Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2O)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[C:16]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH:21]([O:20][C:18]([C:16]1[N:15]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)[CH:14]=[N:13][CH:17]=1)=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: OC1CCCc2ccc(Br)cc21
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(Br)cc21
Reaction time: 0.17 h

Procedure:
To a suspension of 7-bromo-1,2,3,4-tetrahydro-naphthalen-1-ol (2.5 g, 11.0 mmol) and isopropyl 4-imidazolecarboxylate (1.18 g, 7.66 mmol), which can be prepared as described in Example 1, (2.33 g, 10.98 mmol) in THF (20 mL) at 0° C. is added triphenylphosphine and dimethyl azodicarboxylate (40% wt. in toluene, 4.01 g, 10.98 mmol). After 10 min, the cooling bath is removed and after another 30 min, water is added and the mixture is extracted twice with ethyl acetate. The organic layers are dried over magnesium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(7-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 363.02, 365.02 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.42 (d, J=6.1 Hz, 3 H), 1.44 (d, J=6.3 Hz, 3 H), 1.73-1.84 (m, 1 H), 1.89-1.98 (m, 1 H), 2.26-2.40 (m, 2 H), 2.82-2.91 (m, 1 H), 3.00 (dt, J=17.2, 5.6 Hz, 1 H), 5.27-5.37 (m, 1 H), 6.50 (t, J=5.3 Hz, 1 H), 7.26 (d, J=8.3 Hz, 1 H), 7.32 (d, J=2.1 Hz, 1 H), 7.51 (dd, J=8.3, 2.1 Hz, 1 H), 8.23 (d, J=1.5 Hz, 1 H), 8.50 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([O:22]C)=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].CC(N(C)C)=O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([OH:22])=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3OC)nc2)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)CC1
Yield: 36.5 %

Procedure:
Combined 4-(1-(5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)-5-methoxy-1H-pyrazol-4-yl)-2-fluoro-3-methylbenzonitrile (70 mg, 0.156 mmol) and DMA (1561 μl) then added lithium chloride (66.2 mg, 1.561 mmol) and heated at 70° C. overnight. The crude reaction was then diluted with DMSO (500 uL) and purified via preparative HPLC (acetonitrile-water, with TFA) to give the title compound (24.6 mg, 0.057 mmol, 36.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.33 Hz, 3H) 2.33 (d, J=2.27 Hz, 3H) 3.16 (t, J=7.20 Hz, 2H) 3.24-4.06 (m, 8H) 7.49-7.84 (m, 2H) 8.04-8.30 (m, 2H) 8.43 (br. s., 1H) 8.60 (dd, J=2.15, 0.63 Hz, 1H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10](Cl)[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1>[C:1]([O:5][C:6]([C@H:7]1[C@H:10]([CH2:11][CH3:12])[CH2:9][N:8]1[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(Cl)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C(=O)OC(C)(C)C
Yield: 86 %

Procedure:
To a stirred solution of [benzhydryl-(2-chlorobutyl)amino]acetic acid tert-butyl ester (7.7 g, 19.9 mmol, 1 eq.) in dry THF (120 mL) at −78° C. was added NaHMDS (49.7 mL, 49.6 mmol, 2.5 eq.) dropwise over 45 min. The reaction was then neutralized with AcOH (0.2 mL). The solid formed was filtered off and washed with EtOAc and the filtrate was concentrated in vacuo. The residue was redissolved in EtOAc, washed with brine, dried over MgSO4, filtered, concentrated in vacuo. The resulting product was chromatographed on silica gel using 50% DCM/hexanes/0.5% EtOAc mixture as eluent to afford (+)-trans-1-benzhydryl-3-ethylazetidine-2-carboxylic acid tert-butyl ester 86% yield. ESMS: m/z 352.3 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:36][CH3:37])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].ClC1C=C(C=CC=1)C(OO)=[O:44]>C(Cl)Cl.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:36]([CH3:37])=[O:44])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: CSc1nc(-c2cc(C(=O)NCc3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.12 g 0.227 mmol) was dissolved in CH2Cl2 (5 mL) and 50-60% 3-chloroperoxybenzoic acid (0.106 g, 0.34 mmol) was added and the mixture stirred for 10 min. The solvents were pumped off, and the residue taken up in EtOAc and washed with H2O, brine, dried over anhydrous Na2SO4 filtered and evaporated. The crude product which contained a small amount of sulfone, was flashed on silica gel (20 g) eluted with a hexane to EtOAc gradient to isolate the title compound. mp (dec) 268-270° C. LC-MS m/z 545 (M+H)+, 1.87 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].II.[I-].[K+]>CO.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])=[CH:5][NH:6]2
Reactant: Fc1cc(F)c2cc[nH]c2c1
Reactant: COC(=O)CS
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CSc1c[nH]c2cc(F)cc(F)c12
Temperature: 25 °C
Reaction time: 60 h
Yield: 15.1 %

