Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])[CH3:23].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of Intermediate 58 (99 mg) and triethylmethanetricarboxylate (0.14 mL) in anhydrous Toluene (3 mL) and anhydrous Tetrahydrofuran (THF) (3.00 mL) under a nitrogen atmosphere was added trimethylphosphine, 1M in Toluene (0.650 mL). The reaction was then cooled to −78° C. and diisopropyl azodicarboxylate (0.13 mL) added dropwise via syringe over 1 min. The reaction was stirred at −78° C. under an atmosphere of nitrogen for 90 mins before being allowed to warm to ambient temperature and stirred for a further 1 h. The reaction was concentrated in vacuo. The residue was taken up in dichloromethane (40 mL) and washed with water (40 mL), dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (139 mg). LC/MS MH+ 519, Rt 2.15 min (5 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3ccncc3)ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccc(-c3ccncc3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][CH:14]=2)[N:3]=1.[CH2:28]([P:31](C1C=C(C=CC=1)N)([CH2:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH3:30].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:26]([P:31]([CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH3:30])=[O:32])[CH:27]=2)[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCCP(=O)(CCC)c1cccc(N)c1
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c1

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 3-(dipropylphosphoryl) aniline (Compound 168C) and 2,4-dichloro-5-trifluoromethylpyrimidine. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.00 (td, J=7.26, 0.88 Hz, 6H), 1.47-1.58 (m, 2H), 1.64-1.77 (m, 2H), 1.82-1.94 (m, 2H), 1.97-2.10 (m, 2H), 7.33-7.40 (m, 1H), 7.51 (td, J=7.83, 3.28 Hz, 1H), 8.00 (d, J=8.34 Hz, 1H), 8.08 (d, J=12.13 Hz, 1H), 8.60 (s, 1H). MS (ES+): m/z=405.97 (100) [MH+]. HPLC: tR=3.47 min (polar—5 min).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(O)(=O)C.[CH3:38][NH2:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.CO>[CH3:38][NH:39][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:25][CH:26]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=C1CCCCC1n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CN[C@@H]1CCCC[C@H]1n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(±)-2-(2-Oxocyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 720, 45 mg, 0.10 mmol) was dissolved in 1,2-dichloroethane (3 mL) and treated with acetic acid (0.029 mL, 0.51 mmol, 5 equiv) and methylamine (0.057 mL, 0.11 mmol, 1.1 equiv). After stirring for 20 minutes at ambient temperature, sodium triacetoxyborohydride (30 mg, 0.14 mmol, 1.4 equiv) was added and the mixture was vigorously stirred for 4 hours. The mixture was treated with methanol (1 mL), poured into water (15 mL) and extracted once with ethyl acetate (20 mL). The organic layer was discarded and the aqueous layer was treated with sodium bicarbonate (15 mL, aqueous saturated) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.45 (1H, s), 8.41-8.38 (1H, m), 7.89 (1H, d, J=2.5 Hz), 7.71 (1H, d, J=1.6 Hz), 7.70 (2H, d, J=8.5 Hz), 7.49-7.43 (2H, m), 7.41-7.38 (1H, m), 7.27 (2H, d, J=8.5 Hz), 6.47-6.46 (1H, m), 5.50 (1H, d, J=16.5 Hz), 5.44 (1H, d, J=16.5 Hz), 4.75 (1H, dt, J=10.5, 3.8 Hz), 3.02 (1H, m), 2.49-2.33 (1H, m), 2.37 (3H, s), 2.14-2.09 (1H, m), 1.98-1.92 (1H, m), 1.87-1.80 (1H, m), 1.70-1.59 (2H, m), 1.57-1.42 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 453.2387 [(M+H)+; calculated for C27H29N6O: 453.2397].
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)([CH3:14])[CH3:13]
Reactant: Ic1cccc2[nH]ncc12
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cccc2[nH]ncc12
Yield: 56.7 %

