Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]3[N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:13][CH2:14][C:10]=3[C:9]([C:20]([O:22]CC)=[O:21])=[N:8][C:7]=12)#[N:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]3[N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:13][CH2:14][C:10]=3[C:9]([C:20]([OH:22])=[O:21])=[N:8][C:7]=12)#[N:2]
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cnn2c3c(c(C(=O)O)nc12)CCN3C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To 10.00 g (30.73 mmol) of ethyl 3-cyano-8-cyclopentyl-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine-5-carboxylate were added 200 ml of tetrahydrofuran and. 200 ml of ethanol. While stirring under cooling with ice water, 54 ml of a 1N aqueous solution of sodium hydroxide were added to the mixture, and stirring was continued for 1 hour at the same temperature. Furthermore, 500 ml of a 1:1 mixed solvent of tetrahydrofuran and ethanol were added, and the resultant mixture was stirred at the same temperature for a while. The reaction mixture was then acidified with concentrated hydrochloric acid, and insoluble solids were collected by filtration, washed with water and dried to give 9.09 g (yield: 91.04%) of the intended compound.
Reaction SMILES: Cl[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].Cl.[O:22](C1C=CC(C(C)=CC(O)=O)=CC=1)C1C=CC=CC=1.[OH-].[K+]>>[O:14]([C:11]1[CH:12]=[CH:13][C:8]([C:2]([OH:22])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=CC(=O)O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(Cl)(CC(=O)O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(O)(CC(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
1 g. of 3-chloro-3-p-phenoxyphenyl-butyric acid (obtainable by an addition reaction of HCl with 3p-phenoxyphenyl-2-butenoic acid) and 25 ml. of 20% potassium hydroxide solution are boiled for 10 minutes, cooled, washed with ether and acidified to give 3-p-phenoxyphenyl-3-hydroxybutyric acid, m.p. 137°-138°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5].Cl[CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.[Na+].[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([S:37]([O-:39])=[O:38])=[CH:33][CH:32]=1>C1COCC1.CN(C)C=O.O>[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([S:37]([CH2:17][CH2:18][S:19]([OH:21])(=[O:5])=[O:20])(=[O:39])=[O:38])=[CH:33][CH:32]=1.[F:1][C:2]([F:14])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: COc1ccc(C(=NO)C(F)(F)F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCS(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 40 mL of THF are dissolved 4.38 g (20.0 mmol) of 2,2,2-Trifluoro-1-(4-methoxyphenyl)-ethanone oxime and the solution is cooled in an ice-bath. To the solution are added successively 2-chloroethanesulfonyl chloride (2.3 mL, 22.0 mmol) and triethylamine (6.4 mL, 46.0 mmol), and the reaction solution is stirred at 0° C. for 1 h. Then, p-toluenesulfinic acid sodium salt (3.56 g, 20.0 mmol) in dimethylformamide (DMF) (80 mL) is added and the reaction solution is stirred at room temperature for 0.5 h. After the reaction mixture is poured into water, the crude product is extracted with ethyl acetate twice, washed with water, dried over MgSO4 and concentrated. The residue is purified by recrystallization from ethanol/toluene to afford the product as white solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.49 (s, 3H), 3.53 (t, 2H), 3.77 (t, 2H), 3.88 (s, 3H), 7.00 (d, 2H), 7.42 (d, 2H), 7.50 (d, 2H), 7.80 (d, 2H). mp. 157-158° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][OH:16])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(NC(=O)CO)cc1
Reaction time: 10 h
Yield: 36.1 %

Procedure:
2-[4-(2-Benzyloxyacetylamino)phenoxy]propionic acid methyl ester 68 (15 grams, 43.7 mmol) was dissolved in methanol (150 ml) in a pressure vessel, palladium on carbon (5%, 8 g) added and the mixture stirred under a hydrogen atmosphere (2.5 Kg) for 10 hrs. The catalyst was removed by filtration and the methanol distilled off. The crude 69 was recrystallised in chloroform:hexane (1:6) to give pure 69 (4 g, 36.3%) as a white powder. M.p: 111-112.6° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][C:36]=1[O:43][CH3:44].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:37][C:36]=1[O:43][CH3:44]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Yield: 104 %

Procedure:
In a manner similar to the method described in Example 379, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (64 mg, 0.137 mmol) and 4-aminomethyl-2-methoxy-benzoic acid methyl ester (55 mg, 0.282 mmol) in N,N-dimethyl formamide (5 mL) were reacted with DIPEA (111.3 mg, 0.861 mmol), HOBt (38.8 mg, 0.287 mmol) and HBTU (107.6 mg, 0.284 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (91.8 mg, ˜100%). HRMS (ES+) m/z Calcd C33H33Cl2F2N3O4+H [(M+H): 644.1889. Found: 644.1885.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][NH:17][C:18](=[O:29])[CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:21][CH:19]([CH3:20])[C:18]([NH:17][CH2:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:29]
Reactant: CCn1c2ccccc2c2cc(CNC(=O)C(C)NC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)N)ccc21
Yield: 99.9 %

