Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15]>C(O)C.C(O)(=O)C>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([C:14]#[CH:15])=[CH:17][CH:18]=2)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: C#Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: C#Cc1ccc(N=Cc2cccc(C(C)(C)C)c2O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
3-tert-butyl salicylaldehyde (1) (0.70 g/3.93 mmol) and 4-ethynyl aniline (0.49 g/4.2 mmol) were dissolved in 100 ml of ethanol. Molecular sieves (3 Å, 15 g) and a few drops of glacial acetic acid were added and the mixture was stirred at room temperature for three days. After filtration over sodium sulphate and removal of the solvent, the residue was extracted several times with n-pentane. The solution was filtered again over sodium sulphate, and the solvent was removed. The title compound was obtained as a yellow powder. Yield: 43%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(c1ccccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Yield: 72 %

Procedure:
2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester from Example E5.1 (100 g) was dissolved in DMF (250 ml). Potassium carbonate (125 g) and ethyl 4-bromobutanoate (60 g) were added and the mixture was heated at 80° C. for 18 h. The mixture was cooled to room temperature, filtered and reduced in vacuo. The residue was partitioned between chloroform and 1M HCl solution. The aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The material was crystallised from EtOAc/hexane and dried in a vacuum oven at 60° C. for 3 hours to yield the title compound (98.6 g, 72%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[C:6]([C:21]#[N:22])=[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.CS(C1N=C(N2CCC(C3C=CC=CC=3)CC2)C(C#N)=C(OCC(F)(F)F)N=1)(=O)=O.[N:70]1[CH:75]=[CH:74][CH:73]=[C:72]([CH2:76][NH2:77])[CH:71]=1>O1CCOCC1>[C:15]1([CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[C:6]([C:21]#[N:22])=[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:4]=[C:3]([NH:77][CH2:76][C:72]4[CH:71]=[N:70][CH:75]=[CH:74][CH:73]=4)[N:8]=3)[CH2:10][CH2:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1cccnc1
Reactant: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Agent: CS(=O)(=O)c1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: N#Cc1c(OCC(F)(F)F)nc(NCc2cccnc2)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 57c, the 2-methylsulfanyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile was oxidized by 3-chloro-perbenzoic acid to the 2-methanesulfonyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile which was then treated in crude form with 3-picolylamine in dioxane at 40° C. during 18 hours to yield the 4-(4-phenyl-piperidin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=469.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)Cl.C(O)(=O)C>[Br:23][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of the crude 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene of Example 2a (12.6 g, up to 30 mmole) in methylene chloride (100 ml) was diluted with 75 ml of acetic acid and cooled to about 5°. A 1M solution of bromine in acetic acid (33 ml, 1.1 equiv) was added and the reaction stirred at about 5°. After 1 hour, additional bromine solution (5 ml) was added. After 2 hours total reaction time, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated in vacuo. Recrystallization from ethanol gave the title compound (7.9 g), m.p. 122°-124°. Infrared and NMR spectral data were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[Si:11](Cl)([C:14](C)(C)C)([CH3:13])[CH3:12]>C1COCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: OCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-hexandiol (44 mmol) in THF (15 mL) is cooled to 0° C. and treated with sodium hydride (44 mmol) followed by tert-butyldimethylsilyl chloride (44 mmol). The reaction mixture is stirred at room temperature overnight. Concentration in vacuo and flash chromatography affords 6-trimethylsiloxy-1-hexanol. To a solution of 6-trimethylsiloxy-1-hexanol (11.6 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 6-trimethylsiloxy-1-hexyl triflate (40) which is used without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:13]=[CH:12][NH:11][C:6]=2[N:7]=[C:8]([NH2:10])[N:9]=1.Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[Si:18]([O:17][CH2:16][CH2:15][N:11]1[C:6]2[N:7]=[C:8]([NH2:10])[N:9]=[C:4]([Cl:3])[C:5]=2[CH:13]=[CH:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Cl)nc(N)nc21
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.618 g, 15.45 mmol) in anhydrous DMF (15 mL) at 0° C. is added slowly a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (2 g, 11.86 mmol) in 5 mL of anhydrous DMF. The mixture is stirred at this temperature under N2 for 15 min, then (2-bromoethoxy)-t-butyldimethylsilane (4.0 mL, 18.64 mmol) is added at 0° C. The mixture is stirred at RT overnight. The reaction mixture is poured into water and extracted with ethyl acetate (EtOAc; 4×). The organic layer is dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash cromatography using EtOAc/cyclohexane (1/1) as eluent to yield 7-[2-(t-butyldimethylsilanyloxy)ethyl]-4-chloro-7H-pyrrolo [2,3-d]pyrimidin-2-amine as white needles: LC/MS (M+1=327). 1H NMR (CDCl3, 400 MHz) δ-0.08 (s, 6H), 0.84 (s, 9H), 3.88 (t, 2H, J=5.2 Hz), 4.17 (t, 2H, J=5.2 Hz), 4.89 (s, 2H, NH2), 6.35 (d, 1H, J=3.6 Hz), 6.96 (d, 1H, J=16 Hz).
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].C([Mg]Cl)(C)C.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[C:30]([F:32])[CH:31]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[F:25][C:26]1[CH:27]=[C:28]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(F)c1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a −15° C. solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g, 7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride (3.6 mL of a 2M solution in Et2O, 7.2 mmol). The reaction was stirred at −15° C. for 15 minutes and then 3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution in THF, 14.72 mmol) was added. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was then poured into saturated NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with water and brine (100 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes) afforded benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. Rf=0.34 (15% EtOAc/hexanes). LCMS=342.3 (M+Na)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)=[N:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(S(C)(=O)=O)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C2(N)CC2)nc1
Reaction time: 4 h
Yield: 250.6 %

