Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.C(Cl)CCl>>[Br:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Br)c2F)c1
Yield: 63.2 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethylbenzonitrile (0.053 g, 0.174 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.036 g, 0.174 mmol) and DIEA (0.061 mL, 0.348 mmol) were combined and treated with EDC (0.067 g, 0.348 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 4-bromo-N-({4-chloro-3-[(3-cyano-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.054 g, 0.110 mmol, 63.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6+1 drop D2O) δ ppm 7.40-7.51 (m, 2H), 7.32 (t, J=7.83 Hz, 1H), 7.14 (d, J=6.73 Hz, 2H), 4.47 (s, 2H), 2.62 (q, J=7.51 Hz, 2H), 2.24 (s, 3H), 1.12 (t, J=7.49 Hz, 3H). LC-MS (ES−) m/z 488.97, 490.93, 492.87 [M−1]. LC-MS (ES+) m/z 491.10, 493.10, 495.07 [M+H].
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8].I[CH:33]([CH3:35])[CH3:34].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([O:30][CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(O)ccn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OC(C)C)ccn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
K2CO3 (32 mg, 0.23 mmol) was added to II (53 mg, 0.15 mmol) in DMF (2 mL) at rt under Ar(g). After 15 min 2-iodopropane (16 μL, 0.165 mmol) was added and the reaction was stirred at 70° C. for 3 h. Brine (50 mL) and EtOAc (25 mL) were added, then the phases were separated, and the aqueous phase was extracted with EtOAc (25 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (70:30) to furnish III as a colourless oil (23 mg, 40%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[CH2:13]([OH:17])[CH2:14]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[O:17][CH2:13][CH2:14][O:4]1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: c1ccccc1
Product: N#Cc1ccc(C2(CBr)OCCO2)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 112 parts of 4-(2-bromoacetyl)-benzonitrile in 320 parts of butanol are added 5 parts of 4-methylbenzenesulfonic acid and 360 parts of benzene. Then there are added dropwise 46.5 parts of 1,2-ethanediol. Upon completion, stirring is continued for 4 hours at reflux. The reaction mixture is evaporated. The oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from methanol, yielding 95.12 parts of 4-[2-(bromomethyl)-1,3-dioxolan-2-yl]benzonitrile; mp. 92.4° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:1]([NH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][C@@H:19]1[CH:20]2[CH2:23][CH2:24][N:17]([CH2:22][CH2:21]2)[CH2:18]1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.4 %

Procedure:
To a solution of 2-benzamido-3-methylbutanoic acid (780 mg, 3.53 mmol) in THF (25 ml), were added (R)-quinuclidin-3-ol (538 mg, 4.23 mmol), DCC (873 mg, 4.23 mmol) and HOBt (572 mg, 4.23 mmol), and the reaction was stirred at RT for 15 hours. The solvent was evaporated. EtOAc was added, and the insoluble was removed by filtration. The organic solution was washed twice with 1N Na2CO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=99/1 to 8/2) to obtain (R)-quinuclidin-3-yl 2-benzamido-3-methylbutanoate (436 mg, 37.4% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].N1C=CC=CC=1.[Cl-:26].[Cl-].IC1C=CC=CC=1>O1CCCC1>[NH2:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[CH:6][C:7]=1[Cl:26]
Reactant: [Cl-]
Reactant: CC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: Ic1ccccc1
Product: CC(=O)c1cc(Cl)c(N)c(Oc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenoxy)acetophenone (1.7 g), pyridine (0.52 g), and iodobenzene dichloride (1.8 g) in tetrahydrofuran (20 ml) was stirred overnight at 5° C. The mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water, an aqueous solution of sodium bisulfite, and water. The organic layer was evaporated to give a powder of 4'-amino-3'-chloro-5'-(2,4-difluorophenoxy)acetophenone (1.5 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.ClC(N(C)C)=C(C)C.[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[CH2:33][CH2:32][NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.N>C(Cl)Cl.CO>[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])[CH2:33][CH2:32][N:31]1[C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: CC(C)=C(Cl)N(C)C
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Cc1ccc2ccccc2c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
105 mg (0.561 mmol) of 2-naphtylacetic acid are reacted in analogy to Example 6 first 92 μl (0.655 mmol) of 1-chloro-N,N,2-trimethyl-1-propen-1-amine and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 130 μl (0.936 mmol) of triethylamine to give the product TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =595.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][C:16]2[CH:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27]>C(O)C>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:23])[N:12]2[CH2:15][C:16]2[CH:17]=[N:18][C:19]([N:34]3[CH2:35][CH2:36][CH:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:32][CH2:33]3)=[CH:20][CH:21]=2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(Cc3ccc(Cl)nc3)c2n1
Solvent: CCO
Product: CCCCOc1nc(N)c2nc(O)n(Cc3ccc(N4CCC(C(=O)OCC)CC4)nc3)c2n1
Reaction time: 8 h
Yield: 44 %

