Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H][H]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCC#Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: OCCCc1ccc(Br)cc1
Yield: 81.1 %

Procedure:
To a solution under inert gas of 36.4 g of 3-(4-bromophenyl)-2-propynol (stage A) in 200 ml of ethanol at 5% of toluene, is added 200 ml of toluene, 7.9 g of Wilkinson's reagent and hydrogen at 1900 mbar for 5 hours. It is evaporated at reduced pressure until the obtainment of 45.9 g of raw product that is purified by chromatography on silica by eluting with the compound CH2Cl2/AcOEt 95/5. 30.1 g of expected product is obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][C:27]([CH3:29])=[CH2:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH2:43]([N:46]1[C:50]([CH2:51][S:52]([C:54]2[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=2)=[O:53])=[CH:49][N:48]=[CH:47]1)[CH2:44][CH3:45]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:33]=[CH:19][C:18]3[N:25]([CH2:26][C:27]([CH3:29])=[CH2:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:58][C:57]4[CH:59]=[CH:60][C:54]([S:52]([CH2:51][C:50]5[N:46]([CH2:43][CH2:44][CH3:45])[CH:47]=[N:48][CH:49]=5)=[O:53])=[CH:55][CH:56]=4)=[O:31])=[CH:20][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Reactant: C=C(C)CN1CCCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)CN1CCCC(C(=O)Nc2ccc(S(=O)Cc3cncn3CCC)cc2)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Reaction time: 3 h

Procedure:
(−)-(4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartarate monohydrate (770 mg) was dissolved in ethyl acetate (5 ml) and 1N hydrochloric acid (3.91 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (3.92 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) three times. The organic layers were combined and washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, after which the solvent was distilled off again under reduced pressure to give (−)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 8-(4-(2-butoxyethoxy)phenyl)-1-(2-methyl-2-propen-1-yl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (400 mg) in tetrahydrofuran (10 ml) were added a drop of DMF, and then thionyl chloride (0.084 ml), and the mixture was stirred under nitrogen atmosphere for 30 minutes. The resulting solution was added dropwise to a solution of (−)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and triethylamine (1.61 ml) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 3 hours, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous acetic acid solution twice, with aqueous saturated sodium bicarbonate solution twice, and with saturated brine once, after which the resultant was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, the resultant was separated and purified with a basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate) to give (−)-8-[4-(2-butoxyethoxy)phenyl]-1-(2-methyl-2-propen-1-yl)-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (316 mg) (Compound 23) as a yellow amorphous material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([OH:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH2:22][O:23][CH3:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(O)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 4-bromo-3-hydroxyphenyl 4-methylbenzenesulfonate in dry DMF (1.0 M) was treated with NaH (1.2 eq of a 60% dispersion in mineral oil) and the mixture was stirred at RT for 30 min. Chloromethyl methyl ether (1.2 eq) was then added dropwise and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and the organic phase washed with 1 N HCl and brine before drying (Na2SO4), filtering and concentrating in vacuo. The crude was purified by FC (PE/EtOAc 1/9) to afford the title compound (77%). (ES+) m/z 387, 389 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:18][OH:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:23][S:20]([O:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH2:5]1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)CC1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a stirred solution of tert-butyl 4,4-bis(2-hydroxyethyl)piperidine-1-carboxylate (500 mg, 1.83 mmol) in DCM (10 ml) were added mesyl chloride (0.33 ml, 4.2 mmol) and TEA (1 ml, 7.32 mmol) at −20° C. and the mixture was stirred for 30 min maintaining the same temperature. TLC revealed completion of the reaction and it was quenched with water and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (silica (100-200), EtOAc-hexane (30%)) to yield the desired compound. Yield: 70%
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2].Cl.C([O-])(O)=O.[Na+]>CCO.O.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Yield: 96.2 %

Procedure:
Intermediate 180.1 (413 mg) in EtOH/water/conc. HCl (3:4:1) was refluxed for 12 h, then was diluted with EtOAc. The aqueous layer was made basic with sat. NaHCO3, then the layers were separated. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated to afford 317 mg of Intermediate 180.2 as a brown/orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20](=[O:26])[CH2:21][O:22]COC)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:27])[CH:3]=1.Cl.CO.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20](=[O:26])[CH2:21][OH:22])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:27])[CH:3]=1
Reactant: COCOCC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)CO)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.6 %

