Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:14]Br>ClCCl>[Br:14][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7]
Reactant: BrBr
Reactant: O=Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(Br)c1
Yield: 56.3 %

Procedure:
A solution of 4-fluorobenzaldehyde (49.6 g) in dry dichloromethane (20 cm3) was added to a cooled (0° C.) suspension of powdered aluminium trichloride (90.4 g) in dry dichloromethane (100 cm3). Bromine (70.4 g) was added, and the mixture heated at the reflux temperature for 16 hours. After cooling, the reaction mixture was carefully poured onto ice and extracted with dichloromethane. The combined organic layers were washed with saturated sodium metabisulphite solution, water and brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a dark red oil, which was purified by distillation under reduced pressure, using a 4" Vigreux column to give 3-bromo-4-fluorobenzaldehyde (45.7 g) as an oil, boiling point 85°-108° C. at 8 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5]>[Pd].CO>[NH2:18][C:16]1[C:15]([F:21])=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[C:2]([F:1])[CH:17]=1
Reactant: CN1CCC(NC(=O)c2cc(F)c([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(NC(=O)c2cc(F)c(N)cc2F)CC1
Reaction time: 16 h

Procedure:
2,5-difluoro-N-(1-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 60; 633 mg 2.1 mmol), 10% Palladium on Carbon (70 mg) and Methanol (50 mL) were combined and stirred at 25 )C under Hydrogen at 3 bar pressure for 16 hours.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C([Sn](=O)CCCC)CCC.C[Si]([N:27]=[N+:28]=[N-:29])(C)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([C:1]2[NH:29][N:28]=[N:27][N:2]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1cccc(C#N)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2nnn[nH]2)c1
Yield: 97.9 %

Procedure:
A mixture of methyl 3-cyanobenzoate (320 mg, 1.98 mmol), dibutyltin oxide (49.7 mg, 0.20 mmol) and trimethylsilyl azide (0.54 mL, 3.96 mmol) in toluene (4.0 mL) was heated at reflux for 24 hours. The solvent was removed under reduced pressure and chased with methanol (1-2 mL). The residue obtained was flash chromatographed on silica gel eluting with acetic acid and methanol in methylene chloride to give the title compound (395.7 mg). 1H NMR (DMSO-d6, 300 MHz) δ3.0-4.5 (br, 1H), 3.92 (s, 3H), 7.75 (t, J=8 Hz, 1H), 8.11 (d, J=8 Hz, 1H), 8.32 (d, J=8 Hz, 1H), 8.54 (s, 1H). MS (DCl/NH3) m/e 205 (M+H)+, 222 (M+H+NH3)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH2:36]([O:35][C:32]1[CH:31]=[CH:30][C:29]([N:26]2[CH2:27][CH2:28][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:24][CH2:25]2)=[CH:34][CH:33]=1)[CH2:37][CH3:38]
Reactant: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-(p-propoxyphenyl)piperazine to give 1-(p-propoxyphenyl)-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]-sulfonyl]piperazine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.C(O[C:17]([C:19]1[C:20](NCCC)=[N:21]C(SC)=NC=1)=O)C.C(N(CC)C(C)C)(C)C.O>C(#N)C.C(N)CC.C(OCC)(=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:21][CH2:20][CH2:19][CH3:17])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCNc1cc(Cl)ncc1C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (S13, 1.0 g) synthesized according to the method described in US200549419 A1 and N,N-diisopropylethylamine (2.37 mL) in acetonitrile (10 mL), propylamine (0.90 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 5 hours and 30 minutes. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90% hexane/10% ethyl acetate) to obtain ethyl 6-chloro-4-(propylamino)nicotinate (S14, 1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[CH3:12][NH:13][CH3:14].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:13]([CH3:14])[CH3:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1cncc(Br)c1
Yield: 79.6 %

Procedure:
(5-Bromo-pyridin-3-yl)-acetic acid (200 mg, 0.93 mmol), 2.0 M dimethylamine solution (0.93 mL, 1.9 mmol), HOBt (25 mg, 0.19 mmol) and triethylamine (0.38 mL, 2.8 mmol) are dissolved in 5.0 mL of DMF. Then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (290 mg, 1.9 mmol) is added. The reaction mixture is stirred for 16 hrs before 30 mL of water and 30 mL of DCM are added. The aqueous layer is separated and extracted with DCM (4×10 mL). The organic layers are combined, dried and concentrated to give the crude product which is purified by flash chromatography to give 180 mg of 2-(5-bromo-pyridin-3-yl)-N,N-dimethyl-acetamide.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:14]=3)=[N:4][CH:5]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)cc2F)cc1

