Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:25]2[CH2:27][CH2:26]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:25]1([N:11]([CH:8]2[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:32]3[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]3)[CH2:10][CH2:9]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)(=[O:13])=[O:14])[CH2:26][CH2:27]1
Reactant: OC1CCNCC1
Reactant: C=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: O=C(CCN1CCC(O)CC1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 150 °C

Procedure:
N-(1-Acryloyl-piperidin-4-yl)-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (1) (125 mg, 0.31 mmol), 4-hydroxypiperidine (313 mg, 3.1 mmol) and ETOH (2.5 ml) were mixed together in a sealed tube and heated to 150° C. with microwave equipment for 30 min. After the reaction, the reaction mixture was evaporated in vacuum and the residue was purified by column chromatography on silica gel (CHCl3/MeOH/NH3 aq.=100/10/1) to afford the desired compound as free base, which was dissolved in AcOEt (2 ml), and treated with 4N—HCl in AcOEt (2 ml) solution. The resulting mixture was concentrated in vacuo, and dried under reduced pressure for 24 hours at 60° C. to afford the title compound 2 as a HCl-salt (white amorphous, 151 mg, yield 90%) LC: 100%. MS: m/z=503.8, 504.49 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[N:9][CH:10]=1)[NH:7][CH2:6][CH2:5][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccnc2c1CCCN2
Solvent: ClCCl
Product: Clc1c(Br)cnc2c1CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 5-chloro-1,2,3,4-tetrahydro-[1,8]naphthyridine (500 mg, 3.0 mmol) in DCM (40 mL) is added N-bromosuccinimide (530 mg, 3.0 mmol). The reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is concentrated to give the crude product. Purification by flash column chromatography affords 680 mg of 6-bromo-5-chloro-1,2,3,4-tetrahydro-[1,8]naphthyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH2:8])[CH3:7])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CC(C)NCc1ccccc1
Reaction time: 20 h
Yield: 27.7 %

Procedure:
To a solution of 3-amino-butyric acid ethyl ester (5.00 g, 34.3 mmol), benzaldehyde (4.1 mL, 40 mmol) and acetic acid (1.9 mL, 34 mmol) in 1,2-dichloroethane (120 mL) was added sodium triacetoxyborohydride (17 g, 80 mmol) at room temperature and the mixture was stirred for 20 hours. The reaction mixture was poured into sodium bicarbonate saturated aqueous solution and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography on silica gel (chloroform/methanol=10/1 as an eluant) to afford 3-benzylamino-butyric acid ethyl ester (2.1 g, 9.5 mmol, 28%) as colorless oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:8]=[CH:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: C#CC(=O)OCC
Reactant: CCNCC
Solvent: CCO
Product: CCOC(=O)C=CN(CC)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of 14.6 g of diethylamine (0.2 m) in 100 ml of ethyl alcohol was added dropwise to a stirred solution of 19.6 g of ethyl propiolate (0.2 m) in 150 ml ethyl alcohol at room temperature. The exothermic reaction mixture was stirred at room temperature for 31/2 hours. The solvent was removed and the residue distilled through a short Vigreux column (boiling point 88° C./6 mm) to give 29.83 g (87 percent) of ethyl 3-(diethylamino)acrylate.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29](Cl)=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:3]=1[C:4]#[N:5].[CH2:36]([N:38](CC)[CH2:39]C)C.Cl.CNC>CN(C=O)C>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([N:38]([CH3:39])[CH3:36])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(Cl)c([N+](=O)[O-])c3)c(C#N)c(N)n2)cc1
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c([N+](=O)[O-])c3)c(C#N)c(N)n2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirred solution of 2-amino-4-(4-chloro-3-nitrophenyl)-6-{2-[(4-methoxybenzyl)oxy]phenyl}-nicotinonitrile (0.850 g, 1.746 mmol) in DMF (5 mL) including triethylamine (1.2 mL) was added dimethylamine hydrochloride (0.996 g, 12.220 mmol), and the mixture was stirred at 70° C. for 3 hrs. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in ethanol. The resulting solid was collected by filtration, washed with ethanol, and dried under reduced pressure to give 2-amino-4-[4-(dimethylamino)-3-nitrophenyl]-6-{2-[(4-methoxybenzyl)-oxy]phenyl}nicotinonitrile as an orange oil (0.820 g, yield 95%).
