Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[Br:17]Br>P(OC)(OC)(OC)=O.O>[CH3:1][C:2]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: BrBr
Reactant: CCOP(=O)(Cc1ccccc1C)OCC
Solvent: COP(=O)(OC)OC
Solvent: O
Product: CCOP(=O)(Cc1ccc(Br)cc1C)OCC

Procedure:
10 g (42 mmol) of diethyl 2-methylbenzylphosphonate were dissolved in 60 ml of trimethyl phosphate and the solution was introduced into a flask protected from light and moisture. 16 g (0.05 mol) of Br2 were added dropwise, while stirring. The mixture was stirred at 90° C. for 15 hours and, after cooling, was diluted with 100 ml of water and extracted three times with 100 ml of n-hexane each time. The organic phase wa dried, concentrated and distilled.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([C:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44](OC)=[O:45])[CH:33]=2)[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]1)[N:17]=2>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([C@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C@H:34]([CH2:44][OH:45])[CH2:33]2)[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:25][CH2:24]1)[N:17]=2
Reactant: COC(=O)[C@@H]1C=C(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1CO
Reaction time: 0.08 h

Procedure:
To a solution of lithium aluminum hydride, 1.0 M solution in tetrahydrafuran (1.165 mL, 1.165 mmol) in 7 mL THF at 0° C. was added a solution of (S)-1-tert-butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (0.555 g, 0.971 mmol) dropwise via syringe, over 5 min. The reaction mixture became a deep purple color. The bath was removed, and after 30 min, the reaction mixture was re-cooled, and treated with ice carefully. 6 mL 1N aq. HCl was added and the aq. Layer was extracted with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography, 0-100% EA/hexanes gradient gave (2S,4S)-tert-butyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate. MS (ESI) m/z: Calculated: 545.2; Observed: 546.1 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Pd].C(O)C>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCc1ccc(-c2ccc(N)cc2)cc1
Yield: 67 %

Procedure:
4′-Nitro-4-n-octyl-biphenyl (1.2 g, 3.9 mmol) was added to a suspension of palladium on carbon (Pd/C, 1.0 g) in a mixed solvent of THF (60 mL) and ethanol (24 mL). The preparation was hydrogenized under constant hydrogen flow for 3 hours. The catalyst was filtered out, and the volatiles were removed in vacuo to give a pale yellow oil. Chromatography on silica gel gave 4-n-octyl-4′-amino-biphenyl as a colorless oil, which solidified upon standing (0.75 g, 67% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[C:4]=2[N:5]=[C:6]([Cl:8])[N:7]=1.Cl.CN.[CH2:24]([N:26]=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CN(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:26][CH3:24])=[O:17])[C:4]=2[N:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)nc2c(-c3cccc(C(=O)O)c3)csc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
3-(4-Amino-2-chlorothieno[3,2-d]pyrimidin-7-yl)benzoic acid (300 mg, 0.98 mmol) was dissolved in N,N-dimethylformamide (5 mL) and then methylamine hydrochloride (329 mg, 4.91 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (282 mg, 1.47 mmol), hydroxybenzotriazole (239 mg, 1.76 mmol) and trimethylamine (0.889 mL, 6.38 mmol) were added. The reaction mixture was stirred at room temperature for a day. The reaction mixture was diluted with ethyl acetate and then washed with ammonium chloride aqueous solution. The organic layer was dried with magnesium sulfate, filtered with celite and then concentrated. Purification by chromatography (1/4 ethyl acetate/hexane) yielded the target compound (280 mg, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][CH:20]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21](N(OC)C)=[O:22])[CH3:18]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:31][CH:32]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCOC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(Cl)c(OC)c2)o1)c1ccc(N2CCOCC2)cc1

