Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])=[O:30])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccccc1F
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccccc2F)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (60.6 mg, 0.221 mmol) in CH2Cl2 (2 mL) was added 2-fluorophenyl isocyanate (0.27 μL, 0.240 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 138 as a colorless solid (85.5 mg, 91%). LCMS m/z (%)=412 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (bs, 1H), 8.25 (bs, 1H), 8.15 (dd, J=8.34, 1.52 Hz, 1H), 7.47-7.42 (m, 3H), 7.40 (d, J=2.78 Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, J=9.09 Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, J=2.02 Hz, 1H), 3.98 (t, J=6.32 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.07 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C-:13]#[N:14].[Na+]>[Zn].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(C)=O)C>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[CH:3][CH:4]=1
Reactant: [C-]#N
Reactant: FC(F)(F)Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCC(C)=O
Product: N#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 6.5 g of bis-triphenylphosphine-nickel dichloride, 5 g of triphenylphosphine and 120 ml of MEK was stirred at room temperature for 10 minutes. 1.9 g of activated zinc powder were then added, and the reaction mixture was stirred at 70° C. for 30 minutes. Following this, the mixture was allowed to cool to 25° C., and 93.25 g of 1-chloro-4-trifluoromethoxybenzene were added dropwise. The mixture was stirred for 10 minutes, 24 g of sodium cyanide were added, and the reaction mixture was stirred at from 65 to 70° C. for 20 h. The conversion was then approximately 75% (GC). After cooling to room temperature, the mixture was filtered, the solid filter residue was washed 2× with 50 ml of MEK and the combined organic phases were concentrated under reduced pressure. Vacuum distillation gave 58.5 g (66% of theory) of 4-trifluoromethoxybenzonitrile as a colourless liquid (boiling point at 120 mbar: 80° C.). 2.6% of coupling products had formed.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[Cl:19][C:20]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O.[C:32]([NH:36][C:37](=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:39]=1)([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[C:32]([NH:36][C:37](=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:46][CH2:47][N:48]([C:22](=[O:24])[C:21]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:20]=3[Cl:19])[CH2:49][CH2:50]2)[CH:39]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3Cl)CC2)c1
Yield: 91.6 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (3.16 g, 92 mmol, 2.95 mL) was added dropwise to a solution of 2-chloro-4-nitrobenzoic acid (1 g, 4.9 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.4169 g, 5.1 mmol) and triethylamine (1.4979 g, 14.7 mmol, 2 mL) in dichloromethane. The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (2.06 g).
Reaction SMILES: Br[C:2](=[CH:4][CH3:5])[CH3:3].[Li].[Br:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=O.O>CCCCC>[OH:13][C:11]([CH2:10][CH2:9][CH2:8][Br:7])([C:2]([CH3:3])=[CH:4][CH3:5])[C:4]([CH3:5])=[CH:2][CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC=C(C)Br
Agent: [Li]
Solvent: O
Solvent: CCCCC
Product: CC=C(C)C(O)(CCCBr)C(C)=CC
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Analogously to example I, 2-lithium-2-butene was prepared from 2-bromo-2-butene (15.0 g; 0.11 mol) and lithium (2.8 g; 0.26 mol). To the product obtained, ethyl 4-bromobutanoate (11.0 g; 0.056 mol) was added dropwise and with reflux at -40-20° C., followed by stirring for 30 minutes at -20° C. Water (200 ml) and subsequently pentane (100 ml) were slowly added dropwise at -20° C. After separation of the layers the water layer was washed two times with 100 ml of pentane/ether (1/1, v/v), after which the combined organic layers were washed with water (50 ml). The organic layer was dried (K2CO3), filtered and evaporated. The yield was 14.0 g (96%).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:3][C@H:4]([C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[C:30]=1[C:31]#[N:32]