Procedure:
[1-(5-Methanesulfonyl-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (148 mg, 0.47 mmol) was dissolved in DCM (4 mL). TFA (2 mL) was added dropwise. After 4 h, the reaction was concentrated in-vacuo to yield 250 mg of crude 1-(5-methanesulfonyl-pyridin-2-yl)-cyclopropylamine as a TFA salt (dark oil), m/z=213.3 [M+1]+. The product was used in subsequent reactions without further purification.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:15]=1)[C:9]([O:11]C)=[O:10]>O.O1CCCC1>[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(CN(C)C)cc(C(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)O)cc(C(F)F)c1
Reaction time: 3.5 h

Procedure:
Lithium hydroxide monohydrate (65.2 mg, 1.55 mmol) in water (0.7 mL) was added to a solution of methyl 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoate (45 mg, 0.13 mmol, from Step C) in tetrahydrofuran (2 mL). Upon stirring for 3.5 hours, the mixture was treated with 1N HCl to adjust the pH to 7, then THF was removed by rotary evaporation. Acetonitrile was added to make a 1:1 ACN:water mixture, the mixture was filtered, and the filtrate was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a white solid. Yield: 0.030 g (100%); LC-MS: 230.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 2H), 7.50 (s, 1H), 7.05 (t, 1H), 3.44 (s, 2H), 2.15 (s, 6H).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:23]I.[CH3:25][N:26]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[N:27]1.ClCCl>C(#N)C>[CH3:25][N:26]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]([I:23])[C:28]([C:34]([F:39])([F:40])[C:35]([F:37])([F:36])[F:38])=[N:27]1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)cc1C(=O)O
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC#N
Product: Cn1nc(C(F)(F)C(F)(F)F)c(I)c1C(=O)O

Procedure:
1.34 g (2.46 mmol) of ammonium cerium(IV) nitrate and then 0.75 g (2.95 mmol) of iodine are added to a solution of 1.20 g (4.91 mmol) of 1-methyl-3-pentafluoroethyl-1H-pyrazole-5-carboxylic acid in 4.3 ml of acetonitrile and the reaction mixture is heated under reflux for 18 hours. After adding 20 ml of dichloromethane, washing is carried out firstly with water, with sodium disulphite solution and finally with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and the solvent is distilled off at reduced pressure on a rotary evaporator. This gives 1.28 g of 4-iodo-1-methyl-3-pentafluoroethyl-1H-pyrazole-5-carboxylic acid (47%) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](O)=[O:7])C.C(O)(C)C.[BH4-].[Li+]>O1CCCC1>[CH2:9]([CH:5]([CH2:6][OH:7])[C:4]([OH:13])=[O:3])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(C(=O)O)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCCC(CO)C(=O)O
Temperature: 16.5 °C
Reaction time: 3 h
Yield: 543.8 %

Procedure:
A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, and nitrogen inlet-outlet is charged with 2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) and isopropanol (4.5 L). The solution is cooled to an internal temperature at 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol) in tetrahydrofuran is added over a period of 1.5 hours while maintaining the internal temperature at 15-25° C. The stirring is continued for an additional 3 h. The reaction mixture is cooled to an internal temperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). This suspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) and the biphasic mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2.0 L). The combined organic layers are washed with 20% aqueous solution of sodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until no further solvent distills to afford crude (±)-2-butyl-3-hydroxypropionic acid (4, 349.4 g, 100%) as a colorless liquid, which is used as such in the next step.