Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[CH3:29][CH2:30][CH2:31]Br>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:29][CH2:30][CH3:31])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCCBr
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCn1cc(C(=O)OCC)c(=O)c2cc(F)c(-n3cccc3)cc21
Yield: 70.1 %

Procedure:
A mixture of 3 g (0.01 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate, 2.8 g (0.02 mol) of potassium carbonate and 6 g (0.04 mol) of n-propyl bromide is heated for 5 hours at 80°-90° C. and left to cool, water is added and the precipitate formed is filtered off, washed with water and recrystallized from ethanol to give 2.4 g of a solid melting at 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][OH:12].Cl.[OH-].[Na+].[CH:16](O)=O>>[Cl:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][OH:12])[CH:16]=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cccc(Cl)c1NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OCCn1cnc2cccc(Cl)c21
Yield: 93 %

Procedure:
The 2-[(2-chloro-6-aminophenyl)amino]ethanol (72.4 g, 0.388 mol), is dissolved in formic acid (350 ml) and stirred under reflux for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure to give a dark solid, then 500 ml of HCl 2N is added to the residue and the mixture is heated under reflux for 30 min. The solution is cooled on ice and 50% NaOH solution is added until alkaline and the obtained suspension is filtered under vacuum and the resulting solid dried to give the desired product (70.8 g 93%)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[N:28]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([S:34]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:36])=[O:35])[CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
A solution of 2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g, 1.75 mmol) (prepared as previously described in Example 19, steps 1 to 3) and triethylamine in dichloromethane (10 mL) was cooled in an ice bath under a nitrogen atmosphere. The mixture was then treated with a solution of 1-piperidinesulfonyl chloride (0.39 g, 2.09 mmol) in dichloromethane (1 mL). The reaction mixture was stirred for 1.5 hours at 0-5° C. and quenched with water. The organic layer was separated, and the aqueous layer extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacuo. The residue was chromatographed on silica gel, eluting with 30% ethyl acetate/hexanes, to give 2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.48 g) as a white solid, m.p. 156-157° C.; Analysis for C19H26N3O3SF3: Calc.: C, 52.64; H, 6.05; N, 9.69; Found: C, 52.84; H, 6.00; N, 9.79.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:28][CH:27]=3)[S:30][C:31]=2[CH3:37])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:18]=[CH:17][C:10]2[C:11](=O)[NH:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>COCCOCCOC>[Cl:20][C:11]1[C:10]2[CH:17]=[CH:18][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][C:9]=2[S:13](=[O:15])(=[O:14])[N:12]=1
Reactant: O=C1NS(=O)(=O)c2cc(-c3ccccn3)ccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: COCCOCCOC
Product: O=S1(=O)N=C(Cl)c2ccc(-c3ccccn3)cc21
Temperature: 150 °C

Procedure:
A mixture of 6-(2-pyridinyl)-1,2-benzisothiazolin-3-one 1,1-dioxide (0.390 g, 1.57 mmol) and phosphorus pentachloride (0.397 g, 1.91 mmol) in diglyme (3.75 ml) was heated to 150° C. in an oil bath to give 3-chloro-6-(2-pyridinyl)-1,2-benzisothiazole-1,1-dioxide. After allowing the temperature to fall to 90° C., acetonitrile (15 ml) was added and then 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (0.503 g, 2.07 mmol) neat in one portion. Heating at 90°-95° C. was continued for three hours during which time a heavy precipitate formed. After coming to room temperature the mixture was filtered to give 0.530 g of a tan solid. Shaking with a mixture of methylene chloride and sat. aq. sodium bicarbonate, separation of the organic layer, extraction of the organic layer with methylene chloride, combination of the organic layers and extracts, drying over anhydrous magnesium sulfate, filtration and evaporation in vacuo gave the free base. Column chromatography on silica gel and recrystallization from methanol/methylene chloride/2-propanol gave 0.267 g of the title compound as a tan solid: m.p. 233°-234° C., IR(KBr) 3270, 1612, 1580, 1455, 1279, 1142, 1120 cm-1. 1H NMR (Me2SO d6) 9.45 (1H, m), 8.80 (1H, d), 8.72 (1H, s), 8.67 (1H, d), 8.50 (1H, d), 8.38 (1H, d), 8.35 (1H, d), 8.04 (1H, t), 7.88 (1H, s), 7.57 (1H, m), 3.57 (2H, t), 2.69 (2H, t), 2.31 (3H, s), 1.83 (4H, m).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH2:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:20]#[CH:21]>>[CH3:18][C:15]1[CH:16]=[CH:17][C:4]2[CH2:3][CH:2]([N:25]3[CH2:26][CH2:27][N:22]([CH2:19][C:20]#[CH:21])[CH2:23][CH2:24]3)[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:14]=1
Reactant: C#CCN1CCNCC1
Reactant: Cc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Product: C#CCN1CCN(C2Cc3ccc(C)cc3Sc3ccc(F)cc32)CC1