Procedure:
0.29 g (0.91 mmol) of 3-fluoro-5-hydroxy-2-(4-octyloxyphenyl)pyridine, 0.19 g (0.91 mmol) of dicyclohexylcarbodiimide, 0.16 g (0.91 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.01 g of 4-(N,N-dimethylamino)pyridine are stirred at room temperature for 18 hours in 10 ml of dichloromethane. Filtration, evaporation to dryness, chromatographic purification (silica gel/hexane: ethyl acetate 8:2) and recrystallization from acetonitrile give 0.19 g of 3-fluoro-2-(4-octyloxyphenyl)pyridin-5-yl trans-4-pentylcyclohexanecarboxylate. ##STR28## The compound has the phase sequence: X 65.2 (40.2) Sc 63 SA 129 N 173 I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[H][H]>CO.[Pd]>[F:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1

Procedure:
3.88 g of 4-(2,6-difluoro-4-nitro-phenyl)-morpholine are dissolved in 50 mL methanol and combined with Pd/C. The mixture is hydrogenated for 18 h at 7 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11](=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CN.[C:23]([BH3-])#[N:24].[Na+]>C1COCC1.CO.CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([NH:24][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [BH3-]C#N
Reactant: O=C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CNC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 50 °C
Yield: 54 %

Procedure:
To a solution of ketone 5 (350 mg, 1.202 mmol) in THF (18 mL) and methanol (24 mL) was added methylamine hydrochloride (980 mg, 10 eq). After the solid dissolved, sodium cyanoborohydride (6.0 mL, 1 M in THF, 5 eq) was added in one portion. The mixture was heated in a 50° C. oil bath overnight before being quenched with aqueous sodium bicarbonate and extracted with MTBE. The combined organic layer was washed with brine and evaporated to give a brown-green oil. The oil was dissolved in MTBE and extracted into 10% aqueous hydrochloric acid. The aqueous layer was basicified with KOH and extracted with MTBE. The volatile components were removed in vacuo and the crude green oil was separated on silica gel to give the methylamine (0.20 g, 54%) as a pale-green oil.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][CH:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)[CH:2]=1.[CH3:31][O:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]Br)=[CH:36][CH:35]=1>>[CH3:31][O:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][N:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH:11]2[CH2:10][CH2:9][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:7][C:3]2[CH:2]=[C:1]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:6]=[CH:5][CH:4]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(-c3ccccc3)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 74.2 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (5.116 g, 12.08 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (3.41 g, 13.3 mmol) over 20 h. Purification by medium pressure chromatography using a solvent gradient (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (5.38 g). 1H NMR (CDCl3) δ7.93 (d, 2H), 7.56 (d, 2H), 7.43 (m, 3H), 7.34 (m, 3H), 7.23 (m, 2H), 7.12 (m, 1H), 3.89 (m, 1H), 3.87 (s, 3H), 3.64 (m, 1H), 3.49 (m, 1H), 2.95-2.61 (m, 5H), 2.30 (m, 2H), 2.01 (m, 1H), 1.89-1.70 (m, 3H), 1.59-1.24 (m, 4H), 0.84 (s, 9H), −0.04 (d, 3H), −0.16 (d, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[O:1][N:2]=[C:3]([C:4]3[C:14]4[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:9][C:8]=4[CH:7]=[CH:6][CH:5]=3)[N:22]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=N)NO)C1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Temperature: 120 °C
Yield: 40.5 %

Procedure:
A solution of 1,1-dimethylethyl 9-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 65) (500 mg, 1.627 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (384 mg, 1.790 mmol), EDC (468 mg, 2.440 mmol) and HOBT (299 mg, 1.952 mmol) in DMF (5 ml) was stirred at RT overnight then heated at 120° C. for 3 hrs. The reaction mixture was cooled, diluted with EtOAc/water and the organics dried over magnesium sulfate and evaporated. Purified by flash chromatography eluting with EtOAc/iso-hexane 1:3 to give the title compound (320 mg) as a white solid. MS (ES): C25H2835ClN3O5 requires 485; found 486 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.CN1[C@@H](C)CNC[C@H]1C.[CH3:37][C@H:38]1[CH2:43][NH:42][CH2:41][C@@H:40]([CH3:44])[N:39]1[CH2:45][C:46]#[N:47].C(N(C(C)C)C(C)C)C>CS(C)=O.CO>[C:46]([CH2:45][N:39]1[C@@H:38]([CH3:37])[CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]3[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:15]=3)=[O:9])=[N:6][CH:7]=2)[CH2:41][C@H:40]1[CH3:44])#[N:47]
Reactant: C[C@@H]1CNC[C@H](C)N1CC#N
Reactant: COc1cc(COc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Agent: C[C@@H]1CNC[C@H](C)N1C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(CC#N)[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.3 %

Procedure:
5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (273 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and 2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol) in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The reaction was incomplete and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) was added and the solution was stirred at 60° C. for a further 2 h. The reaction mixture was diluted with methanol (20 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (65 mg, 18%) as a yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][N:30]([CH3:29])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: CN(CCCCCCCl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN(C)c2ccccc2)CC1
Yield: 70.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.3 g) as starting compound, potassium carbonate (2.0 g) and 6-(N-methyl-N-phenylamino)hexyl chloride (0.8 g) were reacted and treated in the same manner as in Example 168 to give 1.2 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(N-methyl-N-phenylamino)hexyl)piperidin-4-yl)-methyl)benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IN1C(=O)C[CH2:27][C:26]1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:26]#[CH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CC#N
Product: C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 65 °C
Yield: 118.3 %