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.127 g, 26% yield). MS: m/z 486.5 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].Br[C:65]1[CH:66]=[N:67][CH:68]=[N:69][CH:70]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:67]1[CH:66]=[C:65]([N:1]2[CH2:5][CH2:4][C:3]3([CH2:10][CH:9]4[CH2:11][N:6]3[CH2:7][CH2:8]4)[CH2:2]2)[CH:70]=[N:69][CH:68]=1
Reactant: C1CC2(CN1)CC1CCN2C1
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ncc(N2CCC3(CC4CCN3C4)C2)cn1
Temperature: 125 °C
Yield: 354.6 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (100 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.0018 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (24 mg, 0.0036 mmol), potassium tert-butoxide (300 mg, 2.6 mmol), and 5-bromopyrimidine (114 mg, 0.7 mmol) in dry toluene (10 mL) was placed in a sealed tube under argon and heated at 125° C. for 17 h. The reaction was cooled to 0° C. and the contents transferred to a 100 mL round bottom flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH:CHCl3:NH4OH (8:2:0.01, v/v) as the eluent, to afford 49.0 mg of 1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (32%) as a viscous brown oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[BH4-].[Na+].Cl>O1CCCC1>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1cc(C)c2c(c1)CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=Cc2c(C)cc(C)cc2C1
Yield: 95.6 %

Procedure:
20.4 g (117 mmol) of 2,5,7-trimethyl-1-indanone (1) were dissolved in 300 ml of a mixture of tetrahydrofuran/-methanol (2:1), and 6.6 g (175 mmol) of NaBH4 were added at room temperature. The mixture was stirred for a further hour, 50 ml of half-concentrated HCl were added and the mixture was extracted with ether. The combined organic phases were dried over sodium sulfate and freed from the solvent. The residue was transferred to a distillation apparatus, and 13 g of magnesium sulfate were added. A vacuum of about 10 mbar was applied and the mixture was heated up until the product distilled over (130°-150° C.). The distillation gave 17.7 g of the indene 2 as a colorless oil. The yield was 96%.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[H][H]>CO.[C].[Pd]>[N:6]1[CH:7]=[CH:2][C:3]([CH:8]([N:11]2[C:12](=[O:21])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])[CH2:9][CH3:10])=[N:4][CH:5]=1
Reactant: [H][H]
Reactant: CCC(c1ncncc1Br)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(c1ccncn1)N1C(=O)c2ccccc2C1=O
Yield: 66.6 %

Procedure:
2-[1-(5-Bromopyrimidin-4-yl)propyl]isoindoline-1,3-dione (568 mg, 1.64 mmol), triethylamine (0.228 mL, 1.64 mmol) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in methanol (10 mL) in a hydrogen atmosphere at room temperature for 1 day. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) give the desired product (292 mg, 66% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:35]=[CH:34][C:28]([CH2:29][C:30]2([NH2:33])[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:33][C:30]2([CH2:29][C:28]3[CH:34]=[CH:35][C:25]([C:24]([F:23])([F:36])[F:37])=[CH:26][CH:27]=3)[CH2:31][CH2:32]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(Cc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Product: O=c1ccc2c(C(O)CNC3(Cc4ccc(C(F)(F)F)cc4)CC3)ccc(OCc3ccccc3)c2[nH]1

Procedure:
Reaction of 587 mg (2.0 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 710 mg (3.3 mmol) 1-(4-trifluoromethyl-benzyl)-cyclopropylamine is carried out analogously to Example 40a43a). Yield: 322 mg (32%); mass spectroscopy: [M+H]+=509.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[CH2:6][N:5]=[C:4]2[S:9][CH:10]=[CH:11][C:3]=12.[Cl:12][C:13]1[CH:22]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:20]=[C:19]([CH3:26])[C:14]=1[O:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][C:13]1[CH:22]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:20]=[C:19]([CH3:26])[C:14]=1[O:15][CH2:16][CH2:17][NH:18][C:2]1[N:7]([CH3:8])[CH2:6][N:5]=[C:4]2[S:9][CH:10]=[CH:11][C:3]=12
Reactant: CCCc1cc(C)c(OCCN)c(Cl)c1
Reactant: CN1CN=c2sccc2=C1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1cc(C)c(OCCNC2=c3ccsc3=NCN2C)c(Cl)c1
Yield: 59.5 %

