Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:33]([Cl:37])=[CH:34][C:35]=2I)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:50]1[CH:55]=[CH:54][N:53]=[N:52][CH:51]=1)CCC.[F-].[Cs+].C(#N)C>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:33]([Cl:37])=[CH:34][C:35]=2[C:50]2[CH:55]=[CH:54][N:53]=[N:52][CH:51]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccccc4F)c(Cl)cc3I)cc2F)c(OC)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccccc4F)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 45 °C
Yield: 39 %

Procedure:
Tetrakistriphenylphosphinepalladium (0) (44 mg, 0.038 mmol) and copper (I) iodide (29 mg, 0.152 mmol) were added to a degassed mixture of 5-chloro-4-(6-chloro-2′-fluoro-4-iodobiphenyl-3-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 93, 600 mg, 0.759 mmol), 4-(tributylstannyl)pyridazine (364 mg, 0.987 mmol), caesium fluoride (230 mg, 1.52 mmol), and acetonitrile (5.0 mL). The reaction was heated at 45° C. for 18 hours and then the cooled reaction mixture was diluted with ethyl acetate (30 mL) and filtered through Arbocel. The filtrate was then washed with water (5 mL), brine (5 mL), dried over MgSO4, filtered and evaporated. The residue was purified by preparative HPLC using acetonitrile/water as eluent (15/85 to 95/5, Phenomenex Luna C18 5 u 110 A 21.2×150 mm) to give the title compound (220 mg, 39%) as a brown foam.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>C1C=CC=CC=1>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([Cl:20])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(-c2ccccc2)cc1
Yield: 100.8 %

Procedure:
A suspension of 4-biphenyl acetic acid (8.48 g, 40 mmole) in dry benzene was cooled and stirred in an ice bath and oxalyl chloride (5.0 ml, 57.5 mmole) was added, followed dropwise by a solution of dry dimethylformamide (0.5 ml) in dry benzene. After the vigorous gas evolution subsided, the resulting solution was stirred at room temperature for 30 minutes. It was then evaporated and dried in vacuo (oil pump ~30) to afford 4-biphenylacetyl chloride as a solid (9.3 g, ~100%). This was used for reaction without further characterization. The above acid chloride was dissolved in CH2C12 (400 ml), stirred in an ice bath and a solution of sodium azide (3.9 g, 60 mmole) and (n-Bu)4N+H-SO4 (1.0 g) in water (120 ml) was added. (Ref. J. R. Pfister and W. E. Wyman, Synthesis, 38 (1983). The mixture was then stirred vigorously in the ice bath. After 45 minutes, the CH2Cl2 layer was separated, washed with water and brine, dried (MgSO4 anhydrous) and evaporated in vacuo (at ~25° ; CAUTION: DO NOT HEAT) to afford the title compound as a solid (8.5 g, 90.4%). The IR spectrum (Nujol) showed a weak peak at 2273 cm-1 (N=C=O) and a very strong peak at 2140 cm-1 (N3). It showed only one spot on tlc (silica gel, EtOAc-hexane, 1:1) and was used in the next step without further characterization.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].C[Mg+].[Br-].[Cl-].[NH4+].[C:20](OCC)(=O)C>C1COCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2)([CH3:20])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc2c(c1)CCNC2=O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)CCNC2=O
Temperature: 0 °C