Procedure:
A solution of the compound obtained in Step 1 (324 mg, 0.82 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room temperature for 15 min, and concentrated under reduced pressure. To the residue were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give 2-amino-N-((9-ethyl-9H-carbazol-3-yl)methyl)propanamide (242 mg, 0.819 mmol, 100%) as a white powder.
Reaction SMILES: C1COCC1.[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH4+].[Cl-]>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.CCO>[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: OC(CN(Cc1cccc(Cc2ccccc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 62 %

Procedure:
To a THF (4 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh3)4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4Cl, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3.0.4 EtOH: C, 72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]+, found: 478.1984. 1H NMR (C6D6) δ1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:7]=[CH:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(c1ccccc1)C=C2
Yield: 59.1 %

Procedure:
To 1.5 L of toluene was added 32 g (0.133 mol) of 6-methoxy-1-phenyl-indan-1-ol and 100 mg of p-toluenesulfonic acid and the mixture was placed on a Rotovap® and the solvent was distilled in vacuo (40 mm) until a brown oil residue was obtained. The brown oil was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 17.47 g (60.2%) of 1-phenyl-6-methoxy-indene as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:15]1[CH2:19][CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16]1)[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(c1ccco1)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(c1ccco1)[C@@H]1CCNC1
Reaction time: 4 h
Yield: 106.2 %

Procedure:
An ethanol (10 ml) solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-benzyloxycarbonylpyrrolidine [F1] (507 mg, 1.37 tool) was mixed with 10% palladium-carbon catalyst (53.8% moisture, 500 mg), and catalytic hydrogenation was carried out at room temperature for 4 hours under ordinary pressure. The reaction solution was filtered and the solvent of the filtrate was evaporated under a reduced pressure to obtain 358 mg of the crude title compound as colorless crystals. This was used in the subsequent reaction without purification.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)#N.Cl.C(C1(C2C=CC=CC=2S[C:40]2[CH:45]=CC=CC=2)CCN(C)CC1)#N.S(Cl)(Cl)=[O:47].[BrH:50]>C(O)C>[BrH:50].[CH2:45]([C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)=[O:47])[CH3:40]
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(C#N)(c2ccccc2Sc2ccccc2)CC1
Agent: Br
Agent: Cl
Solvent: CCO
Product: CCC(=O)C1(c2ccccc2Sc2ccccc2)CCN(C)CC1
Reaction time: 16 h

Procedure:
A mixture of 4-cyano-1-methyl-4-(2-phenylthiophenyl)-piperidine, free base of Example 3, in 15 ml of 48% hydrobromic acid is stirred at reflux for 16 hours. Thereafter, the excess acid is removed under reduced pressure, leaving a solid to which is added 10 ml of freshly distilled thionyl chloride. A clear solution results as the mixture is warmed on a steam bath. The excess thionyl chloride is distilled off, leaving a residue which is dissolved in 50 ml of absolute ethyl alcohol. The alcoholic solution is stirred at reflux for 1 hour and then permitted to stand for 16 hours. Then, the ethyl alcohol and any excess acid is removed under reduced pressure. The residue is dissolved in water and the aqueous solution is basified with dilute, ice cold sodium bicarbonate, liberating an amine which is dissolved in ether. The ethereal solution is dried before concentrating in vacuo. The residue, in ether, is converted to its hydrobromic acid salt which is recrystallized from a methyl alcohol-acetone-ether mixture to give 4-ethylcarbonyl-1-methyl-4-(2-phenylthiophenyl)piperidine hydrobromide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][C:28](=[O:30])[CH2:27][C:26](=[O:31])[CH:25]1C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CCOCC.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][C:28](=[O:30])[CH2:27][C:26](=[O:31])[CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CC(=O)C2C(=O)OC)c(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)CC(=O)C2)c(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 59.6 %

Procedure:
A mixture of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-carbomethoxy-1,3-cyclohexanedione (20.8 g, 43.5 mmole), dioxane (40 ml) and 20% sodium hydroxide (40 ml) was heated at 100° C. for 2.5 hours. It was cooled in an ice bath and acidified with concentrated hydrochloric acid. This mixture was heated for one hour at 100° C., cooled to 0° C. and then neutralized with sodium bicarbonate. The resultant mixture was added to saturated sodium bicarbonate and ether. The ether extract was dried over magnesium sulfate and evaporated to an oil. Purification of this oil via column chromatography on one kg of silic gel eluted with 10% acetone-ether gave 10.9 g (60%) of the title compound.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([NH:14][C:15]1[C:16](=[O:26])[O:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[OH:25])(=[O:13])[CH3:12].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]1([S:7]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[O:17][C:16](=[O:26])[C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:24]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1cc2cccc(O)c2oc1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2cccc(OS(=O)(=O)c3ccccc3)c2oc1=O
Yield: 85.4 %