Procedure:
To a solution of 4,6-difluoro-indole (1.00 g, 6.53 mmol) and methyl thioglycolate (584 μL, 6.53 mmol) in methanol:water (25 mL:7.0 mL) was added iodine (1.65 g, 6.53 mmol) and potassium iodide (1.09 g, 6.53 mmol). The reaction mixture was stirred at ambient temperature for 60 hours. Methanol was removed in vacuo and the aqueous layer diluted with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated in vacuo and the resulting residue was purified on a silica gel column (0-100% ethyl acetate:hexanes over 19 min) to afford the desired product (253 mg, 19% yield). LCMS>98% at 254 nm, RT=1.33 min, m/z=258 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:19](Cl)(Cl)=[S:20]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:19]=[S:20]
Reactant: Nc1ccc(-c2nc(-c3cccnc3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: S=C=Nc1ccc(-c2nc(-c3cccnc3)no2)cc1
Yield: 30 %

Procedure:
A solution of 5-(4-aminophenyl)-3 -(3-pyridyl)-1,2,4-oxadiazole in tetrahydrofuran is reacted with thiophosgene according to Example 14 to give the title compound in 30% yield, m.p. 121°-123° .
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][CH:16]=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.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[N:15][CH:16]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: OB(O)c1cncc(Cl)c1
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
Solvent: O
Product: Cc1oc(-c2cncc(Cl)c2)cc1C=O
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 5-chloropyridine-3-boronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 49%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[OH:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc([N+](=O)[O-])c(N)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 5-fluoro-2-nitroaniline (2.00 g) and tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (2.25 g) in DMF (50 mL) was added sodium hydride (60% in oil, 0.564 g), and the mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.75 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>C1COCC1>[CH3:11][N:2]([CH3:1])[C:3](=[O:10])[CH:4]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH3:13]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)C(=O)Cc1ccsc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)N(C)C)c1ccsc1
Temperature: 25 °C

Procedure:
To a solution of acetamide from Step 1 (510 mg) in THF (15 mL) at -78° C. was added LDA (mono THF, 1.5M, cyclohexane, 250 μL) followed by MeI (700 μL) after 30 min. The mixture was warmed to r.t., quenched with a saturated NH4Cl sol. and then extracted with Et2O. The organic phase was washed with H2O, brine, dried (MgSO4) and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (60:40)) to afford the title compound as a oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:12]([N+:20]([O-])=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]>O1CCCC1.[Pd]>[NH2:20][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[C:13]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CCNc1nc2ccccc2c([N+](=O)[O-])c1N1CCOCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCNc1nc2ccccc2c(N)c1N1CCOCC1

Procedure:
The 2-ethylamino-3-morpholino-4-nitroquinoline (2.0 g, 0.0066 mol) was dissolved in tetrahydrofuran (10 ml) and subjected to reduction in the presence of 10g palladium-on-carbon (0.3 g). After completion of the reaction, the palladium-on-carbon catalyst was filtered off and the mother liquor was concentrated. Following purification by chromatography on an alumina column using chloroform as a developing solvent, recrystallization from ethanol gas conducted, whereupon 4-amino-2-ethylamino-3-morpholinoquinoline was obtained in an amount of 1.2 g (yield, 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH2:19]1[CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:20]1>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:27]4[O:28][CH2:29][CH2:19][O:20][C:21]=4[CH:22]=3)[N:7]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: CCOc1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine with 3,4-ethylenedioxyaniline gave N4-(4-ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.87 (d, 1H, J=3 Hz), 7.47 (dd, 2H, J=2.4 and 5.1 Hz), 7.18 (d, 1H, J=2.4 Hz), 6.91-6.85 (m, 3H), 6.79-6.73 (m, 2H), 6.64 (bs, 1H), 4.25 (bs, 4H), 4.05 (q, 2H, J=6.9 Hz), 1.43 (t, 3H, J=7.2 Hz); 19F NMR (CDCl3): −47467; LCMS: ret. time: 24.32 min.; purity: 90%; MS (m/e): 383 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.15 g, 6.28 mmol) in ethanol (30 mL) was added 4-fluorobenzaldehyde (0.68 mL, 6.31 mmol), glacial acetic acid (0.4 mL, 6.99 mmol), and sodium cyanoborohydride (1.04 g, 15.7 mmol) at 25° C. After stirring for 3 h, the mixture was diluted with ethyl acetate (50 mL) and quenched with saturated aqueous sodium bicarbonate solution (50 mL) for 0.5 h. The mixture was filtered through Celite. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). When all solvent was removed, a solid was formed. The solid was filtered, washed with water, and dried in vacuo to afford the desired product, (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.74 g, 5.97 mmol, 95%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.05-1.16 (2H, m), 1.21 (1H, dt, J1=8.0 Hz, J2=1.6 Hz), 1.27 (3H, t, J=7.4 Hz), 1.45-1.61 (2H, m), 1.94 (1H, dt, J1=10.1 Hz, J2=1.9 Hz), 2.28 (1H, d, J=3.9 Hz), 2.43 (1H, d, J=3.3 Hz), 2.60 (1H, dd, J1=8.8 Hz, J2=1.5 Hz), 2.94 (1H, d, J=7.8 Hz), 3.66 (1H, d, J=13.2 Hz), 3.80 (1H, d, J=13.5 Hz), 4.13 (2H, q, J=7.0 Hz), 6.97 (2H, t, J=8.5 Hz), 7.26 (2H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>>[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[N:12]
Reactant: CNc1ccccc1
Reactant: C=CC#N
Product: CN(CCC#N)c1ccccc1
Temperature: 120 °C