Procedure:
In a manner analogous to that described in Example 1, from 10-chloro-10,11-dihydro-3-methyl-8-fluoro-dibenzo[b,f]thiepin and N-(2-propynyl)-piperazine there is obtained 1-[10,11-dihydro-3-methyl-8-fluoro-dibenzo[b,f]thiepin-10-yl]-4-(2-propynyl)-piperazine, the dimethanesulfonate of which melts at 168°-174° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCNC1
Reaction time: 48 h

Procedure:
1-Benzyl-3-(RS)-(N-tert-butoxycarbonylaminomethyl)pyrrolidine (22.2 g, 0.76 mol) was dissolved in a mixture of methanol and acetic acid (1:1, 100 mL) and added to a Parr flask charged with palladium on carbon (10%, 4 g) suspended in methanol and acetic acid (1:1, 100 mL). The flask was transferred to the Parr reduction apparatus and the suspension shaken under an atmosphere of hydrogen at 60 psi for 2 days. The reaction mixture was filtered through a celite plug, eluting with a mixture of methanol/methylene chloride. The solvent was concentrated and the residue co-evaporated with toluene to afford 3-(RS)-(N-tert-butoxycarbonylaminomethyl)pyrrolidine as a colorless oil which was used directly.
Reaction SMILES: [CH3:1][O:2][C:3](=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>CCCCCC.C1COCC1>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:32]([CH:33]=[CH:1][O:2][CH3:3])[C:31]=1[Cl:30]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=Cc1cccc(Cl)c1Cl
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
Into a flask under argon containing 700 ml of dry THF was placed 159 g (0.47 mole) of methyl(triphenylphosphoranylidene)acetate. To the stirred suspension cooled in an ice/water bath was added dropwise 320 ml (0.47 mole) of 1.45M n-butyllithium in hexane. After stirring for 20 min, 74 g (0.42 mole) of 2,3-dichlorobenzaldehyde in 700 ml of dry THF was added. After 2 hr the reaction mixture was washed with an ammonium chloride solution, brine and dried (MgSO4). The solvent was evaporated in vacuo. The residue was taken up in ether, the undissolved solid was filtered off, and the solvent was evaporated in vacuo. The residue was distilled in a Kugelrohr apparatus at 0.005 mm Hg and the fraction distilling between 80°-100° C. collected. The distillate was distilled at 0.005 mm Hg using a Vigro column and the product collected between 101°-116° C. A preparative hplc on silica gel using hexane as the elutant gave 28.02 g of the title compound as an oil (33%).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)#[N:2].[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH:30]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][CH2:30][CH:22]3[CH2:21][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[CH:12][CH:13]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)#[N:2]
Reactant: O=CC1Cc2ccccc2C1
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1cc(-c2cccnc2)nn1-c1ccc(NCC2Cc3ccccc3C2)cc1