Reactant: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
To a solution of 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile dihydrochloride (110 mg, 0.29 mmol) in IPA (3 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (45 mg, 0.29 mmol) and DIPEA (148 μL, 0.87 mmol) and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 330 as a white solid (65 mg, 56%). 1H NMR 400 MHz δ (d6-DMSO): 8.08 (1H, dd, J=8.9, 4.9 Hz), 7.78 (1H, s), 7.70 (1H, d, J=7.2 Hz), 7.62-7.56 (1H, m), 7.55-7.43 (4H, m), 7.33 (1H, dd, J=10.4, 9.0 Hz), 7.15 (2H, br s), 5.28 (1H, quin, J=6.9 Hz), 1.48 (3H, d, J=6.9 Hz), LCMS (Method K): RT=3.73 min, [M+H]+=399
Reaction SMILES: [C:1]([C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:24])[C:8]3[CH:9]=[CH:10][C:11]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:5][CH:4]=1)#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>>[NH:25]1[C:1]([C:3]2[CH:16]=[C:15]3[C:6]([C:7](=[O:24])[C:8]4[CH:9]=[CH:10][C:11]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[CH:12][C:13]=4[C:14]3=[O:17])=[CH:5][CH:4]=2)=[N:2][N:27]=[N:26]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)C(=O)c1cc(N3CCCCC3)ccc1C2=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=C1c2ccc(-c3nnn[nH]3)cc2C(=O)c2cc(N3CCCCC3)ccc21
Yield: 70.4 %

Procedure:
The above nitrile (1 g) was treated with sodium azide (0.66 g) and ammonium chloride (0.57 g) as in the preceding example to give 1-[7(1H-tetrazol-5-yl)-anthraquinon-2-yl] piperidine (0.8 g), m.p. 297-8°C, after crystallisation from dimethylformamide/acetic acid.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O-:13])(=[S:12])[CH3:11].[K+]>CN(C=O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:12][C:10](=[O:13])[CH3:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)SC(C)=O
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of ethyl α-bromoisobutyrate (62 g, 0.32 mol) in DMF (500 mL) at room temperature is added potassium thioacetate (72 g, 0.63 mol). The reaction is stirred for 16 h and then concentrated under reduced pressure. The residue is diluted with a 2M aqueous hydrochloric acid solution (500 mL) and extracted with ethyl acetate (3×500 mL). The organic fractions are combined, washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with heptanes/dichloromethane provides 44 g of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester. Yield: 73%; m/z 191 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.18-1.30 (3 H, m), 1.57 (6 H, s), 2.27 (3 H, s), 4.19 (2 H, q, J=7.16 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([C:13]([O:15]C)=[O:14])[CH2:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].O.[OH-].[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(CC1CCC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N[C@@H](CC1CCC1)C(=O)O
Reaction time: 3 h

Procedure:
10.8 g (47 mmol) of methyl ethoxycarbonyl-3-cyclobutyl-DL-alaninate (synthesised in Step B) is dissolved in 20 ml of benzene in the 250 ml vessel of the titrator. 100 ml of water is added and the pH of the solution is adjusted to 7.5 with 1M NaOH under stirring. 40 mg of enzyme [Subtilisin Carlsberg, Protease, Type VIII (Sigma)] is added, the pH readjusted to 7.5 and kept at this value during titration. The enzymatic hydrolysis is complete in 3 hours. The phases are separated. From the aqueous phase pure ethoxy-carbonyl-3-cyclobutyl-L-alanine can be isolated. The benzene phase is washed with 2×10 ml of 5% NaHCO3 and 2×10 ml of water, dried over anhydrous sodium sulphate and evaporated at a pressure of 2.0-2.5 kPa. The resulting yellowish oil is considered to be pure and used without further treatment in the next step.