Procedure:
3.7 g (0.02 mole) of 4-chloro-3-methylthieno[2,3-d]pyrimidine, 4.6 g (0.02 mole) of 2-(2-chloro-6-methyl-4-propylphenoxy)ethylamine and 2 g (0.02 mole) of triethylamine were dissolved in 50 ml of benzene, and the solution was heated under reflux for 6 hours. At the end of this time, the solvent was distilled off and the residue was washed with water and dried in air. It was then recrystallised from a mixture of benzene and hexane, to give 4.5 g (yield 60%) of the desired Compound No. 19 in the form of colourless needles melting at 66°-68° C.
Reaction SMILES: [Cl-].[Li+].[H-].C([Al+]CC(C)C)C(C)C.[Mg].Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[F:22].[C:23]([CH:25]1[CH2:27][CH:26]1[C:28](N(OC)C)=[O:29])#[N:24].[Cl-].[NH4+]>C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:28]([CH:26]2[CH2:27][CH:25]2[C:23]#[N:24])=[O:29])=[C:16]([F:22])[CH:17]=1
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: Fc1cc(Cl)ccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: N#CC1CC1C(=O)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
5.67 g (134 mmol) of lithium chloride and 0.7 ml of a 0.1N solution of diisobutylaluminum hydride in THF were added to 6.50 g (268 mmol) of magnesium turnings in 30 ml of THF. The mixture was stirred for five minutes and cooled to 0° C., 22.4 g (107 mmol) of 1-bromo-4-chloro-2-fluorobenzene were added, and the mixture was allowed to warm to RT and was stirred at RT overnight. The reaction solution was added dropwise under argon to a solution of 15.0 g (97.3 mmol) of the compound from Example 73A in 10 ml of THF, and the reaction mixture was heated under reflux for 2 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with dichloromethane, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5) to result in 5.40 g (25% of theory) of the title compound.
Reaction SMILES: C[Mg]Br.[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>O1CCCC1>[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 118 %

Procedure:
A solution of methylmagnesium bromide in tetrahydrofuran (1N, 15 ml) was added to diethyl malonate (7.33 g) at 0° C. for 10 minutes. The mixture was stirred for 2 hours at ambient temperature. To the mixture, 4-tert-butyl-2-(5-chloromethylbenzofuran-2-yl)thiazole (3.50 g) was added and stirred for 23 hours at 45° C. The resulting mixture was concentrated under reduced pressure and added to the solution of 4N hydrogen chloride in ethyl acetate. The resulting precipitates were collected by filtration and washed with n-hexane and diisopropyl ether to give the salt. The salt was added to the aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-tert-butyl-2-[5-(2,2-diethoxycarbonylethyl)benzofuran-2-yl]thiazole (5.80 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)C>[C:14]([C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCO
Product: N#Cc1cccnc1N1CCNCC1
Yield: 72.3 %

Procedure:
A mixture of piperazine (0.5 mol) and 2-chloro-3-cyanopyridine (0.1 mol) in absolute ethanol (225 ml) was heated at reflux for 16 hours. The cooled mixture was filtered to remove precipitated piperazine hydrochloride and the filtrate evaporated in vacuo. The residue was diluted with water (200 ml), made basic (pH>10) with 5N sodium hydroxide and extracted with ether (5×300 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo affording 13.6 g of a white solid (72.5% yield); mp 99°-103° C. Spectral data are consistent with the assigned structure. This material was used without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:27]=[CH:26][C:18]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:17][C:16]=1[Cl:28].CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:28][C:16]1[CH:17]=[C:18]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:26]=[CH:27][C:15]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: Clc1cc(OC2CCCCO2)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC3CCCCO3)cc2Cl)CC1
Yield: 55.1 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (3.94 g, 21.6 mmol), 2-(4-bromo-3-chlorophenoxy)tetrahydropyran (5.61 g, 19.2 mol), palladium acetate (86.4 mg, 0.39 mmol), BINAP (172 mg, 0.58 mmol) and sodium tert-butoxide (2.4 g, 25.0 mmol) in toluene (40 ml) was refluxed under a nitrogen atmosphere for 2 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford tert-butyl 4-[2-chloro-4-(tetrahydropyran-2-yloxy)phenyl]piperazine-1-carboxylate (4.72 g, yield 62%) as a yellow oil.
Reaction SMILES: CO.[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl.[C].[Pd]>[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Yield: 66 %

