Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[K+]>CCO.O.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc([N+](=O)[O-])ccc1C(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(N)ccc1C(C)(C)C
Temperature: 25 °C
Yield: 72.5 %

Procedure:
To a refluxing solution of 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 0.4 mmol) in EtOH (2 mL) was added potassium formate (300 mg, 3.6 mmol) in water (1 mL), followed by 10% Pd—C (15 mg). The reaction mixture was refluxed for additional 60 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to dryness to give 4-tert-butyl-3-methoxyaniline (C-2) (52 mg, 72%) that was used without further purification. HPLC ret. time 2.29 min, 10-99% CH3CN, 5 min run; ESI-MS 180.0 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[CH2:20][C:21](=O)[C:22]([CH3:33])([C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=1)[CH3:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][CH:20]=[C:21]([C:22]([CH3:33])([C:24]3[CH:25]=[C:26]([F:32])[C:27]([F:31])=[C:28]([F:30])[CH:29]=3)[CH3:23])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC(C)(C(=O)CCl)c1cc(F)c(F)c(F)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C(C)(C)c3cc(F)c(F)c(F)c3)cs2)ccc1-n1cnc(C)c1
Yield: 69.1 %

Procedure:
A suspension of 78.7 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and of 90.2 mg (0.36 mmol) 1-chloro-3-methyl-3-(3,4,5-trifluoro-phenyl)-butan-2-one in ethanol (3 ml) was heated to reflux over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride/methanol 19/1 to 9/1 as eluent to yield 95 mg (69%) of the title compound as a light yellow solid. MS ISP (m/e): 459.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.38 (s, 1H), 7.83 (s, 1H), 7.63 (s, 1H), 7.23-7.18 (m, 3H), 7.01 (s, 1H), 6.88 (d, 1H), 6.69 (s, 1H), 3.68 (s, 3H), 2.13 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:15][C:16](OCC)=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(=O)C.[BH4-].[Li+].O>O1CCCC1>[OH:4][CH2:5][CH2:6][N:7]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[CH2:15][CH2:16][OH:17]
Reactant: CCOC(=O)CN(CCOC(C)=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCN(CCO)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of N-ethoxycarbonylmethyl-N-(4-fluorophenyl)-aminoethyl acetate (13.51 g) in tetrahydrofuran (135 ml) was added lithium borohydride (4.15 g) and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (9.2 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([N:28]2[C:33](=[O:34])[NH:32][C:31](=[O:35])[CH:30]=[N:29]2)[CH:25]=[C:24]([Cl:36])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:22]C)=[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]=1.B(Br)(Br)Br>ClCCl>[Cl:36][C:24]1[CH:25]=[C:26]([N:28]2[C:33](=[O:34])[NH:32][C:31](=[O:35])[CH:30]=[N:29]2)[CH:27]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:22])=[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1NS(=O)(=O)c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cnn(-c2cc(Cl)c(Oc3ccc(O)c(NS(=O)(=O)c4ccc(F)cc4)c3)c(Cl)c2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.), stirred solution of N-{5-[2,6-dichloro-4-(3,5-dioxo4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-methoxy-phenyl}-4-fluoro-benzenesulfonamide (96 mg) in dichloromethane (5 mL) was added boron tribromide (64 μL) and the resulting solution was allowed to stir at ambient temperature for 4 h. The reaction mixture was poured over ice, stirred for 0.5 h and extracted with ethyl acetate. The organic phase was dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (40% acetone/hexanes) to afford the title compound of this EXAMPLE as a colorless foam, 68 mg. m.p. 222-225° C. (dec), MS Calc.:539.2 Found:536.8.
Reaction SMILES: [OH:1][C@@H:2]([C:13]1[C:14]([CH3:36])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([OH:35])=O)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>C1COCC1>[OH:1][C@@H:2]([C:13]1[C:14]([CH3:36])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:35])[CH2:31][CH2:32]3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
1-(4′-{4-[(S)-1-Hydroxy-2-((R)-1-phenyl-ethoxy)-ethyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (0.022 g, 0.044 mmol) was dissolved in THF (3 mL) and carbonyldiimidazole (0.022 g, 0.14 mmol) was added. After 1.5 hours an additional portion of carbonyldiimidazole (0.011 g) was added. The reaction stirred for 40 minutes then carbonyldiimidazole (0.044 g) was added. The reaction stirred overnight then carbonyldiimidazole (0.044 g) was added and the reaction was heated to 50° C. After heating for 3 hours, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.100 mL, 0.67 mmol) and methanesulfonamide (0.050 g, 0.53 mmol) were added and the reaction was heated to 100° C. The reaction was monitored by analytical LCMS and when it was complete it was cooled and purified on preparatory HPLC to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](O)[CH2:10][C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]#[CH:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: C#CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Fluorophenol (5.00 g, 44.6 mmol), 3-butyn-1-ol (3.38 ml, 44.6 mmol), and triphenylphosphine (17.5 g, 66.9 mmol) were dissolved in tetrahydrofuran (100 ml), and diethyl azodicarboxylate (11.7 g, 66.9 mmol) was added thereto in an ice bath followed by stirring for 18 hours at room temperature. After the solvent was concentrated in vacuo, hexane (200 ml) and ethyl acetate (20 ml) were added thereto, and the resulting precipitate was filtered out, and then the filtrate was concentrated in vacuo. The obtained residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=1:0) to afford the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:3].[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)=[O:3])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)Oc1cccc(C(F)(F)F)c1
Product: C#CCC1CCN(C(=O)Oc2cccc(C(F)(F)F)c2)CC1

