Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Cl:1][CH2:2][C:3]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
164 ml. (235.1 g., 2.04 moles) of chloroacetyl chloride is added over a 50 min. period to a mixture of 400 ml. (410 g., 4.22 moles) of fluorobenzene and 300 g. (2.25 moles) of anhydrous aluminum chloride stirred at 75° C. under nitrogen. The reaction mixture is stirred at 80° C. under nitrogen for 1 hour, cooled to 50° C., 500 ml. of fluorobenzene is added, and the reaction mixture is cooled to 0° C. and gradually (over a 30 min. period) siphoned into 1 l. of 6N. hydrochloric acid stirred at 0° C. (The temperature of the aqueous acid is maintained at or below 25° C. throughout the addition.) The quenched, acidified reaction mixture is stirred for 15 min., and the aqueous phase is separated and extracted with 350 ml. of fluorobenzene. The two organic phases are combined and washed twice with 500 ml. portions of 3N. hydrochloric acid and once with 500 ml. of water. The fluorobenzene is distilled at 30 mm. Hg. and 60° C. and, upon cooling, the obtained oily residue solidifies. The crude solid product need not be purified.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C(Cl)(=O)[C:11]([Cl:13])=O>ClCCl.CN(C=O)C>[Cl:13][CH2:11][C:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)=[O:9]
Reactant: O=C(O)C1CCCCO1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCl)C1CCCCO1
Temperature: 2.5 °C

Procedure:
Tetrahydropyran-2-carboxylic acid (3.3g) in dry dichloromethane (60ml) was treated with oxalyl chloride (4.8g, 3.3ml) and DMF (2-3 drops). After the initial effervescence had ceased the mixture was left for a further 1h at ambient temperature. The solvent and excess oxalyl chloride were removed in vacuo and the resultant oil [vmax (CH2Cl2)1830cm-1 ] was dissolved in dichloromethane (20ml). This acid chloride solution was then added dropwise to a freshly prepared ethereal solution of diazomethane (ca 2 fold excess) cooled to 0-5° C., t.l.c. analysis (60% ethyl acetate in hexane) showed a single mobile spot, i.r. spectrum of a sample showed clean conversion to the diazoketone [vmax (CH2Cl2) 2100cm-1 ]. Hydrogen chloride gas was bubbled through the solution until no further starting material was observed by t.l.c. The mixture was washed with brine, dried and the solvent removed in vacuo and the residue purified by flash chromatography on silica gel. The title compound was obtained as a pale yellow oil, (2.8g, 68%); vmax (CH2Cl2) 1740cm-1 ; δH (CDCl3) 1.4-1.7 (4H, m), 1.91-1.98 (2H, m), 3.42-3.53 (1H, m), 3.95-4.07 (2H, m) and 4.48 (2H, s) [Mass spectrum: +ve ion (NH3), MH+ (163), MNH4+ (180)].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[C:27]([NH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:27]([NH:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1cccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3n2)c1
Yield: 65.5 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and [3-(acetylamino)phenyl]boronic acid (57.5 mg, 0.32 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.7 mg, 0.010 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed and the reaction mixture was irradiated (microwave) at 150° C. for 30 min. After cooling, 2 mL of water was added and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH and DCM, filtered, and dried to afford the title compound (65 mg, 63%) as a white solid. LCMS E-S (M+H)=473.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1H), 9.02 (t, J=4.80 Hz, 1H), 8.61-8.68 (m, 2H), 8.37-8.43 (m, 2H), 8.21 (s, 1H), 7.94 (d, J=7.83 Hz, 1H), 7.65 (t, J=7.83 Hz, 1H), 5.91 (s, 1H), 5.37 (quin, J=6.63 Hz, 1H), 4.42 (d, J=4.80 Hz, 2H), 2.84 (d, J=4.29 Hz, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C>O1CCOCC1>[CH2:25]([O:24][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[C:4]([OH:27])=[O:3])[CH3:26]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(SC)cc2)cc1)OCC
Solvent: C1COCCO1
Product: CCOC(Cc1ccc(OCCc2ccc(SC)cc2)cc1)C(=O)O