Procedure:
A mixture of 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone 10j (15 mg, 0.033 mmol), 10% aqueous HCl (0.3 mL), methanol (0.01 mL), and water (0.05 mL) is stirred for 3 days at room temperature. The reaction mixture is neutralized with saturated aqueous NaHCO3, and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (1.5% MeOH in CH2Cl2) to afford the desired product (7.3 mg, 54%): MS APCI (+) m/z 412, 414 (M+, Br pattern) detected; 1H NMR (400 MHz, acetone-d6) δ 8.64 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.58 (d, 1H), 7.31 (dd, 1H), 6.59 (dd, 1H), 4.94 (s, 2H), 4.06 (s, 3H); 19F NMR (376 MHz, acetone-d6) −132.45 (s, 1F).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][NH:31]C(OC(C)(C)C)=O)[CH:26]=[CH:27][C:28]=1[F:29].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:30]([C:25]3[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=3)[N:31]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)c(Cl)c1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 46.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.300 g), tert-butyl 2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.300 g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].CS[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][N:19]=1>N1C=CC=CC=1>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][N:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: CCCN(CCCCN)c1ccccn1
Reactant: CSc1ncc(CC2CCCCC2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CCCN(CCCCNc1ncc(CC2CCCCC2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (1.17 g) and 2-methylthio-5-cyclohexylmethylpyrimid-4-one (0.9 g) were heated together under reflux in pyridine (2.5 ml) for 28 hrs. After stripping, the residue was chromatographed (silica gel, dichloromethane/methanol 40:1) crystallized from ethanol/water and recrystallized from acetone/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-cyclohexylmethyl pyrimid-4-one 1.4 H2O, 0.62 g (38%) m.p. 62°-64° C.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:19][N:18]([CH2:33][C:34]([OH:36])=[O:35])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:19][N:18]([CH2:33][C:34]([OH:36])=[O:35])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccc3ccccc3c2)CN(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1CC(c2ccc3ccccc3c2)SCC(NC(CCc2ccccc2)C(=O)O)C1=O
Yield: 70.3 %

Procedure:
200 mg of α-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-2-(2-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid (prepared as described in Example 40 above) were hydrolyzed with aqueous sodium hydroxide in the same manner as described in Example 38, to give 133 mg of the title compound as a powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:42])[N:13]([CH3:41])[NH:14][CH:15]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:42])[N:13]([CH3:41])[NH:14][CH:15]([C:31]([OH:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(NC(CCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(NC(CCCCN1C(=O)c2ccccc2C1=O)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 96.7 %

Procedure:
A solution of azapeptide ester 24 (0.402 g; 0.679 mmol) in ethyl acetate (5 ml) and acetic acid (0.2 ml) was hydrogenated with 110 mg of 10% Pd C for 18 hours. Filtration of catalyst and removal of solvent gave azapeptide 25 as a white foam (0.330 g). TLC (silica gel; EPAW 20:5:1:1) Rf=0.7. MS m/e 574 (M+, monotrimethylsilyl). NMR (CDCl3): δ1.42 (9H.s); 1.5-2.1 (10H,m); 3.00 (3H,s); 3.4-3.8 (5H,m); 4.3-4.6 (1H,m); 7.6-7.8 (4H,m); 7.8-8.0 (1H, broad).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1.ClC1C(C(OC)=O)=C(C)C=CC=1[N+]([O-])=O.O.O.Cl[Sn]Cl>CCO>[NH2:13][C:5]1[C:6]([CH3:12])=[C:7]([C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1C
Agent: COC(=O)c1c(C)ccc([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(Cl)ccc(N)c1C
Temperature: 25 °C

Procedure:
To above stirred mixture of methyl 6-chloro-2-methyl-3-nitrobenzoate 62 and methyl 6-chloro-2-methyl-5-nitrobenzoate in EtOH (500 mL), SnCl2.2H2O (224 g, 992 mmol, 4 eq) was added and the resulting mixture was stirred at reflux for 3 h. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The residue was poured into water (1 L) and extracted with ethyl acetate (5×500 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-10% ethyl acetate-hexanes) to afford the regio-isomer methyl 3-amino-6-chloro-2-methylbenzoate 63.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:12].[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:13]([OH:15])=[O:14])[CH:21]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(-c2cccc(C(=O)O)c2)cccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 197.4 %

Procedure:
1-Bromo-2-methoxy-3-nitro-benzene 1c (23.25 g, 0.10 mol), 3-carboxyphenylboronic acid (19.5 g, 117 mmol) and tetrakis(triphenylphosphine)palladium (8.86 g, 7.7 mol) were dissolved in a solvent mixture of 100 mL of 2 M sodium carbonate solution and 500 mL of 1,4-dioxane. The reaction mixture was heated to reflux at 105° C. for 43 hours. The mixture was concentrated under reduced pressure and then 300 mL of 6 N hydrochloric acid and 400 mL of ethyl acetate were added. The aqueous layer was extracted with ethyl acetate (200 mL×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound 2′-methoxy-3′-nitro-biphenyl-3-carboxylic acid 1d (53.93 g) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][S-:25].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:24][S:25][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C[S-]
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCOCC3)cc2n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCOCC3)cc2n1
Temperature: 100 °C
Yield: 99.9 %