Procedure:
To an 100 ml methanol solution of 3.51 g of the 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine synthesized in Step B was added a 200 mg of palladium carbon and 1 ml of acetic acid. The resultant mixture was hydrogenated under atmospheric pressure at room temperature. After completion of the reaction, the insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in methylene chloride, adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10, then shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (methylene chloride:methanol=20:1) to give the above-referenced compound, 4-(4-phenoxyphenyl)piperidine in an amount of 2.32 g (yield 66%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14].[OH-].[Na+]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCc1nccn1Cc1ccccc1

Procedure:
A mixture of 1-benzyl-imidazole (5 g, 32 mmol), formaldehyde 37% (10 ml, 134 mmol) and sodium hydroxide (100 mg) is refluxed for 7 days and is extracted with ethylacetate. Concentration in vacuo yields 1-benzyl-2-hydroxymethyl-imidazole.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.[N:20]#[C:21]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.CCO.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: N#CBr
Reactant: CC(C)c1cc(Cl)nnc1NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)c1cc(Cl)nn2c(N)nnc12
Reaction time: 8 h

Procedure:
(6-Chloro-4-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.009; 258 mg) was initially charged in ethanol/water (6/1 ml) at RT while stirring. Thereafter, cyanogen bromide (182 mg, dissolved in a mixture of 1.5 ml of EtOH and 0.5 ml of water) was cautiously added dropwise. After stirring for 5 hours, the mixture was left to stand overnight, another 1 eq. of the cyanogen bromide solution was added and the mixture was stirred all day. After standing overnight, the solvent was drawn off and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 180 mg of the title compound were obtained in sufficient purity. LC-MS rt: 0.65 min [M+H]+: 212.1 (met. b)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[SH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].CCO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: N#Cc1cccnc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc2ncccc2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of 2-chloro-3-cyanopyridine (330 g), ethyl 2-mercaptoacetate (361.2 g), sodium carbonate (265 g) and EtOH (1.2 L) was heated to reflux for 4.5 hours. It was then cooled to ambient temperature, added to water (10 L) and the addition was washed in with water (5 L). The resulting slurry was stirred for 30 minutes and then it was filtered. The filter cake was washed with two portions of water (2×2.5 L) and dried at the pump. The solids were then dried to constant weight under vacuum at 45° C. to yield the title compound as a brown solid (493.1 g, 93.2%). δH (CDCl3) 8.68 (1H, dd, J 4.7, 1.2 Hz), 7.93 (1H, dd, J 8.5, 1.2 Hz), 7.29 (1H, dd, J 8.5, 4.7 Hz), 5.90 (2H, b), 4.38 (2H, q, J 7.0 Hz), 1.40 (3H, t, J 7.0 Hz). LCMS RT 2.9 minutes, 223 (M+H)+
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH2:7][NH:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([F:13])[F:12])C>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[CH:9]([N:8]1[CH2:7][C:6]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:5][C:4]1=[O:3])[CH2:10][CH:11]([F:13])[F:12]
Reactant: CCOC(=O)C=C(CNC(CC(F)F)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 180 °C
Yield: 75.5 %

Procedure:
A solution of 3-(2-chloro-phenoxy)-4-(3,3-difluoro-1-methoxycarbonyl-propylamino)-but-2-enoic acid ethyl ester (1.19 g, 3.04 mmol) in acetonitrile (4 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 180° C. for 3 h. The mixture was then cooled to room temperature and concentrated in vacuo with silica gel (3 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid methyl ester (794 mg, 40% over two steps) as an amber oil: HR-ES-MS m/z calculated for C15H14NO4ClF2 [M+H]+ 346.0652, observed 346.0651.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1N

Procedure:
To a solution of 2-amino-4-fluorobenzoic acid (2.0 g, 12.9 mmol) in methanol (50 mL) was added thionyl chloride (1.8 mL, 25.8 mmol). The mixture was refluxed overnight and concentrated to dryness. The residue was extracted with CH2Cl2 (30 mL), washed by aq. NaHCO3 (20 mL), water, and brine, dried and concentrated to give methyl 2-amino-4-fluorobenzoate as yellow solid (1.4 g).