Procedure:
2-Ethoxy-3-{4-[2-(4-methylsulfanylphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 81) was hydrolyzed using the same method as in Example 2 but with dioxane instead of tetrahydrofuran to give 2-ethoxy-3-{4-[2-(4-methylsulfanylphenyl)ethoxy]-phenyl}propanoic acid.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.[NH2:17][C@H:18]([C:25]([O:27][CH3:28])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1.Cl.[N-]=[N+]=[N-].C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2][CH2:3][C:4]([NH:17][C@H:18]([C:25]([O:27][CH3:28])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:6]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: O=P(O)(Oc1ccccc1)Oc1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 12.3 g of Z-β-Ala-OH and 16.0 g of H-His-OCH3 ×2 HCl in 300 ml of DMF is cooled to 0° and there are added dropwise thereto first a solution of 22.75 g of phosphoric acid diphenyl ester azide in 110 ml of DMF and then a solution of 30.7 ml of triethylamine in 110 ml of DMF. The suspension so obtained is stirred for 2 days at room temperature and then concentrated to an oily suspension in a high vacuum. The residue is taken up in ethyl acetate, washed with sodium bicarbonate and brine, dried and concentrated by evaporation. The crude product is separated by flash chromatography (1.6 kg of silica gel [type 60, Merck], 40-63 μm, 0.4 bar, fractions of 400 ml, eluant: CH2Cl2 /MeOH[13:2]). By concentration by evaporation of the appropriate fractions, Z-β-Ala-His-OCH3 is obtained as a slightly yellowish foam; Rf (L)=0.69.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.C1(N)CC1.ClC1C=C(C=CC=1Cl)CN(C)C([C:35]1C[N:37]([CH3:42])[C:38](=O)[C:39]=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH2:42][N:37]([CH:38]2[CH2:39][CH2:35]2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: NC1CC1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C2CC2)C1
Yield: 30 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and cyclopropylamine as described in the preparation of Compound 12. The title compound was extracted with EtOAc and the organic layer was washed with H2O, and dried over Na2SO4. After concentration, the resulting residue was triturated with EtOAc/Hexane (1:1) to give a white solid (52.7 mg, 30% yield). Mp=163–164° C. 1H NMR (300 MHz, CDCl3) δ: 9.97 (bs, 1H), 7.42, (d, 1H, J=8.42), 7.35 (s, 1H), 7.10 (dd, 1H, J=8.42, J=1.47), 4.60 (s, 2H), 4.09 (s, 2H), 3.02 (s, 3H), 2.81 (m, 1H), 0.86 (m, 4H). HRMS (M+H) calcd for C16H17N2Cl2O3: 355.0616. found: 355.0618.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][N:36]([C:46](=[O:48])[CH3:47])[CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1ncccc1Oc1cc(Nc2nc(C3CCNCC3)cs2)ncc1Sc1ccnc2ccsc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2csc(Nc3cc(Oc4cccnc4C)c(Sc4ccnc5ccsc45)cn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
4-(2-Methylpyridin-3-yloxy)-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride (0.051 g, 0.08 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (0.10 mL, 0.74 mmol) and acetic anhydride (0.017 mL, 0.19 mmol) were added and the reaction was stirred at ambient temperature overnight. Saturated sodium bicarbonate solution was added, and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (0.051 g, 70% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.50 (d, 1H), 8.41 (dd, 1H), 7.73 (d, 1H), 7.56 (d, 1H), 7.19 (m, 1H), 7.17 (m, 1H), 6.92 (d, 1H), 6.40 (d, 1H), 6.36 (s, 1H), 4.67 (m, 1H), 3.86 (m, 1H), 3.13 (m, 1H), 2.69 (m, 2H), 2.16 (s, 3H), 1.94 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]([F:26])[F:25])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[F:26][CH:24]([F:25])[N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:27]
Reactant: O=c1n(-c2ccc(OCc3ccccc3)cc2)c2ncccc2n1C(F)F
Agent: [Pd]
Solvent: CCO
Product: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C(F)F
Reaction time: 3 h
Yield: 94.6 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (420 mg) and 10% Pd—C (60.8 mg) in EtOH (50 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=[CH:10][C:9]=2[NH2:25])=[CH:4][CH2:3]1.[K+].[C:28]([C:30]1[N:31]=[C:32]([C:43]([O-])=[O:44])[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=1)#[N:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=[CH:10][C:9]=2[NH:25][C:43]([C:32]2[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=[C:30]([C:28]#[N:29])[N:31]=2)=[O:44])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 60.0 mg of crude 2-(4,4-dimethyl-cyclohex-1-enyl)-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with 53.3 mg (0.174 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 111 mg (0.238 mmol) of PyBroP to form a slurry, which was treated with 82.8 μL (0.476 mmol) of DIEA. The mixture was stirred at RT for 4 h, diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 60.3 mg (crude) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C31H41N5O5SSi, 628.3 (M+H). found 628.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8]2)[CH:2]=1.[C:13](O)(=[O:15])[CH3:14].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C@H:9]1[CH2:10][CH2:11][C@@H:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: O[C@@H]1CC[C@@H](c2cccnc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.4 %

