Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9](O)[CH2:8][CH:7]([CH3:12])[O:6]1.[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SH:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28].ClC(Cl)(Cl)C(O)=O>O.CC(C)=O>[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9]([S:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28])[CH2:8][CH:7]([CH3:12])[O:6]1
Reactant: O=S(=O)([O-])CCS
Reactant: CC1CC(O)NP(=O)(N(CCCl)CCCl)O1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: O
Solvent: CC(C)=O
Product: CC1CC(SCCS(=O)(=O)[O-])NP(=O)(N(CCCl)CCCl)O1
Reaction time: 20 h

Procedure:
1.45 g (5 mmol) of 2-(bis-(2-chloroethyl)-amino)-4-hydroxy-6-methyl-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 1.2 g (5 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 5 ml of water and in 5 ml of acetone, acidified with trichloroacetic acid and left to stand for 20 hours at 0° C. The mixture was then filtered, the filtrate was carefully concentrated under vacuum, the residue was taken up twice in acetone and was concentrated. The residue was then dissolved in acetone, precipitated with ether, and washed with ether and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:32])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A suspension of N-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 39A (100 mg, 0.314 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (73 mg, 0.44 mmol) in THF (2 mL) was treated with DIPEA (160 mg, 1.26 mmol) and TBTU (150 mg, 0.47 mmol). The mixture was stirred at rt overnight and then purified directly by preparative HPLC. The product crystallized upon trituration with diethyl ether to afford 76 mg (56%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:24][CH2:25][CH3:26])[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 70 °C
Reaction time: 14 h
Yield: 93.2 %

Procedure:
To a solution of 6-nitro-2,3,4,9-tetrahydro-1H-carbazole (250 mg, 1.16 mmol) and potassium carbonate (479 mg, 3.47 mmol) in DMF (8 mL) was added 1-bromopropane (0.263 mL, 2.89 mmol), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was cooled, and to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 55% ethyl acetate/hexane) to give 6-nitro-9-propyl-2,3,4,9-tetrahydro-1H-carbazole (279 mg, 1.081 mmol, 93%) as a yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[N:7]=2)[CH:3]=[N:2]1.[CH:21]1([CH:24]=[CH:25][C:26]#[N:27])[CH2:23][CH2:22]1.CN(C=O)C.C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[CH:21]1([CH:24]([N:2]2[CH:3]=[C:4]([C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[CH:9]=[C:8]([C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[N:7]=3)[CH:5]=[N:1]2)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22]1
Reactant: Cc1nnc(-c2cc3nccn3c(-c3cn[nH]c3)n2)s1
Reactant: N#CC=CC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)s1
Temperature: 25 °C
Reaction time: 40 h
Yield: 31.2 %

Procedure:
In a 20 mL flask, 2-(5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)-5-methyl-1,3,4-thiadiazole (17.4 mg, 0.0614 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 17.2 mg, 0.184 mmol) were dissolved in DMF (614 μL, 0.0614 mmol). To this was added DBU (23.0 μA, 0.154 mmol) and stirred at ambient temperature for 40 h. The reaction was incomplete, so another portion of DBU (23.0 μA, 0.154 mmol) and 3-cyclopropylacrylonitrile (17.2 mg, 0.184 mmol) were added. After 4 hours, the reaction mixture was diluted in EtOAc, and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated down to a yellow oil. The crude material was purified by silica chromatography using a 0-10% MeOH/EtOAc gradient to afford 3-cyclopropyl-3-(4-(7-(5-methyl-1,3,4-thiadiazol-2-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (7.2 mg, 31% yield). MS (apci) m/z=377.2 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][C:8]1([OH:22])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.O[Li].O.O.CO>CCO>[OH:22][C:8]1([CH2:7][C:6]([OH:23])=[O:5])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CC1(O)CC2CCC1C=C2c1ccccc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: CCO
Product: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.1 %