Procedure:
3-(trifluoromethyl)phenyl chloroformate (5.0 g, 29.3 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.50 g, 6.72 mmol) according to general procedure 1. Yield=1.1031 g, 64%. m/z MH+=302.02. HPLC rt=10.8 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][NH2:35])[CH:25]=[CH:26][CH:27]=2>>[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:25]=[CH:26][CH:27]=2
Reactant: NCCN1C(=O)c2cccc3cccc(c23)C1=O
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
Batch size: 7.5 g (50.4 mmol) 3-(3-pyridyl)-acrylic acid, 17.4 g (137.4 mmol) oxalyl chloride and 11.0 g (45.8 mmol) 2-(1,3-dioxo-1H, 3H-benzo[de]isoquinolin-2-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH3:21])[C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH2:18][CH2:17][CH:16]2[C:15](=[CH:24][N:25]([CH3:26])[CH3:27])[C:14](=[O:20])[CH:13]3[CH3:21])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-2-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (500 mg, 1.52 mmol) in DMF (1 mL) was added N,N-dimethylformamide dimethyl acetal (1 mL). The resulting mixture was heated to 110° C. for 2 h after which the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=2.2 min, Method [1], MS (ESI) 356 (M−NMe2+OH+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1CCCCC1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc2c(-c3cccc(C#Cc4ccccc4)c3)c(Cc3ccccc3)cnc12
Temperature: 90 °C
Yield: 77.7 %

Procedure:
A solution of 3-benzyl-4-(3-ethynyl-phenyl)-8-trifluoromethyl-quinoline (80 mg, 0.2 mmol), iodobenzene 84 mg, 0.4 mmol), piperidine (80 mg, 0.9 mmol) in toluene (2.0 mL) is treated with Pd(Cl)2(PPh3)2 (8.0 mg) and heated at 90° C. for 3 h. The reaction is then cooled and concentrated in vacuo. The residue is taken up in ethyl acetate and washed with 10 mL (1N HCl). The organic layer is dried and concentrated in vacuo to provide after chromatography 72 mg (75%) of the title compound. MS (ES) m/z 464.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:42])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 125.1 %