Procedure:
A solution of (1R,3R)-3-(3-pyridyl)cyclopentanol (3.47 g, 21.3 mmol) in THF (100 mL) was cooled to 4° C. and treated with acetic acid (1.34 mL, 23.4 mmol), Diisopropylazodicarboxylate (4.61 mL, 23.4 mmol) and triphenylphosphine (6.14 g, 23.4 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (NH, Hexane/EtOAc=6/1) to yield (1S,3R)-3-(3-pyridyl)cyclopentyl acetate (4.39 g, 100%) as colorless oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=O)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:57]1([N:60]2[CH2:65][CH2:64][N:63]([C:66]3([CH2:72][NH:73][C:74](=[O:81])[C:75]4[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=4)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:62][CH2:61]2)[CH2:59][CH2:58]1>ClCCl.CN(C=O)C>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:69]2[CH2:68][CH2:67][C:66]([CH2:72][NH:73][C:74](=[O:81])[C:75]3[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=3)([N:63]3[CH2:62][CH2:61][N:60]([CH:57]4[CH2:58][CH2:59]4)[CH2:65][CH2:64]3)[CH2:71][CH2:70]2)=[O:24])[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)N2CCC(CNC(=O)c3ccncc3)(N3CCN(C4CC4)CC3)CC2)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)ethoxy)acetic acid AC7 (0.225 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to yield the crude product which was purified by column chromatography. Yield: 60%. MS, Rt=2.8 min, m/z 683.5 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][OH:13].[Cl:14][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:16][C@@H:17]1[C@H:19]([C:20](Cl)=[O:21])[C:18]1([CH3:24])[CH3:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:14][C:15]([C:25]([F:26])([F:27])[F:28])=[CH:16][C@@H:17]1[C@H:19]([C:20]([O:13][CH2:12][C:3]2[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=2[CH3:1])=[O:21])[C:18]1([CH3:24])[CH3:23]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: Cc1ccc(C(C)C)c(C)c1CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(C(C)C)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C

Procedure:
[2,6-Dimethyl-3-(1-methylethyl)phenyl]methanol (0.7 g, 0.004 mole), cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (0.97 g, 0.004 mole), pyridine (2 ml) and dry toluene (150 ml) were combined to give [2,6-dimethyl-3-(1-methylethyl)phenyl]methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (242 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (377 mg, 73%). MS (ISN) 510.0 [(M−H)−]; mp 240° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:30][CH2:31][CH3:32]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=1[CH2:30][CH2:31][CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1ccc(S(C)(=O)=O)cc1I
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCCc1ccc(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-4-(methylsulfonyl)-1-propylbenzene (Intermediate 62), the title compound was obtained as a white solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(NCCN)nc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)nc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamnine(1.95 ml), and then diphenylphosphinic chloride(1.34ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylamino)-5-methoxypyridine(1.17 g) added thereto, was stirred for 8 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.22 g of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:12][CH2:13][NH:14]1
Reactant: COC(=O)c1ccnc(Cc2ccc(F)cc2F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccc(F)cc2F)C1
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
Methyl 2-(2,4-difluorobenzyl)isonicotinate (7.011 g, 26.63 mmol) was dissolved in acetic acid (50 mL) and platinum(IV) oxide (0.302 g, 1.33 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator for 4.5 h at room temperature and 5 bar. platinum(IV) oxide (174 mg) was added and the hydrogenation continued at room temperature at 5 bar for 2 h. Additional platinum(IV) oxide (185 mg) was added and the hydrogenation continued at room temperature at 5 bar for 2 h. The catalyst was filtered off and washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The water phase was extracted with DCM and the combined organic phase washed with water, passed through a phase separator and evaporated to yield methyl 2-(2,4-difluorobenzyl)-piperidine-4-carboxylate (7.103 g, 99%) as a yellow oil. MS m/z 270 (M+H)+
Reaction SMILES: C([O:9][C@@H:10]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:11](OCC(OC(C)(C)C)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl.F[C:37](F)(F)[C:38]([OH:40])=[O:39]>CO>[C:27]1([C@H:10]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:40][C:38](=[O:39])[CH2:37][O:9]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CO[C@H](c1ccccc1)[C@@H](OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CO[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 266.3 %

Procedure:
To 6X (2.94 g, 6.79 mmol) was added a solution of sodium hydroxide (326 mg, 8.15 mmol) in methanol (27.2 ml). After stirring for 20 h at rt, 37% hydrochloric acid (669 μl, 8.15 mmol) was added. After concentration in vacuo, a 0.4 M solution of hydrochloric acid (50 ml) was added. The resultant product (hydroxy carboxylic acid) was extracted with ethyl acetate four times and the organic layer was dried over anhydrous sodium sulfate. After concentration, the residue was dissolved in toluene (34 ml) followed by addition of trifluoroacetic acid (105 μl, 1.36 mmol). After stirring for 6 h at 80° C., the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluted with 6:1 hexane:AcOEt) to give 2X (921 mg, 53%) as a white solid.