Procedure:
1071.5 Parts by weight (10 mol) of N-methylaniline and 15.0 parts by weight of Tonsil® K 10 are placed in a 3-neck stirred flask fitted with a reflux condenser and inlet tube. The mixture is heated to 120° C. and 265.3 parts by weight (5 mol) of acrylonitrile are added at this temperature via the inlet tube. The reaction mixture is subsequently stirred for 18 hours at from 120° to 130° C. and then cooled to 60° C. The catalyst is filtered off and the liquid phase is subjected to fractional distillation. 47.7 parts by weight of acrylonitrile and 620.9 parts by weight of N-methylaniline are recovered and can be used again as starting material. The yield of N-β-cyanoethyl-N-methylaniline is 605.0 parts by weight ~75.5% conversion. The purity is 99.5% N-β-cyanoethyl-N-methylaniline.
Reaction SMILES: [ClH:1].C([S@@]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)[S@](=O)N1CCC[C@@H]1c1cc(F)ccc1F
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(F)c([C@H]2CCCN2)c1
Reaction time: 4 h

Procedure:
4M HCl solution (in Dioxane) (75 mL) was added to stirred solution of (R)-1-((S)-tert-butylsulfinyl)-2-(2,5-difluorophenyl)pyrrolidine (15 g, 52.19 mmol) in Dioxane (25 mL) and stirring was continued at 20-35° C. for 4 h. After which the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by washing with diethyl ether to afford 7.5 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC.C[C:30]1[N:35]=[C:34]([CH:36]=O)[CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH:1]([C:30]1[N:35]=[C:34]([CH3:36])[CH:33]=[CH:32][CH:31]=1)=[CH:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C=O)n1
Reactant: [Li]CCCC
Agent: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC=Cc1cccc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
n-Butyllithium (7.5 mL, 1.6M/hexanes, 12 mmol) was added to a slurry of propyltriphenylphosphonium bromide (4.62 g, 12 mmol) in THF (40 mL) at -78° C. The mixture was warmed to 0° C. and stirred 30 min., then cooled again to -78° C. A THF (10 mL) solution of 6-methyl-2-pyridinecarboxaldehyde (1.21 g, 10 mmol) was added dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 2 hours. Silica gel was added and the slurry was filtered on a short (SiO2) column eluting with 10% EtOAc in hexanes to give 990 mg of the title compound.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccccc1-c1cccc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Product: Cc1ccccc1-c1cccc2c1OC(CN)C2
Yield: 67 %

Procedure:
Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (7.79 g, 19.74 mmol) with sodium azide (5.13 g, 78.99 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.5 g, 10 wt. %) generally according to the procedure described for Example 1 provided 3.63 g (67%) of (±)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >200° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.83; H, 6.64; N, 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[CH:15]=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.C1C(=O)N([I:25])C(=O)C1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:25])=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(I)c2n1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridine (700 mg, 3.04 mmol) in THF (25 mL) was treated with n-iodosuccinimide (753 mg, 3.34 mmol, Alfa-Aesar). The reaction was stirred at 23° C. under N2. After 30 min, the solution was diluted with EtOAc (250 ml) and washed with brine (175 ml), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-40% EtOAc/hexane), affording 5-(2,6-difluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (255 mg, 78%). MS (ESI, pos. ion) m/z: 356.9 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](C2C=CC=CC=2)=[C:11]2[CH:19]=[CH:18][C:14](=[N+](C)C)[CH:13]=[CH:12]2)=[CH:6][CH:5]=1)[CH3:3].[Cl-].S(=O)(=O)(O)[OH:28]>>[CH3:1][N:2]([CH3:3])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:11]2[CH:19]=[CH:18][CH:14]=[CH:13][CH:12]=2)=[O:28])=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc(C(=C2C=CC(=[N+](C)C)C=C2)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Product: CN(C)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
Doebner, Ann. 217, 257 (1883), discloses the reaction of malachite green with sulfuric acid to give 4-(dimethylamino)-benzophenone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([CH:20]1[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]([NH2:29])=[N:23][C:22]2[CH:30]=[CH:31][CH:32]([CH3:35])[C:33](=[O:34])[C:21]1=2)=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([CH:20]1[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]([NH2:29])=[N:23][C:22]2[CH:30]=[CH:31][CH:32]([CH3:35])[C:33](=[O:34])[C:21]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC1C=CC2=C(C1=O)C(C(=O)[C@H](C)N)CC(C)(C)C(N)=N2
Agent: Cl
Product: CC1C=CC2=C(C1=O)C(C(=O)[C@H](C)NC(=O)[C@@H](O)c1cc(F)cc(F)c1)CC(C)(C)C(N)=N2

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-B), the title compound was prepared. The product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=413.07.