Procedure:
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) in anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) was heated at 65° C. under nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) using ethyl acetate/hexane (1:1 v:v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2SO3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.73 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.29 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0210 (M+H calculated for C19H16NO2FI requires 436.0196). Step 2. Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([C:17]4[C:18]([CH3:26])=[N:19][N:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=45)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:27]1CCOCC1.C(#N)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([C:17]4[C:18]([CH3:26])=[N:19][N:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=45)[S:16][C:12]=3[C:11](=[O:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1nn2ccccc2c1-c1nc2c(s1)C(=O)CCC2c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
In a 100 mL round bottomed flask was placed 4-(4-chlorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4,5,6,7-tetrahydro-1,3-benzothiazole (250 mg, 0.66 mmol) along with 1,4-dioxane (15 mL) and acetonitrile (15 mL). To the mixture were added a solution of copper (II) sulfate pentahydrate (670 mg, 2.7 mmol) in water (10 mL) and a solution of potassium persulfate (770 mg, 2.8 mmol) in water (10 mL). The mixture was stirred for 6 hr at 90° C. The mixture was allowed to cool to rt and then insoluble materials were removed by filtration through a celite pad. The celite pad was washed with water and EtOAc. The aqueous phase was separated from the filtrate and then extracted with EtOAc (50 mL×2). The combined organic phases were washed with a 10% aqueous solution of NaHSO3 (50 mL), then a saturated aqueous solution of NaHCO3 (50 mL), then a saturated aqueous solution of NH4Cl (50 mL), and then dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (12 g) column chromatography, eluting with 0% to 50% EtOAc/hexane to yield the title compound (100 mg; 40%) as a yellow crystalline solid. LCMS: (FA) ES+ 394, 396; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.42 (dt, 1H), 8.15 (dt, 1H), 7.32-7.35 (m, 3H), 7.17 (d, 2H), 6.90 (td, 1H), 4.45 (dd, 1H), 2.57-2.75 (m, 5H), 2.29-2.37 (m, 1H), 2.00-2.15 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH2:24][C@H:25]([CH3:28])[CH2:26][OH:27]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: C[C@@H](N)CO
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: C[C@H](CO)NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and (R)-2-aminopropan-1-ol. MS (ESI): mass calcd. for C20H19FN4O2, 366.15; m/z found, 367.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.15-7.97 (m, 2H), 7.94-7.82 (m, 1H), 7.55-7.39 (m, 4H), 7.37-7.26 (m, 2H), 6.71 (s, 2H), 4.64 (s, 1H), 3.92-3.73 (m, 1H), 3.26-3.10 (m, 2H), 0.98 (d, J=6.1, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:17]2[CH:16]=[N:15][CH:14]=[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:3]([CH3:2])[C:4](=[O:25])[CH2:5][CH2:6]4)[CH:18]=2)[CH2:21]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Agent: Cl
Product: CCOC(=O)N1CC[C@H](Oc2cncc(-c3ccc4c(c3)CCC(=O)N4C)c2)C1

Procedure:
In analogy to the procedure described in example 76, 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 60) has been reacted with chloroformic acid ethyl ester to give the title compound as a light yellow amorphous solid. MS: 396.5 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O[C@H:11]2[CH2:28][CH2:27][C@@:26]3([CH3:29])[C:13](=[CH:14][CH2:15][C@@H:16]4[C@@H:25]3[CH2:24][CH2:23][C@@:21]3([CH3:22])[C@H:17]4[CH2:18][CH2:19][C:20]3=[O:30])[CH2:12]2)(=O)=O)=CC=1.[CH2:32]([OH:36])[CH2:33][CH2:34][OH:35].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[OH:35][CH2:34][CH2:33][CH2:32][O:36][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1
Reactant: OCCCO
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]43)C2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C[C@]12CC[C@H](OCCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
3β-(p-Toluensulfonyloxy)androst-5-en-17-one (12.00 g) was added to a suspension of propane-1,3-diol (61 mL) and PTSA (610 mg) at 95° C. After stirring for 40 minutes, the mixture was cooled to room temperature, and poured in water (800 mL), bringing the pH to 7 with 5% NaHCO3. After 3 hrs the solid was filtered and dissolved in CH2Cl2. The solution was dried over Na2SO4 and evaporated to dryness under reduced pressure to give 3β-(3-hydroxypropoxy)androst-5-en-17-one (9.10 g, 97%), used without further purification. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 5.35 (1H, m), 4.34 (1H, t), 3.43 (4H, m), 3.06 (1H, m), 2.45-0.85 (21H, m), 0.96 (3H, s), 0.79 (3H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[CH2:22][O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)OCc3ccccc34)nn2)n1

Procedure:
The object product (66 mg, 26%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg), 3H-spiro[2-benzofuran-1,4′-piperidine] hydrochloride (159 mg) and potassium carbonate (244 mg).