Procedure:
In an adaption of GP 8a, 4-Iodo-1H-indazole (1.00 g, 4.10 mmol) was reacted with trimethylsilyl acetylene (0.61 mL, 4.30 mmol) at 90° C. for 5 h to give 498 mg (57%) of pure 4-(trimethylsilyl)ethynyl-1H-indazole.
Reaction SMILES: [I-:1].[Na+].CNCCNC.Br[C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1.CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[I:1][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(I)c1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
A Schlenk tube was charged with CuI, sodium iodide (fine powder, dried, 300 mg, 2.00 mmol), evacuated and backfilled with argon. N,N′-Dimethylethylenediamine, 5-bromo-m-xylene (136 μL, 1.00 mmol), and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 22 h. The resulting suspension was allowed to reach room temperature. Ethyl acetate (2 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC. The results are tabulated below.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>CN(C)C=O>[NH:3]1[C:2]([NH:1][C:9](=[O:10])[CH2:8][Cl:7])=[N:6][N:5]=[N:4]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1nnn[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of anhydrous 5-aminotetrazole, 85.0 g., 1.0 mole, in 400 ml of dimethylformamide, chloroacetyl chloride, 113 g., 1.0 mole, was added from a dropping funnel during about 25 minutes. The temperature of the mixture rose to a maximum of 85° C and was kept at approximately 80° C for 1 hr. longer by heating the mixture. The mixture was evaporated to approximately one-half the volume, poured into 1500 ml of water and cooled several hrs. in a refrigerator. The precipitated solid was collected on a filter and washed with cold water. The solid was dried at 50°-60° C to give 100.2 g., m.p. 218° C dec., 62% crude yield. Treatment of the solid with decolorizing carbon and crystallization from alcohol gave a white, fluffy, crystalline solid, m.p. 227°-228° C dec.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=[O:16])[C:8]2=[O:22])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([OH:17])=[O:16])[C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 94.7 %

Procedure:
A solution of methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate (4.57 g, 13.90 mmol) and lithium hydroxide monohydrate (4.05 g, 96.52 mmol) in tetrahydrofuran (170 mL) and water (85 mL) was stirred for 19 hours. The organic solvent was removed in vacuo. The aqueous solution was acidified with 12 M hydrochloric acid solution until pH 3. The solid was filtered, washed with water (30 mL), hexanes (20 mL) and dried in vacuo to give 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid as a colorless solid (4.15 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.37-7.31 (m, 3H), 7.18-7.13 (m, 2H), 4.39 (s, 2H), 3.94 (t, J=8.1 Hz, 2H), 3.35 (t, J=8.1 Hz, 2H); MS (ES+) m/z 316.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl-].[NH4+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:8]2[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]3[S:18][N:17]=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])=[C:22]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=2)[CH:21]=1
Reactant: CN(C)c1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)c1cc(-c2cc(Cl)ccc2Oc2ccc(S(=O)(=O)Nc3ncns3)cc2C#N)ccn1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 40 mg, 0.14 mmol), 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol (Preparation 865, 35.0 mg, 0.141 mmol) and potassium carbonate (58 mg, 0.42 mmol) in dimethyl sulfoxide (1 mL, 20 mmol) was stirred at 150° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (12 g SiO2, hexanes to 20% methanol in ethyl acetate). The product-containing fractions were concentrated in vacuo then lyophilized from water and minimal acetonitrile to afford the product as a light yellow powder (40 mg, 60%).
Reaction SMILES: [CH2:1](Br)[CH3:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:25])[NH:13][C:14]([S:23][CH3:24])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH2:1]([N:13]1[C:12](=[O:25])[C:11]([C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)=[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:15]=[C:14]1[S:23][CH3:24])[CH3:2]
Reactant: CCBr
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1c(SC)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 8 h