Procedure:
To a slurry of 680 mg of 6-Acetyl-3,4-dihydro-2H-isoquinolin-1-one in 25 mL of THF cooled to 0° C. was slowly added 3.6 mL of 3.0 M MeMgBr in THF. After 1 h the mixture was poured into a solution of ammonium chloride in ice water. Ethyl acetate was added and the organic phase was partitioned, dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography afforded 380 mg of 6-(1-Hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])[C@@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(OCC)(=O)C>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:33])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1ccn(CCO)n1)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
In a flask containing N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionamide (66 mg, 0.13 mmol) was added ethanol (3 mL) and concentrated hydrochloric acid (three drops) and was stirred at 25° C. for 2 h. It was then diluted with ethyl acetate (30 mL) and washed with water (1×10 mL) and saturated aqueous brine solution (1×10 mL). The organic layer was then dried over sodium sulfate and absorbed onto silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (26 mg, 51%) as a colorless gum: [α]26589=−22.5° (c=0.16, methanol); ES-HRMS m/e calcd for C20H24N3O2F3 (M+H)+ 396.1894, observed 396.1892; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.20 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.07-2.19 (m, 1H, CH), 3.67 (q, J=5.6 Hz, 2H, OCH2), 3.89 (dd, J=9.0, 5.5 Hz, 1H, ArCH), 3.99 (t, J=5.6 Hz, 2H, NCH2), 4.83 (t, J=5.6 Hz, 1H, OH), 6.42 (d, J=2.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.54-7.73 (m, 4H, Ar), 10.74 (s, 1H, NH).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[CH:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1O)([CH3:47])[CH3:46]>O1CCCC1>[CH:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2)([CH3:47])[CH3:46]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CC(C)c1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccccc1OCCc1cccc2c1CC(=O)N2
Reaction time: 0.25 h
Yield: 8.8 %

Procedure:
Diethyl azodicarboxylate (1.58 mL, 10 mmol) was added to a solution of triphenylphosphine (2.62 g, 10 mmol) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.77 g, 10 mmol) followed by 2-isopropylphenol (1.36 mL, 10 mmol). The mixture was stirred at room temperature for 18 hours and the solvent was evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate: hexane 2:8 to give 0.26 g (9%) of 4-[2-(2-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([NH:21][S:22]([C:25]1[S:26][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:29]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:17]([NH:21][S:22]([C:25]1[S:26][C:27]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:28][CH:29]=1)(=[O:23])=[O:24])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Brc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 100 °C
Reaction time: 15 h
Yield: 66.9 %

Procedure:
A mixture of 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.071 mmol, 1.0 eq), N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (443.7 mg, 1.285 mmol, 1.2 eq), Pd(dppf)Cl2 (87.5 mg, 0.1071 mmol, 0.1 eq), Na2CO3 (454.1 mg, 4.284 mmol, 4 eq) in 1,4-dioxane (20 ml) and water (4 ml) was stirred at 100° C. under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool to room temperature and concentrated to give a residue, which was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 50:1 as eluent) to afford N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (300 mg, 66.9%) as a solid. LC-MS (m/z)=419.1 [M+H]+.
Reaction SMILES: C[C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.[C:26]([CH2:28][CH2:29][CH2:30][CH2:31]CCCCCCC(Cl)=O)#[N:27].C(Cl)Cl.[N:44]1[CH:49]=CC=C[CH:45]=1>>[CH3:45][N:44]([C:31]1[CH:30]=[CH:29][CH:28]=[CH:26][N:27]=1)[CH3:49]
Reactant: c1ccncc1
Reactant: N#CCCCCCCCCCCC(=O)Cl
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: ClCCl
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 1, but using 365 mg of radicicol, 11-cyanoundecanoyl chloride (prepared from 1.055 g of 11-cyanoundecanoic acid), 7 ml of dry methylene chloride, 1.21 ml of pyridine and a catalytic amount of dimethylaminopyridine, 707 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=O)[CH2:4]1)[CH3:2].S(Cl)([Cl:12])=O>>[CH2:1]([CH:3]1[CH2:6][CH:5]([C:7]([Cl:12])=[O:9])[CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC1CC(C(=O)O)C1
Product: CCC1CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
A mixture of 3.3 g (0.027 mole) of 3-ethylcyclobutanecarboxylic acid (prepared in 1E) and 9.4 g (5.7 ml, 0.080 mole) of thionyl chloride was prepared and allowed to stir at room temperature for about 15 hr. Excess thionyl chloride was removed by distillation at atmospheric pressure. The residue was distilled at reduced pressure to yield 2.4 g of the title compound having the following physical characteristics:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.C(Cl)(Cl)Cl.CO.C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:13]2[CH2:14][CH2:15][CH:11]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]#[N:10])[CH2:12]2)=[C:29]([O:37][CH3:38])[CH:30]=1)(=[O:36])[CH3:35]
Reactant: N#CC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNC1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(C#N)(c2ccc(F)cc2)c2ccc(F)cc2)C1
Yield: 67.4 %