Procedure:
Benzenesulfonyl chloride (4.0 g, 22.8 mmol) was added to a solution of 3-acetylamino-2-oxo-8-hydroxychromen (5.0 g, 22.8 mmol) in pyridine (50 mL) followed by stirring for one night. Chloroform (100 mL) was added thereto and crystals were filtered therefrom and washed with hexane. The crystals were dried to give 7.0 g (85%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([F:15])=[C:13]2[C:8]([CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:14]([F:15])=[C:13]2[C:8]([CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(c1F)NC(c1cccc(Br)c1)C(C)(C)C2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1F)NC(c1cccc(N3CCOCC3)c1)C(C)(C)C2
Temperature: 120 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (63.0 g, 154 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (30.2 g, 50%) as a yellow oil: LC/MS m/e calcd for C19H19BrFNO2 (M+H)+: 393.27, observed: 392.0 & 394.0. A mixture of 2-(3-bromo-phenyl)-8-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (6.0 g, 15.3 mmol), morpholine (13.3 mL, 153 mmol), copper(I) iodide (874 mg, 4.6 mmol), N,N-dimethylglycine hydrochloride (1.3 g, 9.2 mmol) and potassium carbonate (8.5 g, 61.2 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (4.8 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27FN2O3 (M+H)+: 399.48, observed: 399.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]2.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)=[CH:24][CH:23]=1
Reactant: NC(=O)N1CCCc2cc(-c3cnccc3Br)cnc21
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cnccc3-c3ccc(F)cc3)cnc21
Temperature: 100 °C
Yield: 74.6 %

Procedure:
6-(4-Bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (50 mg, 0.15 mmol), 4-fluorophenylboronic acid (42 mg, 0.30 mmol) and 2.0 M Na2CO3 aqueous solution (0.15 mL, 0.30 mmol) are dissolved in 1.0 mL of 1,4-dioxane. The Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (7.7 mg, 0.011 mmol) is added. The mixture is heated at 100° C. for 3.5 hrs and then it is cooled down to room temperature. 30 mL of DCM and 20 mL of water are added and the organic layer is separated. The aqueous layer is extracted with DCM (2×20 mL) and all the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 39 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]=[CH:5][C:6]1[N:7]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12](Br)=[CH:11][CH:10]=2.CO>[Ni].C1COCC1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[N:7]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C=Cc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A mixture of 3-[2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl]acrylic acid methyl ester (100 mg), Raney-nickel (suitable amount), methanol (2.0 ml) and THF (2.0 ml) was stirred at room temperature under a hydrogen atmosphere for 3 hrs. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (55 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)(CC=C(C)C)C(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(CCC(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 21 h
Yield: 97.2 %

Procedure:
Palladium on carbon (4.26 g, 5%, “50% wet”, Alfa) was added to a solution of rac-2-methyl-2-(3-methyl-but-2-enyl)-malonic acid diethyl ester (12.15 g, 50.1 mmol) in ethyl acetate (225 mL) at 25° C. The atmosphere above the reaction mixture was evacuated and replaced with hydrogen from a balloon (3 cycles). The reaction mixture was then stirred under an atmosphere of hydrogen (3 balloons) at 25° C. for 21 h, and then was filtered through Celite. The filtrate was concentrated in vacuo to afford rac-2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (11.91 g, 48.7 mmol, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (6H, d, J=7.0 Hz), 1.07-1.13 (2H, m), 1.25 (6H, t, J=6.9 Hz), 1.39 (1H, s), 1.48-1.57 (1H, m), 1.84-1.88 (1H, m), 4.13-4.21 (2H, m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7]([O-])(=[O:9])=[O:8].[Na+].P(Cl)(Cl)([Cl:19])=O>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7]([Cl:19])(=[O:9])=[O:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Product: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reaction time: 5 h
Yield: 90.2 %

Procedure:
10 g of sodium 3-trifluoromethylbenzylsulfonate was slowly added to 17.7 ml (29.1 g) of phosphorous oxychloride. The resulting slurry was stirred at 100° to 105° C. for five hours. The reaction mixture was then cooled and filtered. The filter cake was washed with methylene chloride, the washings were combined with the filtrate and then evaporated to dryness affording 8.9 g of 3-trifluoromethylbenzylsulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:17](=[O:18])[C:16]([F:23])([F:22])[F:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCNCCOc1cccc(Br)c1
Solvent: C1CCOC1
Product: O=C(NCCNCCOc1cccc(Br)c1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
To a stirred, 0° C., solution of N1-(2-(3-bromophenoxy)ethyl)ethane-1,2-diamine (4.7 g, 17.9 mmol) in anhydrous tetrahydrofuran (180 mL) was added ethyl trifluoroacetate [383-63-1] (2.1 mL, 17.9 mmol). The resultant solution was allowed to stir under N2 blanket for 15 minutes then evaporated to dryness to obtain N-{2-[2-(3-Bromo-phenoxy)-ethylamino]-ethyl}-2,2,2-trifluoro-acetamide as 6.3 g of yellow solid. LRMS (ESI) m/z 355.1/357.1 [(M+H)]+, calc'd for C12H14BrF3N2O2: 355.16.