Procedure:
Ethyl bromide (600 ml, 8.03 mmol) was added to a stirred mixture of 5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (1.8 g, 5.97 mmol) and sodium hydride (60% oily suspension, 320 mg, 8 mmol) in N,N-dimethylformamide (60 ml) at room temperature. More ethyl bromide (2×600 ml, 2×8.03 mmol) was added after 2 and 3.5 h. After 8 h, the reaction mixture was neutralized with acetic acid and evaporated. The remainder was taken up in dichloromethane, the organic solution was washed with water, dried and evaporated. Flash chromatography on a column of silica gel (hexane-acetone=3:1, 2:1). provided in the second main fraction the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][NH:23]2)=[CH:18][CH:17]=1>C(C#N)(C)=O>[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][N:23]2[C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:18][CH:17]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Clc1ccc2c(c1)NCCC2
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(c1)N(c1ncnc(Cl)n1)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of the compound 2,4-dichloro-1,3,5-triazine (1.0 g, 5.97 mmol) and solid K2CO3 (4.0 g, 29 mmol) was suspended in AcCN (20 mL) under nitrogen at 0° C., followed by slow addition of 7-chloro-1,2,3,4-tetrahydro-quinoline (Step 1) (1.1 g, 6.56 mmol) as a solution in AcCN (20 mL) over 15 min. The mixture was stirred at 0° C. for 1 h. The solids were removed by suction filtration and washed with AcCN. The organics were concentrated under reduced pressure and the crude compound was purified via column chromatography to give 7-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1,2,3,4-tetrahydro-quinoline).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([CH3:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)C(Cl)Cl>[Br:16][CH2:15][C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=Cc1ccc(Cl)cc1Cl)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)C(Cl)Cl
Product: CC(C)(C)C(=Cc1ccc(Cl)cc1Cl)CBr
Yield: 62.1 %

Procedure:
A mixture of 24.3 g (0.1 mol) of 1-(2,4-dichlorophenyl)-2,3,3-trimethylbut-1-ene, 17.8 g (0.1 mol) of N-bromosuccinimide and a spatula-tip of azodiisobutyrodinitrile in 100 ml of absolute 1,1,2,2-tetrachloroethane is boiled under reflux overnight. For working up, the mixture is concentrated in vacuo, the residue is taken up in carbon tetrachloride, the mixture is filtered and the filtrate is distilled. 20 g (62.1% of theory) of 2-bromomethyl-1-(2,4-dichlorophenyl)-3,3-dimethylbut-1-ene of boiling point 108° C. at 0.13 mbar are obtained. ##STR100##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH2:69][N:70]1[CH2:75][CH2:74][O:73][CH2:72][CH2:71]1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([NH:66][CH2:67][CH2:68][CH2:69][N:70]5[CH2:75][CH2:74][O:73][CH2:72][CH2:71]5)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:31][CH:32]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCOCC5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.23 mmol) in 10 ml of anhydrous DMF were added HATU (106 mg, 0.28 mmol) and N,N-diisopropylethylamine (90 mg, 0.70 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)morpholine (68 mg, 0.47 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 110 mg, 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[CH3:12].[Cl-].[NH4+].O>[Fe].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]([F:13])([F:14])[CH3:12]
Reactant: CC(F)(F)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(F)(F)c1cc(N)ccc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
480 mg (2.17 mmol) of 1-chloro-2-(1,1-difluoro-ethyl)-4-nitro-benzene, 464 mg (8.67 mmol) of ammonium chloride and 365 mg (6.51 mmol) of iron powder were added to a mixture of 1.5 mL of water and 3 mL of methanol. The slurry was stirred at 70° C. for 1 h, and then cooled down, filtered through a pad of celite washing with excess methanol and concentrated down under reduced pressure. The residue was dissolved in ethyl acetate, evaporated under reduced pressure on silica gel and purified on silica eluting with a 5-30% ethyl acetate in hexanes to give 365 mg of the pure product as a white solid. LC-MSD, m/z for C8H8ClF2N [M+H]+=192.0, 194.0;
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>CS(C)=O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[CH:17][C:18]=1[C:24]([F:25])([F:26])[F:27])#[N:21]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 75 °C
Reaction time: 39 h
Yield: 99.9 %