Procedure:
A solution of 2-[4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione (7.65 g, 17.3 mmol) in dichloromethane (100 mL) was treated with mCPBA (4.65 g, 20.7 mmol), and the resulting orange solution was stirred for four hours at room temperature. The solution was then diluted with dichloromethane (100 ml), washed with brine (3×100 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide 9.92 g of 2-[4-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione as a red semi-solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Yield: 100.9 %

Procedure:
Using general procedure A, benzylamine (1.2 mL, 11 mmol) and 1-Boc-4-piperidone (2.0 g, 10 mmol) gave 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.93 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:8]=1[CH2:16][CH3:17])C>C1COCC1.[OH-].[Na+].O>[C:14]([C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([CH2:6][CH2:5][C:4]([OH:18])=[O:3])=[C:8]([CH2:16][CH3:17])[CH:9]=1)#[N:15]
Reactant: CCOC(=O)CCc1c(C)cc(C#N)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C#N)cc(C)c1CCC(=O)O
Yield: 84 %

Procedure:
A solution of 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid ethyl ester (55.0 g, 224 mmol) in THF (220 mL) and 1N aq. NaOH solution (220 mL) is stirred at rt for 2 before it is diluted with water (200 mL) and extracted with DCM (2×200 mL). The aqueous phase is added to 32% aq. HCl solution (50 mL) at 15-30° C. A precipitate forms. The solid material is collected, washed with water and dried under high vacuum to give 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (40.87 g) as pale brown crystals; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 2.30-2.39 (m, 5H), 2.67 (q, J=7.3 Hz, 2H), 2.87-2.94 (m, 2H), 7.47 (s, 2H), 12.30 (s, 1H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].B.[OH-:10].[Na+].OO>O.O1CCCC1>[CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: [OH-]
Reactant: C=CCCCCC=C
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture containing 1.7 liter of anhydrous tetrahydrofuran (distilled from sodium/benzophenone ketyl) and 600 g (5.4 mol) of distilled 1,7-octadiene (Aldrich Chemical Co. Inc.) was prepared under nitrogen. Borane in tetrahydrofuran (1 M, 600 ml, 0.60 mol) was added dropwise to the mixture over a 1.0 hr period while the mixture was maintained at 25° C. The resultant solution was stirred for 1 hr at room temperature and then 25 ml of water was added thereto followed by 300 ml of 3 M sodium hydroxide. These additions were followed by 300 ml of 30% aqueous hydrogen peroxide while maintaining the mixture at 30° to 40° C. The mixture was stirred for 15 min and the phases which formed were separated. The aqueous phase was extracted 3 times with an equal volume of pentane. The combined pentane extracts were washed with 200 ml of 10% aqueous sodium bisulfite, then with saturated aqueous sodium chloride and then dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated and distilled to yield the title compound (bp 62°-64° C., 20 mm) as a colorless oil having the following physical characteristics:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[N:25]=2)=[O:22])=[CH:13]1)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[N:25]=2)=[O:22])=[CH:13]1
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3cn(Cc4ccccc4)c4ccccc34)n2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c[nH]c4ccccc34)n2)CC1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
Add aluminum trichloride (106 mg, 0.795 mmol) to a suspension of 1-benzylindol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamide (180 mg, 0.398 mmol) in benzene (6 mL) and heat the mixture at reflux for 1.25 hr. Then add another 2 equivalents of aluminum trichloride (108 mg) and continue heating at reflux for an additional 5.5 hr. Cool the reaction mixture to room temperature. Then pour the reaction into ice cold H2O (50 mL) and then dilute with ethyl acetate. Adjusted the pH of the solution to 11 with saturated Na2CO3, separate the layers and extract the aqueous layer with ethyl acetate (3×50 mL). Combined the organic fractions, dry with Na2SO4, filter and concentrate in vacuo. Purify the intermediate by flash chromatography on a silica gel column, eluting with CHCl3/methanol/NH4OH (93:7:1) to obtain the sub-title compound (96 mg, 67%). 1H NMR (CD3OD) 8.45 (d, J=8 Hz, 1H), 8.25 (s, 1H), 8.21 (m, 1H), 7.96 (t, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.48 (m, 1H), 7.18-7.27 (m, 2H), 3.90 (m, 1H), 2.94-3.01 (m, 2H), 2.31 (s, 3H), 2.19-2.28 (m, 2H), 1.92-2.02 (m, 2H), 1.71-1.84 (m, 2H). CIMS (Methane) m/z 363 [C21H22N4O2]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:16])=O>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=CCOc1ccc(C(=O)Cl)cc1