Procedure:
A solution of 5-cyano-3-(3-pyridyl)-1-(4′-aminophenyl)pyrazole (185 mg, 0.7 mmol) and indane 2-carboxaldehyde (0.96 mmol, 140 mg) in methanol (9 mL) and acetic acid (1 mL) was stirred at room temp for 30 min. Sodium cyanoborohydride (124 mg, 2 mmol) was added and stirring continued at room temperature. After 3 h the solvent was evaporated under vacuum, and the residue was taken up in sodium bicarbonate solution (50 mL) and extracted with methylene chloride (3×50 mL). The combined extract was washed with water, dried over anhydrous sodium sulfate and evaporated. Chromatography of the residue over silica gel (eluant, 15% ethyl acetate in methylene chloride) gave the title compound as a cream colored solid, m.p. 156-158° C. 1H NMR (DMSO-d6): δ 2.68-2.82 (3H, m), 3.05-3.15 (4H, m), 6.36-6.42 (1H, br. t), 6.75-6.77 (2H, d, J=8.9 Hz), 7.09-7.15 (2H, m), 7.21-7.24 (4H, m), 7.45-7.47 (2H, d, J=8.8 Hz), 7.51-7.54 (1H, m), 7.98 (1H, s), 8.21-8.28 (1H, br. d.), 8.6-8.62 (1H, br. d.), 9.1 (1H, d, J=1.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.Cl.Cl.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][N:33]=[CH:32]1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:39][CH2:38][CH2:37][CH2:36][N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:11])=[CH:6][CH:7]=1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 1.54 g. of 4-fluorophenylacetic acid, 1.62 g. of 1,1'-carbonyldiimidazole and 30 ml. of tetrahydrofuran was stirred for 2 hours, then 1.98 g. of 1H-imidazole-1-propanamine dihydrochloride was added. Stirring was continued at room temperature for an additional 18 hours, then at reflux temperature for 5 hours, 5 ml. of water was added, the mixture was heated for 30 minutes and then concentrated to remove the volatile material. The residue was diluted with methylene chloride and 25 ml. of 1N sodium hydroxide and the layers separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated, giving the desired product as a viscous oil.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CC=CC=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CC=CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC=CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
3-Cyclopentene-1-ol (0.500 g, 5.94 mmol) was stirred in DCM (95 mL). Pyridine (2.40 mL), N,N-dimethylaminopyridine (0.10 g, 1.00 mmol) and methanesulfonyl chloride (0.690 mL, 8.92 mmol) were added, and the reaction mixture was stirred at 35° C. for 4 h. N,N-Dimethylaminopyridine (0.14 g, 1.2 mmol) and methanesulfonyl chloride (0.69 mL, 8.92 mmol) were added, and the reaction was stirred overnight. TLC indicated complete conversion. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography, eluting with DCM, to afford the title compound as a clear oil (0.660 g, 68%).
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH2:12][OH:13])=[C:10]([CH:14]2[CH2:16][CH2:15]2)[N:9]=[C:8]([CH3:17])[C:7]=1[O:18][C:19](=[O:21])[CH3:20])(O)=O>CO.O.[Pd]>[OH:13][CH2:12][C:11]1[C:6]([CH3:5])=[C:7]([O:18][C:19](=[O:21])[CH3:20])[C:8]([CH3:17])=[N:9][C:10]=1[CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)Oc1c(C)nc(C2CC2)c(CO)c1COC(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCc1nc(C)c(OC(C)=O)c(C)c1CO
Yield: 84.5 %

Procedure:
The acetic acid 4-carboxyoxymethyl-6-cyclopropyl-5-hydroxymethyl-2-methyl-pyridin-3-yl ester (175) (10.6 g, 35.9 mmol) in methyl alcohol:water (1:1, 100 mL) was hydrogenated in the presence of 10% palladium on carbon (3.8 g) at room temperature for overnight. The product was filtered through a celite pad and evaporated to give acetic acid 5-hydroxymethyl-2,4-dimethyl-6-propyl-pyridin-3-yl ester (176) (7.2 g, 89% yield).
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[Cl-:15].[Al+3].[Cl-:17].[Cl-]>>[CH:1]([Cl:17])([Cl:15])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: [Cl-]
Reactant: O=C(O)c1ccccc1O
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Product: Oc1ccccc1C(Cl)Cl
Temperature: 42.5 °C

Procedure:
A mixture of 10 grams salicylic acid, 7 ml of thionyl chloride, and 0.02 gram of aluminum chloride was heated at 40 to 45°C. for 11/2 hours. The excess thionyl chloride was removed in vacuum and the salicylyl chloride reaction product can be used without further purification.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:11]2([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[F:27][C:25]([F:28])([F:26])[O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:29])([F:1])[F:30])=[CH:9][CH:8]=2)[C:11]2([OH:17])[CH2:16][CH2:15][N:14]([CH2:40][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][O:32][CH3:31])=[CH:43][CH:42]=3)[CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: COCCOc1ccc(C=O)cc1
Reactant: OC1(C(c2ccc(OC(F)(F)F)cc2)c2ccc(OC(F)(F)F)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccc(CN2CCC(O)(C(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 2.2 grams (0.0050 mole) of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol, 1.1 grams (0.0061 mole) of 4-(2-methoxyethoxy)benzaldehyde and 1.35 grams (0.0064 mole) of sodium triacetoxyborohydride in 25 mL of methylene chloride was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with 200 mL of water and stirred at ambient temperature for 5 hours. The phases were separated. The organic phase was washed three times; first, with 100 mL of an aqueous mixture of 10% sodium hydroxide, second, with 100 mL of an aqueous mixture of 10% lithium chloride, and, third, with 100 mL of brine. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride:1%-5% methanol as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.C=O.[CH2:14]([Cl:16])Cl>>[Cl:16][CH2:14][C:11]1[C:3]([CH3:2])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2c(c1)OCO2
Reactant: ClCCl
Agent: C=O
Agent: [Br-]
Product: Cc1cc2c(cc1CCl)OCO2
Reaction time: 8 h