Procedure:
To a suspension of D-allo-threonine (4.30 g, 36.1 mmol) and K2CO3 (8.73 g, 63.2 mmol) in DMSO (50 mL) was added 4-fluoro-2-(trifluoromethyl)benzonitrile (5.69 g, 30.1 mmol) at room temperature. The reaction mixture was heated to 75° C. and stirred for 39 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (400 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a brown oil (8.67 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.69 (d, J=8.6 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.07 (dd, J=2.5, 8.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.35 (dd, J=4.9, 8.4 Hz, 1H), 4.29 (dq, J=4.9, 6.5 Hz, 1H), 1.32 (d, J=6.4 Hz, 3H).
Reaction SMILES: CCCCCCCCC=CCCCCC[CH2:16][CH2:17][C:18]([OH:20])=[O:19].C1OC(C(O)CO)C(O)C1O.[C:32]([NH2:36])(=[O:35])[CH:33]=[CH2:34].C(O)(=O)C=C.[OH-].[NH4+].C(OO)(C)(C)C.[Na+].[Na+].[Na+].[Na+].C(N(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=O>O>[C:18]([O-:20])(=[O:19])[CH:17]=[CH2:16].[NH4+:36].[C:32]([NH2:36])(=[O:35])[CH:33]=[CH2:34]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)O
Agent: C=CC(=O)O
Agent: C=CC(N)=O
Agent: CC(C)(C)OO
Solvent: O
Product: C=CC(=O)[O-]

Procedure:
An organic solution is prepared by combining a low odor paraffin oil (252.0 g), sorbitan sesquioleate (8.5 g) and polyoxyethylene sorbitol fatty acid (39.5 g) in a reactor with stirring. To this solution is added an aqueous solution of pH =8.0 containing acrylamide (84.0 g), acrylic acid (36.0 g) neutralized with aqueous ammonium hydroxide (35.7 g), tert-butyl hydroperoxide (0.048 g), ethylenediaminetetraacetic acid tetra sodium salt (0.24 g), and water (144.0 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH:9]([OH:11])[C:8]3[S:12][CH:13]=[CH:14][C:7]=3[CH2:6]2)[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18](F)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([O:11][CH:9]2[CH2:10][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:6][C:7]3[CH:14]=[CH:13][S:12][C:8]2=3)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CN(CC2CC2)Cc2ccsc21
Product: Clc1ccc(OC2CN(CC3CC3)Cc3ccsc32)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 5-cyclopropylmethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 15) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[S:9]([CH2:12][C:13](OC)=[O:14])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18].O>O1CCCC1>[CH2:1]([N:8]([CH3:17])[S:9]([CH2:12][C:13]([NH2:18])=[O:14])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)S(=O)(=O)CC(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a stirred solution of methyl (N-benzyl-N-methylsulfamoyl)acetate (from step (a), 3.9 g, 15.2 mmol) in tetrahydrofuran (10 ml) at ambient temperature was added aqueous ammonia (10 ml, s.g.=0.88) in one portion. The orange solution was then stirred at ambient temperature for 18 hr, before being poured into water (50 ml) and extracted with ethyl acetate (3×25 ml). The organic extract was evaporated in vacuo to give the subtitle compound (2.8 g, 76%) as a white solid. m.p. 124-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:10][CH2:11][N:12]([CH3:28])[CH2:13][CH2:14]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCNCC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a mixture of benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate (Preparation Example 455) (1.52 g) and 1,2-dichloroethane (70 mL), formalin (3.62 mL) and sodium triacetoxyborohydride (1.42 g) were added and stirred overnight at room temperature. After addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0.1) to give benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (1.26 g) as a white solid.