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH:9][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](O)=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:11]([C:12]([Cl:21])=[C:7]2[CH:6]=[N:5]1)=[CH:15][CH:16]=[CH:17][CH:18]=3)([CH3:3])[CH3:2]
Reactant: CC(C)n1nccc1Nc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1ncc2c(Cl)c3ccccc3nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
A mixture of N-(1-isopropylpyrazol-5-yl) anthranilic acid (52 g, 0.212 mol) and POCl3 (436 ml, 4.68 mol) is refluxed for 3 hours, then is stirred at room temperature overnight. The excess POCl3 is removed by distillation and then the residue is poured into ice/water. The mixture is neutralized with 35% NaOH and then extracted with CH2Cl2. The CH2Cl2 layer is separated and washed with water, then brine and then is dried over MgSO4, filtered and evaporated. The residue is dissolved in CH2Cl2 and then is purified by column chromatography on silca gel eluting with CH2Cl2 to afford 21.3 g (40.9%) of 1-isopropyl-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br:6][C:7]1[C:8]([O:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])=[CH:9][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Br:6][C:7]1[C:8]([O:17][C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])=[CH:9][C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)Nc1cc(Oc2c(F)cccc2F)c(Br)cn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1

Procedure:
A mixture of 1-chloropropan-2-one (1.01 g, 11 mmol), 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)thiourea (3.24 g, 9.0 mmol), triethylamine (1.41 g, 14 mmol) and ethanol (15 mL) is heated at reflux for 16 hours. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried and concentrated. The residue is purified via chromatography to afford N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([OH:13])=O.[Cl-].[CH2:19]([O:21][C:22](=[O:34])[CH:23]([OH:33])[CH:24]([NH3+:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]>>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:32][CH:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:23]([OH:33])[C:22]([O:21][CH2:19][CH3:20])=[O:34])=[O:13]
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1Cl
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting (R)-1-(2-chlorobenzyl)-5-oxopyrrolidine-2-carboxylic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+=459.2.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].[OH-].[Na+]>CC(O)=O>[CH2:1]([O:8][NH:9][CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CNOCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCNOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of O-benzyl-N-vinyl-hydroxylamine (LXVI, 6.52 g, 43.70 mmol) in AcOH (10 mL), NaCNBH3 (11.00 g, 175.05 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 h. The mixture was neutralized (pH 7) with 1N NaOH and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with saturated NaHCO3 solution (2×100 mL), dried over Na2SO4, and purified by flash column chromatography (eluent: petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (1:4)) to yield O-benzyl-N-ethyl-hydroxylamine (LXVII, 2.10 g, 32%). 400 MHz 1H NMR (DMSO-d6, ppm) 7.36-7.24 (5H, m), 6.50 (1H, t, J=6.4 Hz), 4.60 (2H, s), 2.81 (2H, qd, J=7.0, 6.4 Hz), 0.98 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([Mg]Br)[CH3:33].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:32][CH3:33])=[C:11]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: COc1cc2nccc(Oc3cc(OCc4ccccc4)ccc3C=O)c2cc1OC
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(OCc2ccccc2)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added thereto at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{4-(benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17].CC(C)([O-])C.[K+].O>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,4,6-trifluoronitrobenzene (1.37 g, 7.74 mmol) and 3,5 difluoroaniline (1 g, 7.74 mmol) in THF (23 mL) was added potassium tert-butoxide (1.3 g, 11.6 mmol) and reaction mixture was stirred at rt for 4 h. After completion of the reaction, water (50 mL) was added and the organic phase extracted with EtOAc (200 mL), dried over sodium sulfate and purified by column chromatography using 100-200 mesh silica gel and 0-10% EtOAc in hexane to provide N-(3,5-difluorophenyl)-3,5-difluoro-2-nitroaniline: LC-MS (ESI) m/z 284.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CN(C)CCCCl
Reactant: Oc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: Cl