Procedure:
To a mixture of methylene chloride (130L), concentrated HCl (130L), and tetrabulylammonium bromide (1.61 Kg) was added 5-methylbenzo[d][1,3]dioxole (10 Kg) followed by the slow addition of formaldehyde (14L, 37 wt% in water). The mixture was stirred overnight. The organic layer was separated, dried with magnesium sulfate and concentrated to an oil. Hexane (180L) was added and the mixture heated to boiling. The hot hexane solution was decanted from a heavy oily residue and evaporated to give almost pure 5-chloromethyl-6-methylbenzo[d][1,3]dioxole as a white solid. Recrystallization from hexane (50L) gave 5-chloromethyl-6-methylbenzo[d][1,3]dioxole (80% recovery after recrystallization).
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C:13]([C:28]1[C:33]([F:34])=[CH:32][N:31]=[C:30]([Br:35])[CH:29]=1)([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37].CO>>[Br:35][C:30]1[CH:29]=[C:28]([C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:7])([F:9])[F:8])[C:4]([NH2:37])=[O:3])[C:33]([F:34])=[CH:32][N:31]=1
Reactant: N
Reactant: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F)C(F)(F)F
Solvent: CO
Product: CC(CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F

Procedure:
A solution of (R)-2-[(RS)-2-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (920 mg, 1.527 mmol) in 7N NH3/MeOH (11 ml) was stirred in a sealed glass vial at 55° C. for 44 h. The reaction mixture was evaporated to dryness to leave a yellow solid that was used for the next step without further purification (diastereomer mixture). RtH4=1.03 min; ESIMS: 573, 575 [(M+H)+]; 1H NMR (400 MHz, CDCl3): b 8.00 (m, 1H), 7.97-7.91 (m, 1H), 7.80-7.63 (m, 3H), 7.55 (m, 1H), 6.63 (m, 1H), 6.41 (m, 1H), 5.74 (m, 1H), 4.15 (m, 1H), 3.97 (m, 1H), 1.84 (2s, 3H), 1.69 (2s, 3H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C1(S([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH:21]=3)[C:16]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)=[C:15]2[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([O:47]C)=[O:46])(=O)=O)C=CC=CC=1>>[CH2:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:21]=2)[C:16]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[C:15]1[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([OH:47])=[O:46])[CH:2]=[CH2:3]
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Reactant: C=CCBr
Product: C=CCn1c(CC(C)(C)C(=O)O)c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
The title compound was prepared under the conditions described in Step A and Step B of Example 38, but substituting allyl bromide for the benzenesulfonyl chloride from Example 38 (Step A).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2CCC(=O)CC2)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 92.2 %

Procedure:
To a solution of 100 mg (0.32 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 150 mg (0.96 mmoles) of piperidin-4-one in 5 ml of DMF, 88 mg (0.64 mmoles) of K2CO3 is added at ambient temperature. After being stirred for 18 hours, the reaction mixture is quenched with H2O and the mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 96 mg of disired 7-(2,2-dimethyl-propyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 92% yield.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.NC1C=CC=CC=1.[O:35]=[C:36]1[NH:41][CH2:40][CH2:39][N:38]([CH2:42][C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:37]1>>[O:35]=[C:36]1[NH:41][CH2:40][CH2:39][N:38]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([NH:47]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:48][CH:49]=2)[CH2:37]1
Reactant: Nc1ccc(CN2CCNC(=O)C2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Solvent: Nc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCNC(=O)C2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(3-oxo-piperazin-1-yl-methyl)-aniline aniline Rf value: 0.46 (silica gel, methylene chloride/methanol=9:1) C28H26N4O4
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1ccc2c(c1)C(C(F)(F)F)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(F)cc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.