Procedure:
2-Chloro-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (0.2 g, 0.56 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100° C. with stirring. After 2 h the contents of the tube were diluted with EtOAc, washed with saturated aqueous NaHCO3 (×2) then brine, and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford the title compound as a light brown solid (0.205 g, 100%). LCMS (Method D): RT=1.80 min, [M+H]+ 366.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH:21]([C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)([CH3:23])[CH3:22]
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(C(C)C)c2o1
Product: CC(C)c1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 5.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (41 mg, 0.26 mmol) and 2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole (55 mg, 0.26 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 4.2 mg (14 μmol, 6%) of 7-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a red oil.
Reaction SMILES: C[O:2][C:3](=[O:16])[C@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)[CH3:5].[OH-].[Li+]>O1CCCC1.CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C@H:4]([CH3:5])[C:3]([OH:16])=[O:2])=[CH:8][C:9]=1[F:15])#[N:14]
Reactant: COC(=O)[C@@H](C)Oc1ccc(C#N)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](Oc1ccc(C#N)c(F)c1)C(=O)O
Yield: 98.3 %

Procedure:
To a stirred solution of (R)-2-(4-cyano-3-fluoro-phenoxy)-propionic acid methyl ester (0.40 g, 1.8 mmol) in 50 mL 1:1 tetrahydrofuran/methanol at room temperature was added lithium hydroxide (5.5 mL 1 M aqueous solution, 5.5 mmol) and the solution was stirred over night. The reaction was quenched into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were pooled and washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a colorless oil (0.37 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N1CCCCC1.C(O)(=O)[CH2:26][C:27]([OH:29])=[O:28].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Temperature: 0 °C
Yield: 500.2 %

Procedure:
5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (3.32 g, 13.4 mmol) was dissolved in pyridine (16.6 ml) and piperidine (0.66 ml) was added. Malonic acid (1.67 g, 1.61 mmol) was added and the reaction mixture was refluxed for 4 h. Cooled reaction mixture was poured into a solution of ice (100 ml) water (100 ml) and conc. HCl (100 ml). The precipitate was filtered and washed with cold water and recrystallised from ethanol to afford 2.55 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.44 (d, 1H), 7.08 (d, 1H), 7.40 (m, 1H), 7.43 (d, 1H), 7.81 (d, 1H), 8.14 (m, 1H), 8.21 (m, 1H), 12.44 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27](O)([CH3:29])[CH3:28])[O:25][CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9].C(N(CC)CC)C.P([Cl:46])(OCC)(OCC)=O.[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C@@H:27]([CH2:29][Cl:46])[CH3:28])[O:25][CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1coc(C(C)(C)O)n1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1coc([C@H](C)CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
(S)—N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide (0.116 mmol, 0.05 g) was dissolved in DMF (5 ml) and triethylamine (0.255 mmol, 0.026 g) was added. Diethyl chlorophosphate (0.232 mmol, 0.040 g) was carefully added with a syringe. The resulting mixture was stirred at RT overnight. A mixture of ice and water was added and the mixture was neutralized with 1 M NaOH. The mixture was extracted twice with DCM. The combined organics were washed with water, dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.0047 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.26 (d, 3H), 2.04 (d, 6H), 4.29-4.36 (m, 1H), 4.38-4.46 (m, 1H), 4.54-4.66 (m, 1H), 6.64 (d, 1H), 7.39 (d, 1H), 7.51 (d, 1H), 7.61 (dd, 1H), 7.72-7.75 (m, 1H), 8.17 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)([OH:12])[CH2:9][O:10][CH3:11])=[O:4].CC(C)([O-])C.[Na+]>C1COCC1>[Cl:20][C:15]1[CH:14]=[C:13]([C:8]2([CH2:9][O:10][CH3:11])[O:12][CH2:2][C:3](=[O:4])[NH:5][CH2:6][CH2:7]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COCC(O)(CCNC(=O)CCl)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(c2ccc(Cl)c(Cl)c2)CCNC(=O)CO1
Yield: 113.6 %

Procedure:
To a solution of 2-chloro-N-[(3RS)-3-(3,4-dichlorophenyl)-3-hydroxy-4-methoxybutyl]acetamide (2.10 g) in THF (150 ml) was added sodium tert-butoxide (592 mg), and the mixture was heated under reflux for 10 min. The reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (1:1)-ethyl acetate:methanol (4:1)) to give the title compound (2.13 g).
Reaction SMILES: ClC1N=CN=C2C=1N=C(C)N2C.Cl.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OCC)=O)[CH2:32][CH2:31]1.[OH-].[K+].CC(O)C>O>[NH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][C:21]2[N:20]([CH2:19][C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)[CH2:31][CH2:32]1
Reactant: CCOC(=O)N1CCC(Cc2nc3ccccc3n2Cc2cccs2)CC1
Agent: Cc1nc2c(Cl)ncnc2n1C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: c1csc(Cn2c(CC3CCNCC3)nc3ccccc32)c1
Yield: 49 %

Procedure:
A mixture of 68 parts of ethyl 4-[[1-(2-thienylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinecarboxylate monohydrochloride, 95 parts of potassium hydroxide, 800 parts of 2-propanol and 10 parts of water was stirred and refluxed for 6 hours. The reaction mixture was evaporated and water was added to the residue. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 27 parts (49%) of 2-(4-piperidinylmethyl)-1-(2-thienylmethyl)-1H-benzimidazole; mp. 117.4° C. (64).