Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH:15][CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2].Br[C:33]1[N:34]=[C:35]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)[C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:49]([N:46]1[CH2:45][CH2:44][N:43]([C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:42]=[C:33]([C:16]3[CH:15]=[CH:14][C:13]([C:7]4([CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:18][CH:17]=3)[N:34]=2)[CH2:48][CH2:47]1)[CH3:50]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2(CCOC(C)=O)CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(C4(CCOC(C)=O)CCOCC4)cc3)cc3ccccc23)CC1
Yield: 90.2 %

Procedure:
4-(2-Acetoxyethyl)-4-(4-tributylstannylphenyl)tetrahydropyran (2.20 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.83 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.14 g) of 1-(4-ethylpiperazin-1-yl)-3-{4-[4-(2-acetoxyethyl)tetrahydropyran-4-yl]phenyl}isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: COCCCCCCSC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCCCCSC1CCNCC1
Yield: 205.8 %

Procedure:
To a solution of 4-(6-methoxyhexylthio)-N-t-butoxycarbonylpiperidine (3.32 g) in dichloromethane (40 ml) were added triethylsilane (8.0 ml) and trifluoroacetic acid (15.4 ml) with stirring in an ice bath. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of dichloromethane and methanol (4:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(6-methoxyhexylthio)piperidine (4.77 g). This compound was immediately used as the starting compound for the next step.
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:38]>[Pd]>[OH:18][C@H:17]1[C@H:16]([OH:19])[C@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:29]=2)(=[O:22])=[O:23])[C@H:12]1[C:10]([OH:11])=[O:38]
Reactant: O=C(NOCc1ccccc1)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CO
Agent: [Pd]
Product: O=C(O)[C@H]1[C@@H](O)[C@H](O)[C@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
The above compound (6) (6.0 g) was dissolved in methanol (180 mL) and 10% Pd—C (1.3 g) was added, and then the mixture was stirred under a hydrogen atmosphere at 45° C. for 2 hours and 30 minutes. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→10:1→5:1) to obtain the titled compound (3.76 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]1)[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CN2CCc3cc(Cl)ccc3C2=O)CC1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A room temperature solution of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (0.100 g) in N,N-dimethylformamide (3 mL) was treated with sodium hydride (95% dispersion in mineral oil, 0.028 g) and stirred for 20 minutes. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (0.184 g) was added and the reaction was stirred at 40° C. overnight. The mixture was diluted with diethyl ether and washed sequentially with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=47:3) to obtain the title compound (0.188 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 33.9 mg (0.08 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67) and 8.5 mg (0.20 mmol) of LiOH-H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2cccc(O)c2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 56 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3-hydroxybenzaldehyde 0.903 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 400 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 0.92 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.C[O:13][C:14](=O)[C:15]([F:18])([F:17])[F:16].CN(C=O)C>ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14](=[O:13])[C:15]([F:18])([F:17])[F:16])[CH2:7]2
Reactant: Oc1cccc2c1CCNC2
Reactant: COC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N1CCc2c(O)cccc2C1)C(F)(F)F
Temperature: 25 °C

Procedure:
2.35 g (15.9 mmol) 5-hydroxy-1,2,3,4-tetrahydroisoquinoline, 1.92 mL (19.0 mmol) methyltrifluoroacetate and 15 mL DMF were mixed and stirred for over night at room temperature. The reaction mixture was diluted with dichloromethane, washed with water containing one drop of dil. hydrochloric acid and with aqueous sodium chloride. After drying over Na2SO4 and evaporation to dryness, the product was purified by silicagel chromatography (system C). Yield quantitative. 1H NMR (CDCl3, 400 MHz): 8.15 (1H, bd), 7.06 (1H, t, 8.1 Hz), 6.6-6.9 (2H, m), 4.75 (2H, ss), 3.86 (2H, m), 2.90 (2H, m).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:21]([CH3:22])=[CH:20][C:19]4[CH2:18][CH2:17][CH2:16][C:15]=4[C:12]=3[O:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:14][O:13][C:12]3[C:15]4[CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:21]([CH3:22])[C:11]2=3)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c3occ(-c4ccc(C(C)C)cc4)c13)CCC2
Solvent: CO
Product: Cc1cc2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCC2
Yield: 59 %

Procedure:
Using 3-(4-isopropylphenyl)-4-methyl-7,8-dihydro-6H-indeno[4,5-b]furan obtained in Reference Example 197, the title compound was synthesized in the same manner as in Reference Example 199. Yield 59%. Melting point: 77-78° C. (methanol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[Cl:7][C:8]1[C:13]([O:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][NH:27]2)=[C:10]([F:32])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:7][C:8]1[C:13]([O:14][C:15]2[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:25]=[C:26]2[N:27]3[N:28]([CH2:2][CH2:3][CH2:4][CH2:5]3)[C:29](=[O:31])[S:30]2)=[C:10]([F:32])[CH:9]=1
Reactant: BrCCCCBr
Reactant: O=c1[nH][nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1sc(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)n2n1CCCC2
Yield: 57.4 %