Procedure:
The 4-(2-propenyloxy)benzoic acid, 5 g (0.028 mol), was refluxed with thionyl chloride (37 mL, 0.51 mol) and several drops of pyridine for 8 hours. The excess thionyl chloride was removed in vacuo leaving 4-(2-propenyloxy)benzoyl chloride as a yellow liquid at 25° C. This acid chloride was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:4]=1[CH:5]=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33](Br)(Br)[Br:34]>ClCCl>[Br:32][C:33]([Br:34])=[CH:5][C:4]1[C:3]([CH2:1][CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:11][CH3:12]
Reactant: CCc1cccc(CC)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc(CC)c1C=C(Br)Br
Reaction time: 0.08 h

Procedure:
To a solution of 3.80 g (23.4 mmol) 2,6-diethyl-benzaldehyde and 12.3 g (47 mmol) triphenylphosphine in 100 ml dry dichloromethane cooled to −20° C. was added drop-wise a solution of 9.32 g (28.1 mmol) tetrabromomethane in 70 ml dichloromethane. The reaction temperature was kept below 5° C. After the addition the reaction mixture was kept at −10° C. for 5 minutes and then for 30 minutes at ambient temperature. The reaction mixture was poured onto water, extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography on silica gel with a heptane/ethyl acetate gradient as eluent: 4.50 g 2-(2,2-dibromo-vinyl)-1,3-diethyl-benzene as colourless liquid: MS (EI): 319.9 and 318.0 and 316.0 (M+.), 239.1 and 237.1 ((M-Br)+.), 158.2 ((M-Br2)+., 100%).
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:8][C:5]1[N:4]=[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)C1CCN(c2nc(Cl)ncc2Br)CC1
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
Product: NC(=O)C1CCN(c2nc(Cl)ncc2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 1-(5-bromo-2-chloropyrimidin-4-yl)piperidine-4-carboxamide E31 (0.10 g, 0.31 mmol), benzene boronic acid (46 mg, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 5 mol %) in DME (8 mL) was added a 0.5 M solution of sodium carbonate. The mixture was heated at relfux for 22 h, then cooled to r.t. and purified on an SCX-2 cartridge (MeOH, followed by 0.5 M NH3 in MeOH). The crude product was purified by chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (58 mg, 59%), m/z 317 (100%, MH+); m/z (ESI) C16H18BrClN4O requires 317.1165 found [M+H]+ 317.1161.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].N1C=CC=CC=1.[NH2:13][C:14]1[C:15]([F:38])=[CH:16][C:17]([F:37])=[C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:19]=1>C(OCC)C>[NH2:13][C:14]1[C:15]([F:38])=[CH:16][C:17]([F:37])=[C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:19]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NCC(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(F)(F)F)c(Cl)c32)c(F)cc1F
Temperature: 40 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
2,2,2-Trifluoroethylamine (50 mg) and pyridine (300 ml) were added to 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (110 mg), and the mixture was stirred at 40° C. for 2 days. Additional 2,2,2-trifluoroethylamine (50 mg) was added, and the mixture was stirred at 40° C. for 2 days. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and solids deposited were collected by filtration and washed with ethanol to obtain the title compound (90 mg) as a colorless powder.