Procedure:
A mixture of α,α-bis(4-fluorophenyl)-3-pyrrolidineacetonitrile (5.13 g, 0.0172 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.17 g, 0.0172 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The butanol was removed by rotary evaporation. The residue obtained was dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed in vacuo to give a dark brown oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate and 25% methanol-75% ethyl acetate for elution. Fractions of similar purity were combined and solvents removed. A dark brown oil was obtained and dried in vacuo 2 days at 80° C. to give 5.85 g (57.5% yield) of the title compound as a dark brown gum.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33](B(O)O)[CH:34]=1)#[N:28]>>[F:38][C:32]1[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][C:31]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Product: CSc1cn(-c2ncc(-c3cc(C#N)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized according to general procedure 1 from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (1.0 g, 2.309 mmol, 1.0 eq) and (5-cyano-2-fluorophenyl)boronic acid (0.451 g, 2.77 mmol, 1.2 eq). Yield: 0.4 g (36% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pd].C(O)C.ClCCl>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1cc(N)cc2ccccc12
Reaction time: 3 h

Procedure:
To 1.15 g (1.08 mmol) of 10% palladium on carbon was added a suspension of 11.6 g (50.0 mmol) of the above methyl 3-nitro-1-naphthoate in 150 mL of anhydrous ethanol and 40 mL of anhydrous dichloromethane. The resulting suspension was agitated under an atmosphere of hydrogen at 40 psi for 3 h during which time all solids dissolved. The reaction mixture was filtered through a plug of Celite®, which was subsequently washed with dichloromethane (300 mL). The combined filtrates were concentrated in vacuo to yield the title compound as a pale green gum which was used without further purification. LC/MS 202.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].[CH3:31][CH:32]([CH3:36])[C:33](O)=[O:34]>>[C:33]([NH:25][S:22]([C:20]1[S:21][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:26])(=[O:24])=[O:23])(=[O:34])[CH:32]([CH3:36])[CH3:31]
Reactant: CC(C)C(=O)O
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(=O)C(C)C)s1
Yield: 56 %

Procedure:
Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and 2-methylpropionic acid give the title compound (56%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3.[NH2:15][NH2:16]>C(O)C>[NH:15]([C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3)[NH2:16]
Reactant: NN
Reactant: ClC1=NC2CCCc3cccc(c32)N1
Solvent: CCO
Product: NNC1=NC2CCCc3cccc(c32)N1