Procedure:
To a solution of 4.0 g of rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester dissolved in 25 mL EtOH were added 2.1 g of LiOH.H2O, 8 mL H2O and 22 mL MeOH. The reaction mixture was stirred at rt for 3 days and then concentrated. The residue was partitioned between water and Et2O. The aq. layer was separated and acidified with 1N HCl resulting in the formation of a white solid. The solid was filtrated, washed with 5 mL dil. HCl and dried in vacuo to obtain 3.19 g of rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9][C:8]([C:18]2[O:19][C:20]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:21]=3[C:22]=2[CH3:23])=[N:7]1)=[O:5])[CH3:2]>C1(C)C=CC=CC=1.O.OO.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]2[O:19][C:20]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:21]=3[C:22]=2[CH3:23])[O:9][C:10]=1[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1N=C(c2oc3cccc(OCCCN(Cc4cccnc4)C(=O)OC(C)(C)C)c3c2C)O[C@H]1CC1CCCCC1
Agent: [Ni]
Agent: OO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2oc3cccc(OCCCN(Cc4cccnc4)C(=O)OC(C)(C)C)c3c2C)oc1CC1CCCCC1
Yield: 22.1 %

Procedure:
5-Cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-trans-4,5-dihydro-oxazole-4-carboxylic acid ethyl ester (10.0 mg) and nickel peroxide hydrate (22 mg) in toluene (2 ml) was heated at 80° C. under the atmosphere of argon for 23 hours. The reaction mixture was directly poured onto silica gel column chromatography and eluted with 2:3 mixture of n-hexane and ethyl acetate to give 5-cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-oxazole-4-carboxylic acid ethyl ester (2.2 mg). FAB-MS: m/z 632 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[F:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[F:25][C:26]1[C:27]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1
Reactant: COc1cc(B(O)O)c(F)cn1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c(F)cn1

Procedure:
The title compound was prepared in a manner similar to Example 213 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (60.0 mg, 0.152 mmol), (5-fluoro-2-methoxypyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.15 (qd, J=12.3, 4.4 Hz, 2 H) 1.55 (d, J=12.9 Hz, 2 H) 1.74 (ddt, J=11.1, 7.4, 3.9, 3.9 Hz, 1 H) 3.13 (t, J=6.3 Hz, 2 H) 3.74-3.82 (m, 5 H) 7.74 (d, J=4.8 Hz, 1 H) 8.03 (d, J=3.0 Hz, 1 H) 8.16 (d, J=2.5 Hz, 1 H 8.30-8.45 (m, 2 H) 8.66 (t, J=5.7 Hz, 1 H) 8.84 (d, J=1.3 Hz, 1 H). MS m/z [M+H]+ 428.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.79 (br s, 1H, NH), 8.65 (dd,1H, J=4.8 Hz, J=1.8 Hz), 7.98 (d, 2H, J=8.8 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.22 (dd, 1H, J=7.7 Hz, J=1.5 Hz), 7.16 (m, 2H), 2.60 (s, 3H), 2.36 (s, 3H). MS: m/z 429 (M+1).
Reaction SMILES: [C-]#N.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Cl[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.OCCCC1C=C[N:47]=[CH:46]C=1>C(#N)C>[C:46]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)#[N:47]
Reactant: OCCCc1ccncc1
Reactant: ClCCCc1ccncc1
Agent: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCc1ccncc1