Procedure:
2-Butoxy-9-(6-chloro-3-pyridylmethyl)-8-methoxyadenine (0.28 mg, 0.77 mmol) was added to 4-ethoxycarbonylpiperidine (10 ml), and the mixture was refluxed under stirring for 8 hours. After the mixture was allowed to cool, ethanol was added thereto. The resulting solid was filtered and purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=80/1˜20/1) to give the captioned compound (0.15 g, 1.41 mmol, yield: 44%) as a white solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1)[CH:6]=O)C.Cl.[CH2:19]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([NH2:32])=[NH:31])[CH2:26][CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23].C[O-].[Na+].[Na]>CO>[CH2:19]([C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]2[N:31]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=3)=[CH:6][N:32]=2)[CH2:28][CH2:29]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1ccc(C(C=O)=COCC)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=N)N)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC[C@H]1CC[C@H](c2ncc(-c3ccc(CCCC)cc3)cn2)CC1

Procedure:
In an analogous manner to that described in Example 3, a mixture of 6.3 g of 3-ethoxy-2-(p-butylphenyl)acrolein, 6.6 g of trans-4-pentylcyclohexanecarboxamidine hydrochloride and 60 ml of absolute methanol is treated with a sodium methylate solution prepared from 1.1 g of sodium in 25 ml of absolute methanol. The reaction duration, working-up and chromatography are as described in Example 3. The pure fractions (in accordance with thin-layer chromatography) resulting in the chromatography are combined and recrystallized twice from hexane. There is obtained analytically pure trans-2-(4-pentylcyclohexyl)-5-(p-butylphenyl)pyrimidine; m.p. 87° C., smectic-nematic phase transition 136.5° C., cl.p. 146.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCC2)c(Cl)c1
Yield: 76 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (52 mg, 0.26 mmol) obtained in Step C of Preparation Example 23 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (70 mg, 0.29 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 84%).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:25]1[CH:30]=[CH:29][C:28]2=[N:31][N:32]=[C:33]([C:34]([F:37])([F:36])[F:35])[N:27]2[N:26]=1>C(O)C>[F:36][C:34]([F:35])([F:37])[C:33]1[N:27]2[C:28]([CH:29]=[CH:30][C:25]([N:4]3[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]3)=[N:26]2)=[N:31][N:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (4.00 g, 20.0 mmol) was added to a mixture of diisopropylethylamine (4.11 mL, 23.7 mmol) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (4.0 g, 18.2 mmol) in ethanol (80 mL). The mixture was heated under reflux for 6 hours and then allowed to cool to ambient temperature to give a precipitate. The precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford tert-butyl 4-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,4-diazepane-1-carboxylate (5.94 g, 85.4%) as a white solid. 1H NMR (300.132 MHz, DMSO) δ 1.15 (9H, d), 1.72-1.93 (2H, m), 3.27-3.39 (2H, m), 3.50-3.63 (2H, m), 3.66-3.75 (2H, m), 3.83 (2H, t), 7.46-7.56 (1H, m), 8.19-8.31 (1H, m); apparently as a mixture of rotamers; m/z 387 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cccc(Cl)c1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,3-dichloroaniline to yield 2-[(2,3-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[N+:11]([C:4]1[CH:3]=[C:2]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)([O-:13])=[O:12]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of 1-bromo-3,5-dinitrobenzene (2.84 g, 11.50 mmol), XPhos (0.493 g, 1.035 mmol), palladium (II) acetate (0.077 g, 0.345 mmol), potassium carbonate (2.225 g, 16.10 mmol), tert-butanol (23.0 mL), and morpholine (1.20 mL, 13.80 mmol) was stirred at 95° C. under nitrogen for 3 h. Upon completion, the reaction was partitioned between EtOAc and water. The organic layer was dried over magnesium sulfate and concd, and the crude material was purified by column chromatography (silica; 0-25% EtOAc in hexanes) to afford 4-(3,5-dinitrophenyl)morpholine as an orange amorphous solid. Mass Spectrum (ESI) m/e=254.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].Br[C:36]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].CN(C)C=O>[F:25][C:23]1[CH:22]=[CH:21][C:20]([C:36]2[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][N:37]=2)=[C:19]2[C:24]=1[C@H:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C@H:7]3[CH2:8][C@@H:6]3[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14][CH:13]=1)[CH2:17][CH2:18]2
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(B4OC(C)(C)C(C)(C)O4)ccc(F)c32)cc1
Reactant: COc1cccnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(-c4ncccc4OC)ccc(F)c32)cc1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 24, 46.6 mg) and 2-bromo-3-methoxypyridine (28.2 mg) are dissolved N,N-dimethylformamide (1 mL) and degassed with a flow of argon. Aqueous 2M cesium carbonate solution (0.1 mL), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (6.5 mg, 0.1 equiv.) are added and the mixture is heated at 80° C. for 2.5 hours under argon. The reaction mixture is acidified with 50% aq. TFA, filtered over basic aluminium oxide and the filter material is washed with N,N-dimethylformamide. The crude product is purified by reversed phase chromatography to give the title compound (Yield 12.0 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2sccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1