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:69]([CH3:71])[CH3:70])([CH:66]([CH3:68])[CH3:67])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:66]([CH3:68])[CH3:67])([CH:69]([CH3:70])[CH3:71])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1Cl)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(Cl)c5)c5ccccc54)cn23)CC1)(C(C)C)C(C)C

Procedure:
A solution of Intermediate G (153 mg, 0.28 mmol) and [5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 167 mg, 0.28 mmol) in 1,4-dioxane (4 mL) and DIPEA (87 μL, 0.50 mmol) was stirred at 95° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM, to give 1-[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea (193 mg). This was dissolved in THF (3 mL) and treated with TBAF (1M in THF, 0.47 mL, 0.47 mmol). The solution was stirred at RT for 1.75 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to give the product. This was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound (72 mg, 56%). LCMS (Method 5): Rt 3.99 min, m/z 685 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.38-1.52 (2H, m), 1.55-1.66 (1H, m), 1.73-1.96 (4H, m), 1.98-2.17 (2H, m), 2.85-2.97 (2H, m), 3.3-3.5 (4H, m, under water signal), 4.52 (1H, br s), 4.77-4.85 (1H, m), 5.55 (1H, br t, J=4.4 Hz), 6.28 (1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.15 (1H, dd, J=2.0, 9.8 Hz), 7.23-7.40 (5H, m), 7.44 (1H, d, J=2.5 Hz), 7.61 (1H, d, J=9.9 Hz), 7.64 (1H, br d, J=1.5 Hz), 8.02 (1H, br s), 10.55 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[C:29]([CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:30]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:36]2[CH:37]=[C:32]([CH2:31][C:29]#[N:30])[CH:33]=[CH:34][CH:35]=2)=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)[C:11]([F:12])([F:13])[F:14]
Reactant: N#CCc1cccc(B(O)O)c1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1cc(Oc2cccc(CC#N)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-cyanomethylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=531.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([OH:25])=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:27].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([OH:25])=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:37][CH2:36][CH2:35][NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)[C:3]=1[F:27]
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](Cc1ccccc1)CO2
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](Cc1ccccc1)CO2
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
A mixture of (3S)-8-Amino-9,10-difluoro-2,3-dihydro-7-oxo-3-phenylmethyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (76.9 mg, 0.207 mmol), 2-(2-pyridylamino)ethylamine (41.8 mg, 0.303 mmol), and triethylamine (42.1 μL, 0.302 mmol) in DMSO (1.5 mL) was stirred at 100° C. for 3 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. Recrystallization of the filtered precipitates from CH2Cl2-EtOH gave (3S)-8-amino-9-fluoro-2,3-dihydro-7-oxo-3-phenylmethyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (55.4 mg, 55%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH:18]=[O:19].C1COCC1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][OH:19]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To an ice cooled solution of ethyl 5-bromo-4-formyl-1-phenyl-1H-pyrazole-3-carboxylate (3.82 g, 11.86 mmol, 1 eq) in a 1:1 mixture of THF: EtOH is added sodium borohydride (0.5 g, 13.04 mmol, 1.1 eq) portion wise. The reaction mixture is stirred at RT for 2 h. The reaction mixture is quenched with sat. NH4Cl solution and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated. The crude is purified by column chromatography to afford 2.91 g (75%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.60-7.56 (m, 5H), 4.95 (t, J=5.4 Hz, 1H), 4.60-4.58 (d, J=5.4 Hz, 2H), 4.32 (q, J=7.01 Hz, 2H), 1.30 (t, J=7.7 Hz, 3H). HPLC (max plot) 96.75%; Rt 3.69 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[N:7]([CH3:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:15])[N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10][CH2:9]1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of methylpiperidin-4-yl-carbamic acid tert-butyl ester (2.0 g, 9.4 mmol) in dichloromethane (50 mL) was added acetaldehyde (1.65 mL, 27.9 mmol). The resultant dark red solution was stirred for 10 minutes, then sodium triacetoxyborohydride (2.97 g, 14.0 mmol) was added portionwise. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (100 mL) and dichloromethane (100 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3×100 mL). The combined organic layer was (Na2SO4), filtered and concentrated in-vacuo. The resultant residue was purified by flash chromatography (silica, 70 g column, Si-SPE, ethyl acetate followed by 10% methanol in dichloromethane) to afford the title compound as an orange oil (1.64 g, 72%). 1H NMR (300 MHz, CDCl3): 3.01 (d, J=11.3 Hz, 2H), 2.74 (s, 3H), 2.41 (q, J=7.2 Hz, 2H), 1.98 (t, J=11.6 Hz, 2H), 1.76-1.72 (m, 5H), 1.46 (s, 9H), 1.08 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH2:18][Br:23])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(CO)ccc1CCc1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-hydroxymethylbenzoate (13.10 g., 45.43 mmol), carbon tetrabromide(18.08 g, 54.52 mmol) and triphenylphosphine (14.30 g, 54.52 mmol) in dichloromethane (400 ml) was stirred at ambient temperature for 4 hours. More carbon tetrabromide (7.54 g, 23.00 mmol) and triphenylphosphine (5.96 g, 23.00 mmo.) in dichloromethane (50 ml) were added. The reaction was applied directly to a silica flash column and eluted with iso-hexane/ethyl acetate (92.5:7.5) to give methyl 2-(4-fluorophenethyl)-5-bromomethylbenzoate (9.30 g) as a clear gum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[OH-].[K+]>CS(C)=O>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:2][CH2:3][CH2:4][Cl:5])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc(CN2CCCNCC2)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: ClCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