Procedure:
Potassium cyanide (11.18 g) and dibenzo-18-crown-6 (1.0 g) are added to a solution of 4-(3-chloropropyl)pyridine (6.68 g) prepared from 4-(3-hydroxypropyl)pyridine, in 300 ml of dry acetonitrile under nitrogen. The mixture is refluxed for 24 hours, the solvent evaporated and the residue partitioned between methylene chloride and water. The aqueous phase is further extracted with methylene chloride (3×100 ml) and the combined extracts are dried over sodium sulfate, decolorized with charcoal and evaporated to yield 4-(3-cyanopropyl)pyridine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH:10]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH2:10][C:12]1[NH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCc1cccc(Cl)c1C(O)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCc1cccc(Cl)c1Cc1ncc[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
This compound was prepared using methodology described in J. Chem. Soc., Perkin Trans. 1, 2002, 1061-1066. To a stirred solution of 2.10 g (8.87 mmol) rac-(2-chloro-6-ethyl-phenyl)-(1H-imidazol-2-yl)-methanol in 10 ml 1,2-dichloroethane in a pressure tube were added dropwise 14.1 ml (88.7 mmol) triethylsilane and 8.04 ml (106 mmol) trifluoroacetic acid. The tube was sealed and the reaction mixture was stirred at 100° C. for 16 hours, before being cooled to room temperature and diluted with dichloromethane. The mixture was washed sequentially with 2 N aqueous sodium hydroxide solution and water and then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) followed by trituration in ether to afford 0.66 g (34%) of the title compound as a white crystalline solid. MS (ISP): 223.1 ([M+H]+), 221.2 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:20])[CH:3]=1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:31])[C:29]=1Cl.OP([O-])(O)=O.[K+]>CS(C)=O>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[NH:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:1][C:29]2[C:28]([Cl:31])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2c(N)cc(=O)[nH]c2c1OC1CCCC1
Reactant: Clc1cncc(Cl)c1Cl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OC1CCCC1
Reaction time: 0.08 h

Procedure:
4-Amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (340 mg, 1.24 mmol) was added in 3, portions over 5, minutes to a mixture of sodium hydride (NaH) (110 mg, 60%, 2.75 mmol) and DMSO (4 mL) at room temperature under N2. After 5 min, 3,4,5-trichloropyridine (271 mg, 1.49 mmol) was added. After 19 h, more sodium hydride (100 mg, 60%, 2.5 mmol) was added followed by more 3,4,5-trichloropyridine (250 mg, 1.37 mmol). After an additional 4 h, the reaction was poured into 1M KH2PO4 (75 mL) and stirred for 5 min. The solids were filtered, washed with water (25 mL), and then purified by reverse-phase HPLC (3:7→1:0; acetonitrile:water). In some cases, additional purification by silica gel chromatography (1:0→9:1; dichlormethane:methanol) was needed to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.86 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.06 (d, 1H), 4.97 (m, 1H), 4.78 (s, 1H), 3.90 (s, 3H), 1.83-1.48 (m, 8H); MS (ESI): 419.7.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH2:26]([O:33][C:34]1[CH:48]=[CH:47][C:37]([CH2:38][C@H:39]([NH2:46])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)C>CN(C)C=O>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:38][CH:39]([NH:46][C:12]([CH:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:40][O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[CH:47][CH:48]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(COC(C)(C)C)Cc1ccc(OCc2ccccc2)cc1
Temperature: 3 °C
Reaction time: 0.67 h