Procedure:
To a mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The cooled reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3](CC(OCC)=O)[CH2:2]1.[CH2:13]([O:15][C:16](=[O:24])[CH2:17]C1C=CC=CN=1)[CH3:14]>>[N:1]1([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1ccccn1
Reactant: CCOC(=O)CC1CCCNC1
Product: CCOC(=O)CN1CCCCC1

Procedure:
The reaction was run in the same manner as ethyl 3-piperidinylacetate, starting with commercially available ethyl-2-pyridylacetate (4.00 g; 24.5 mmol). This gave ethyl 2-piperidinylacetate (2.41 g) as a light yellow oil without further purification. MS m/z (positive ion) 172 (MH+; 100).
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[O:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].S(=O)(=O)(O)O>>[C:1]([O:6][O:7][C:9]1([O:8][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)OO
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCCC1(OOC(C)(C)CC)OOC(C)(C)CC
Temperature: -10 °C

Procedure:
Ethyl 2,2-di(tertiary-amylperoxy)-1-cyclohexanecarboxylate was prepared by the addition of 92.64% TAHP (tertiary amyl hydroperoxide) (42.16 g, 0.3750 mol) to 95% ethyl 2-oxo-1-cyclohexanecarboxylate (17.92 g, 0.1000 mol) at room temperature in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was cooled to −10° C. via a dry ice-acetone bath and 78% sulfuric acid (15.09, 0.1200 mol) was added dropwise to the solution with the temperature at −10° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed for purity by gas chromatography (53% by area). Purification by chromatography (silica gel, 95:5 petroleum ether/diethyl ether) afforded a liquid product: 13C NMR (75 MHz, CDCl3) δ 171.8 (C═O), 106.0 (O—C—O, cyclic), 81.1 (C—(CH3)2CH2), 81.0 (C(CH3)2CH2), 59.6 (O—CH2CH3), 44.0 (CH, cyclic), 3.16 (CH3—CH2—C), 31.5 (CH3CH2—C), 26.0 (CH2, cyclic), 23.6 (C(CH3)2, (2x)), 21.8 (CH2, cyclic), 22.0 (CH2, cyclic), 13.8 ((O—CH2CH3) (2X)), 8.0 ((CCH2CH3) (2x)); IR (neat) ν 1736, 1364, 1220, 872 cm−1.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH:18]=[O:19])[C:5]([NH:7][C:8]1[S:9][C:10]([CH:13]2[CH2:15][CH2:14]2)=[N:11][N:12]=1)=[O:6])[C:2]#[CH:3].Cl>O>[CH:13]1([C:10]2[S:9][C:8]([N:7]3[CH:18]([OH:19])[CH2:17][CH2:16][N:4]([CH2:1][C:2]#[CH:3])[C:5]3=[O:6])=[N:12][N:11]=2)[CH2:14][CH2:15]1
Reactant: C#CCN(CCC=O)C(=O)Nc1nnc(C2CC2)s1
Agent: Cl
Solvent: O
Product: C#CCN1CCC(O)N(c2nnc(C3CC3)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-propargyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1>C(Cl)(Cl)Cl>[CH2:15]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:56][C:53]1[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[CH:51][CH:52]=1)=[NH:47])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)Nc2ccc(OC)cc2)c1
Reaction time: 16 h
Yield: 73 %

Procedure:
A mixture of ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles), p-anisidine (369 mg., 3.0 mmoles) and chloroform (10 ml.) was held at room temperature for 16 hours. It was then diluted to 400 ml. with chloroform, washed with 1N HCl (2 × 50 ml.), dried (Na2SO4) and evaporated in vacuo to a foam. The foam was crystallized from 1,2-dimethoxyethane [868 mg., 73% yield, Rf .64 (4:1, benzene:ethanol on silicic acid), mp.--forms a gel at 84°-86° C.].