Procedure:
61.8 g (0.3 mol) of 2-chloro-3a,4,5,6-tetrahydroperimidine are heated to 80° C. with 19.2 g (0.6 mol) of anhydrous hydrazine in 250 ml of ethanol for 4 hours. After cooling the mixture, 250 ml of petroleum ether are added and the crystals formed are isolated by filtration. 2-Hydrazino-3a,4,5,6-tetrahydro-perimidine is obtained. Yield: 54 g (89% of theory) of melting point 191°-193° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([C:42]3[CH:43]=[N:44][N:45](C(OC(C)(C)C)=O)[CH:46]=3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[NH:44]1[CH:43]=[C:42]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:32](=[O:33])[N:31]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[N:30]=[CH:29][CH:28]=4)=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[CH:46]=[N:45]1
Reactant: COc1ccc(Cn2nc(-c3cnn(C(=O)OC(C)(C)C)c3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(-c4cn[nH]c4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A 50 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido) phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrazole-1-carboxylate (29.7 mg, 0.0398 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 60° C. for 4 hours. Then the solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (17.8 mg, 85.0%). LRMS (APCI pos): >99% purity, 254 nm, m/e 527 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 13.0 (s, 1H), 11.74 (s, 1H), 8.38 (d, 1H), 8.32 (d, 1H), 8.27 (d, 1H), 8.22 (s, 1H), 8.01-8.12 (m, 2H), 7.69 (m, 2H), 7.61 (m, 2H), 7.42 (m, 2H), 6.32 (d, 1H).
Reaction SMILES: Cl.[CH2:2]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:6]=2[CH2:5][CH2:4][NH:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(C)CC(=O)C.[I-].[K+]>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:3]2[CH2:4][CH2:5][C:6]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:7]=3[CH2:2]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: c1ccc2c3c(oc2c1)CCNC3
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1ccc(CN2CCc3oc4ccccc4c3C2)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (1:1), (0.05 mol), 1-(chloromethyl)-4-nitrobenzene (0.05 mol), Na2CO3 (7 g) and potassium iodide (0.1 g) in 4-methyl-2-pentanone (250 ml) was stirred and refluxed for 8 hours. The mixture was allowed to cool to room temperature. The reaction mixture was filtered and the filtrate was evaporated. The oily residue was dissolved in CH3CN/diisopropyl ether and stirred. The precipitate was filtered off and dried, yielding 8 g of 1,2,3,4-tetrahydro-2-[(4-nitrophenyl)methyl]benzofuro[3,2-c]pyridine (intern. 11). The filtrate was stirred with HCl/2-propanol. The precipitate was filtered off and dried, yielding 9 g of 1,2,3,4-tetrahydro-2-[(4-nitrophenyl)methyl]benzofuro[3,2-c]pyridine hydrochloride (.HCl) (interm. 12).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: COC(=O)C1CCCC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1CCCC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of methyl 3-hydroxycyclohexanecarboxylate [J. Am. Chem. Soc., 70, 1898 (1948)] (61 g) in ether (500 ml), 2,3-dihydropyran (49 g) and p-toluenesulfonic acid monohydrate (1 g) were added. The mixture was stirred at room temperature for 6 hours and washed with water and dried (MgSO4). The ether was distilled off, and the oily residue was distilled under reduced pressure to give methyl 3-(2-tetrahydropyranyloxy)cyclohexanecarboxylate (61.5 g, 60.2%, b.p. 120°-123° C./0.3 mmHg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: CC1CCC(N)CC1
Product: CC1CCC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1
Yield: 30.2 %

Procedure:
Using the procedure of example 1, 4-methylcyclohexylamine (92 mg) was reacted with compound 1f (100 mg) to provide compound 17 (25 mg, 30%) as a mixture of cis- and trans-isomers. 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=8.0 Hz, 1H), 8.92 (d, J=8.0 Hz, 1H), 8.28 (m, 2H), 8.20 (s, 1H), 8.19 (s, 1H), 8.14 (d, J=5.2 Hz, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.25 (m, 2H), 7.03 (d, J=5.6 Hz, 1H), 7.00 (d, J=5.6 Hz, 1H), 4.15 (m, 1H), 3.83 (m, 1H), 2.15 (m, 2H), 1.89-1.14 (m, 16H), 1.01 (d, J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
50 g (0.37 mol) of commercially available p-hydroxybenzoic acid was dissolved in 370 ml glacial acetic acid by heating with stirring. Heating was continued after the acid dissolved and 59 g (0.37 mol) bromine dissolved in 60 ml glacial acetic acid was rapidly added to the boiling solution to avoid bumping. The solution was refluxed for six hours with continuing stirring. Following reflux, the reaction solution was permitted to stand and cooled to room temperature. The cooled solution was poured into two liters of cold water. A white precipitate was formed. The white crystals were filtered by suction and were recrystalized with glacial acetic acid to yield 55.2 g of purified 3-bromo-4-hydroxybenzoic acid. The calculated yield was 70.3%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[S-:11][CH2:12][CH3:13].[Na+].CN(C)C=O>O.[Cl-].[Na+].O>[Br:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([S:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CC[S-]
Reactant: COc1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(Br)cc(OC)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a mixture 1,3-dibromo-5-methoxy-benzene (2.65 g, 10 mmol) and sodium thioethoxide (1.01 g, 12 mmol) was added dimethylformamide (30 mL) at room temperature. Then, the resulting light yellow solution was heated to 105° C. and stirred for 2 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and diluted with water (50 mL) and brine solution (50 mL). Then, the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution (150 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 120 g column chromatography, eluting with 0-20% ethyl actetate in hexanes to obtain 1-bromo-3-ethylsulfanyl-5-methoxy-benzene (1.35 g, 55%) as a white solid: EI(+)-HRMS m/e calcd for C9H11BrOS (M)+ 245.9715, found 245.9713.