15.7 g of 1-bromo-3-chloropropane were added to a cooled solution of 15.0 g of 1-(4-chlorobenzyl)homopiperazine and 12.0 g of potassium hydroxide in 50 ml of dimethyl sulfoxide. The mixture was stirred at 5°-10° C. for one hour, and then an additional 30 minutes at room temperature. After the addition of ice water, the product was extracted with ether, and the extract was dried (magnesium sulfate) and concentrated in vacuo. Final purification was effected on a silica gel column (methylene chloride:methanol, 9:1), and the solvent was removed in vacuo to give 8.4 g (42% of theory) of 1-(4-chlorobenzyl)-4-(3-chloropropyl)homopiperazine as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)CC(NC3C=CC(F)=CC=3)=O)=[CH:11][C:10]=2[F:29])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].ClC1C=CN=C([C:43]([NH2:45])=[O:44])C=1>CN(C=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:43]([NH2:45])=[O:44])[CH:7]=2)=[C:10]([F:29])[CH:11]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1)Nc1ccc(F)cc1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of 4-amino-2-fluorophenol (Compound A of Example 20, 0.81 g, 6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassium tert-butoxide (0.79 g, 7.1 mmol, 1.1 eq) at room temperature and the reaction mixture was stirred for 1 h. 4-Chloropicolinamide (1.0 g, 6.4 mmol, 1.0 eq) was added and the reaction mixture was heated to 110° C. for 8 h. The reaction was cooled to room temperature and the reaction mixture quenched with water. The resulting heterogeneous solution was filtered and the solid material was washed with water. The solid was triturated with a small amount of MeOH followed by Et2O. The solid was filtered and dried in vacuo to afford the product (1.3 g, 82%) as a solid. 1H NMR (DMSO-d6) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (br s, 1H), 7.35-7.36 (m, 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H), 6.44-6.47 (m, 2H), 5.53 (s, 2H); MS (ESI+) m/z 248 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[F:21][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]([C:6]1[O:5][N:4]=[C:3]([CH2:2][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1)[CH3:22]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CN2CCOCC2)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a solution of 1.52 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 30 ml of DMF was added 1.68 g of morpholine. The mixture was allowed to stand at room temperature overnight, then poured into ice-water and extracted with benzene. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene-ethyl acetate (5:2, v/v) as an eluent to yield 1.83 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-morpholinomethyl-1,2,4-oxadiazole as an oil. It was crystallized from diisopropyl ether to give colorless needles, m.p. 91.5°-92.5° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=417.2 (M+H)+
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.373 g, 4.11 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed DMSO (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: CCCCCC.[C:7]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)(=[O:9])[CH3:8].C(OCC)(=[O:17])C>>[S:12]1[CH:13]=[CH:14][C:10]([C:7]([CH:8]=[O:17])=[O:9])=[CH:11]1
Reactant: CC(=O)c1ccsc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: O=CC(=O)c1ccsc1

Procedure:
3-Acetylthiophene (20.0 g., 0.159 mol) and SeO2 (19.4 g., 0.175 mol) were dissolved 100 ml. dioxane and 8 ml. H2O by warming to 35°, then heated at reflux 16 hours. The reaction mixture was cooled, filtered and the filtrate stripped to a sludge (the hydrate of title product in crude form). The latter was distilled at reduced pressure to yield title product contaminated with about 10% starting material, 8.53 g.; tlc (5:3 hexane:ethyl acetate) Rf 0.27 (title product) and 0.59 (3-acetylthiophene). The latter was chromatographed on silica gel with 5:3 hexane:ethyl acetate is eluant. Clean product fractions were combined stripped to a solid, triturated with hexane, filtered and the solids (5.60 g.) sublimed to yield purified title product, 3.20 g.; tlc Rf 0.27 as above; sublimation point 70°/1 mm; ms: parent 141, base 111.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[O:34])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: O=C(c1ccccc1Br)N1CCOCC1
Product: O=C(c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1)N1CCOCC1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. for C24H20FN3O2, 401.15; m/z found, 402.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.58-8.48 (m, 1H), 8.21-8.13 (m, 1H), 7.61-7.30 (m, 8H), 6.63-6.57 (m, 1H), 3.78-3.56 (m, 3H), 3.48-3.33 (m, 2H), 3.14-3.00 (m, 1H), 2.94-2.75 (m, 2H).