Procedure:
A 3° C. solution of 106 mg (0.41 mmol) (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (Example 1, Step B) and 0.137 mL (0.41 mmol) 4-methylmorpholine in 2 mL N,N-dimethylformamide was treated with 165 mg (0.44 mmol) O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uranium hexafluorophosphate (Novabiochem, La Jolla, Calif.), and stirred for 30 minutes, at which time a solution of (S)-1-(4-benzyloxy-benzyl)-2-tert-butoxy-ethylamine in 3 mL dimethylformamide was added and the mixture stirred at 3° C. for 40 minutes. The clear solution was poured into 15 mL diethyl ether and washed successively with 15 mL of each of the following: 5% aqueous HCl, brine, saturated aqueous NaHCO3, brine (twice) then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo affording 180 mg of white solid, which was recrystallized from hexane to give 116 mg (51%) of the title compound as a white solid; mp 98-99° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]([CH3:65])[CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]([CH3:65])[CH:59]1[CH2:64][CH2:63][N:62]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:61][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: CN(c1ccccc1Br)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(c1ccccc1Br)C1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)on2)CC1
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (62.9 mg, 0.00025 mol) in DMF (2 mL) was added DIPEA (0.159 g, 0.00123 mol), HOBt (41.4 mg, 0.00031 mol) and EDCI.HCl (58.8 mg, 0.0003° mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-methyl-piperidin-4-yl-amine hydrochloride (0.068 g, 0.00025 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using basic aluminium oxide (50-100% ethyl acetate in hexane) afforded 0.039 g (35%) of 5-phenyl-isoxazole-3-carboxylic acid (2-{4-[(2-bromo-phenyl)-methyl-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 497.11 (M+1)+, 97.87%, 1H NMR (DMSO-d6): δ 8.58 (t, 1H), 7.93 (m, 2H), 7.52 (m, 4H), 7.4 (s, 1H), 7.15 (m, 2H), 6.9 (m, 1H), 4.3 (d, 1H), 4.15 (t, 2H), 3.8 (d, 1H), 3.0 (m, 1H), 2.65 (m, 1H), 2.55 (s, 3H), 1.75 (m, 3H), 1.5 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=O)[CH3:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(OCC)C.CCCCCC.Cl[Ti](Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:15]=[C:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[CH:12][CH:11]=1
Reactant: CC(=O)C(F)(F)F
Reactant: COc1ccc(CN)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1ccc(CN=C(C)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirring solution of trifluoroacetone (7.75 g, 69.2 mmol) in diethyl ether (60 ml) at −40° C. was added 4-methoxybenzyl amine (9.49 g, 69.2 mmol) and triethylamine (14 g, 138 mmol) in diethyl ether (40 ml). A cooled (0° C.) mixture of TiCl4 (6.56 g, 34.6 mmol) in hexane (40 ml) at was added dropwise over 10 minutes and the resulting mixture was allowed to warm up to ambient temperature over 20 mins and stirred at 50° C. for 2.5 h. The inorganic precipitate was removed by filtration and washed with diethyl ether. The filtrate was concentrated in vacuo to afford a yellow oil. Purification of the crude product by chromatography on silica eluting with 0% to 25% EtOAc in iso-hexane afforded the title product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:16]([C:18](=[O:37])[C@H:19]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([C:13]([NH:17][NH:16][C:18](=[O:37])[C@H:19]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: NNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Int. A) (200 mg, 0.702 mmol) in NMP (6 ml) was treated with (R)-benzyl 2-hydrazinyl-2-oxo-1-phenylethylcarbamate (Int. JR) (231 mg, 0.772 mg) followed by portionwise addition of HATU (293 mg, 0.772 mmol). After stirring at RT for 45 minutes, the reaction mixture was added to EtOAc (50 ml) and washed with 0.1 M NaOH (50 ml). The aqueous layer was back extracted with EtOAc (25 ml). The combined organic portions were washed with water (75 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo. The crude product was loaded in MeOH onto a pre-wetted (MeOH) Isolute® PE-AX (anion exchange) cartridge. The cartridge was eluted with MeOH (70 ml) and the filtrate was concentrated in vacuo to give a yellow solid which was placed under high vacuum to give the title compound as a yellow solid;
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34].C(N(CC)CC)C>C1COCC1>[F:23][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=3)=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC(F)(F)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCC(F)(F)C3)c(-c3ccnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
A mixture of 4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (64 mg, 0.20 mmole), 4-fluoro-3-methyl-benzoyl chloride (52 mg, 0.30 mmole), and triethylamine (56.5 μL, 0.40 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 29 mg, 32% yield). Exact mass calculated for C24H25F3N4O2 458.2. found 459.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1cc(C(=O)Nc2c(Cl)cncc2Cl)ccc1OC
Temperature: 25 °C

Procedure:
A stirred solution of N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (2.0 g; that is prepared as described in Reference Example 12) in dimethylformamide (20 mL) at room temperature under nitrogen is treated portionwise with a suspension of sodium hydride (60% dispersion in oil; 0.26 g), and then it is stirred for a further hour at room temperature. It is then treated dropwise with 1-bromononane (1.2 mL) and stirred at 60° C. for 5 hours. The solution is then cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated, to give a white solid, which is subjected to flash chromatography on silica gel, eluting with t-butyl methyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-nonyloxy-4-methoxybenzamide (0.56 g), m.p. 151-153° C. [Elemental analysis: C,60.3; H,6.45; N,6.3%; calculated: C,60.1; H,6.4; N,6.4%].