Product: CN(C)CCCOc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxyquinazoline was reacted with 3-dimethylaminopropyl chloride hydrochloride to give 4-(3'-chloro-4'-fluoroanilino)-6-(3-dimethylaminopropoxy)quinazoline in 72% yield; NMR Spectrum: 1.98 (m, 2H), 2.34 (s, 6H), 2.51 (t, 2H), 4.22 (t, 2H), 7.48 (t, 1H), 7.52 (m, 1H), 7.75 (d, 1H), 7.85 (m, 1H), 7.91 (m, 1H), 8.18 (m, 1H), 8.54 (s, 1H), 9.72 (broad s, 1H); Elemental Analysis: Found C, 60.5; H, 5.3; N, 14.9; C19H20ClFN4O requires C, 60.5l; H, 5.3; N, 14.9%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1>C(O)(C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[C:3]([N:11]1[C:12]2[C:19]3[C:9]([CH2:8][C@@H:7]4[C:17]([C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:18][C@@H:3]([CH2:2][OH:1])[CH2:4][N:5]4[CH3:6])=[CH:10]1)([CH3:18])([CH3:4])[CH3:2]
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)(C)O
Product: CN1C[C@H](CO)C=C2c3cccc4c3c(cn4C(C)(C)C)C[C@H]21
Reaction time: 90 h
Yield: 122.9 %

Procedure:
To a mixture of 8 g of lysergol in 150 ml of t-butanol, 200 ml of trifluoroacetic anhydride were added dropwise with vigorous stirring. After the solution had been left at room temperature for 90 hours, it was evaporated. The residue was dissolved in water, made alkaline with ammonium hydroxide and the aqueous layer was extracted with ethyl acetate. After removal of the ethyl acetate, the residue was purified by silica gel column chromatography using 1:1 cyclohexane:ethyl acetate for elution to give 6 g of the title compound melting at 181° to 183° C.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[C:18]([CH:19]=O)=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=1.[C:21]1([C@H:27]2[C@@H:32]([NH2:33])[CH2:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4]1[C:18]([CH2:19][NH:33][C@H:32]2[CH2:31][CH2:30][CH2:29][NH:28][C@H:27]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1cc2sc(-c3ccccc3)nc2cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2sc(-c3ccccc3)nc2cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A round bottom flask equipped with a Dean Stark water separator and condenser was charged with 0.96 grams (3.6 mmol) 6-methoxy-2-phenyl-benzothiazol-5-aldehyde and 0.57 grams (3.2 mmol) of (2S, 3S)-2-phenyl-3-amino-piperidine in 90 mL of hours. The reaction mixture was evaporated in vacuo and the residue was redissolved in 90 mL of 1,2-dichlorethane. The solution was treated with 0.89 grams (4.2 mmol) of sodium triacetoxyborohydride and was stirred for 16 hours at room temperature. The reaction mixture was diluted with methylene chloride (600 mL) and washed with 150 mL of bicarbonate solution, 150 mL of water and finally with 150 mL of saturated brine solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 97/2/1 methylene chloride, methanol, conc. aqueous ammonium hydroxide solution. Product containing fractions were combined, evaporated and crystallized from hot ether--MeOH to afford 1.1 grams (80%) of the desired product.
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:10]([F:35])[C:9]=2[F:36])[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:10]([F:35])[C:9]=2[F:36])[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 96.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (161 mg, 0.259 mmol) prepared in Example 132a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (118 mg, 97%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH:8]([CH2:10]OS(C3C=CC(C)=CC=3)(=O)=O)[O:9][C:5]=2[CH:4]=1.[CH3:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH:8]([CH2:10][N:33]3[CH2:34][CH2:35][C:30]([CH2:29][C:28]4[CH:27]=[CH:26][C:25]([CH3:24])=[CH:38][CH:37]=4)([OH:36])[CH2:31][CH2:32]3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)C2
Temperature: 130 °C
Yield: 66 %

Procedure:
(RS)-toluene-4-sulfonic acid 6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester (110 mg, 0.33 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (148 mg, 0.72 mmol) were dissolved in DMF (3 ml) and heated at 130° C. for 1 h. DMF was then evaporated, the residue was dissolved in CH2Cl2 (5 ml) and washed with H2O (5 ml). Organic phase was dried over Na2SO4, and concentrated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2-MeOH(19:1) to provide (RS)-1-(6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (80 mg, 66%) as a yellow oil, MS:m/e=368.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
4-Benzyloxybenzoic acid (15.0 g, 65.72 mmol) in dichloromethane (150 mL) and dimethylformamide (0.75 mL) was cooled to 0° C. After 30 minutes, the mixture was treated with neat oxalyl chloride (11.5 mL, 131.44 mmol) dropwise over 25 minutes. The resulting mixture was stirred at room temperature for 120 minutes followed by evaporation of solvent under reduced pressure to provide the title compound as a light yellow solid (18.2 g, 112% yield). 1HNMR (300 MHz, CDCl3) δ 7.03 (d, 2H, J=8.9 Hz), 7.23-7.43 (m, 5H), 8.07 (d, 2H, J=8.9 Hz).