the title compound (98%) as yellow pale oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=1.N1C=CC=CC=1CC(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cc(F)ccc1O
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1Oc1ccc2c(c1)CCCC2=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol), 4-fluoro-2-methylphenol (1.7 g, 13.3 mmol), 1-pyridin-2-ylacetone (240 mg, 1.8 mmol) and Cs2CO3 (5.8 g, 17.8 mmol) in DMSO (40 mL) was added CuBr (127 mg, 0.9 mmol) at rt under N2. The reaction was stirred at 100° C. overnight. The reaction was cooled, diluted with water (50 mL), and extracted with EtOAc (3×50 mL). Organics were washed with water (3×50 mL) and brine (50 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (PE:EtOAc=30:1) gave 2.3 g (95%) of the title compound as a colorless oil. [M+H] Calc'd for C17H15FO2, 271. Found, 271.