Procedure:
1,4-Dibromobutane (0.64 g) was mixed with 5-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-1,3,4-thiadiazolidin-2-one (1.0 g) in acetone (25 ml) and potassium carbonate (0.85 g) added. The mixture was heated at reflux for 2 hours and the solvent evaporated. The residue was processed and the resulting oil chromatographed (silica gel, hexane:ethyl acetate, 4:1) to give the product (0.65 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)=[O:5]>C(Cl)Cl.CO.O=[Mn]=O>[Cl:20][C:16]1[CH:17]=[N:18][CH:19]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C(NCc1ccc(CO)cc1)c1c(Cl)cncc1Cl
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc(CNC(=O)c2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a partially dissolved solution of 3,5-dichloro-N-(4-hydroxymethyl-benzyl)-isonicotinamide (730 mg, 2.35 mmol) in CH2Cl2 (12 mL) and MeOH (1 mL) was added MnO2 (2.43 g, 23.5 mmol) and the resultant suspension was stirred at 40° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The cake was washed with CH2Cl2/MeOH (100:3) and the filtrate was concentrated under reduced pressure to afford a crude white solid (630 mg). Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) afforded the desired aldehyde (480 mg, 66%) as a white solid. 1H NMR (CDCl3) δ 4.78 (d, 2H, J=6.0 Hz), 6.19 (br s, 1H), 7.58 (d, 2H, J=9.0 Hz), 7.90 (d, 2H, J=9.0 Hz), 8.55 (s, 2H), 10.02 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6]2[CH:23]=[C:24]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:30]=4[N:29]=3)[CH:25]=[C:26]([CH3:27])[C:5]=2[N:4]=1)[CH3:2].[Cl-].[NH4+].[N-:41]=[N+:42]=[N-:43].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:43][N:42]=[N:41][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:23]=[C:24]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:30]=4[N:29]=3)[CH:25]=[C:26]([CH3:27])[C:5]=2[N:4]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of 1.9 g (3.8 mMol) of 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl, 4.1 g (76 mMol) of ammonium chloride and 4.9 g (76 mMol) of sodium azide in 30 ml of dimethylformamide is heated to 140° C. for 15 hours, then a further 2.0 g of ammonium chloride and 2.4 g of sodium azide are added and the mixture is heated for another 4 hours to 140° C. Then the solution is stirred into about 80 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (150 g of silica gel; eluant: methylene chloride/ethanol=19:1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].P(Cl)(Cl)(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1onc(-c2nonc2NCc2ccc(CN3CCS(=O)(=O)CC3)cc2)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 46.4 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzamide trifluoroacetate (20 mg, 28 μmol) in pyridine (0.5 mL) was treated with phosphorus pentachloride (18 mg, 85 μmol) and stirred at 0° C. for 4.5 h. The reaction mixture was concentrated, diluted with ethanol (1 mL), treated with sodium cyanoborohydride (5 mg, 85 mop, and stirred for 2 h. The reaction mixture was purified by preparative LCMS to give the desired product (9 mg, 47%). LCMS for C22H21BrFN6O5S (M+H)+: m/z=579.0, 581.0.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.Br[C:14]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>>[Cl:20][C:17]1[CH:16]=[N:15][C:14]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:19][CH:18]=1
Reactant: Clc1cnc(Br)nc1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Product: CN(c1ncc(Cl)cn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 120 °C

Procedure:
In analogy to example 1.7, trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol and 1.5 equivalent of 2-Bromo-5-chloro-pyrimidine [synthesized from 5-chloro-2-hydroxy-pyrimidine in analogy to Brown, Desmond J.; Arantz, B. W., Pyrimidine reactions. XXII. Relative reactivities of corresponding chloro-, bromo-, and iodopyrimidines in aminolysis. J. Chem. Soc. C (1971), Issue 10, 1889–91] were heated for 0.5 h at 80° C., 1 h at 120° C., then 0.5 equivalent of 2-Bromo-5-chloro-pyrimidine were added and heated for 1 h at 120° C. to give after work up trans-3-{4-[(5-Chloro-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, mp: 148–150° C., dec.; MS: 280 (MH+, 1Cl).
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[NH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16].C(N(CC)CC)C>C(O)CCC>[OH:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][NH:12][S:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)(=[O:10])=[O:2]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CC(C)(CN)CO
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1

Procedure:
A mixture of sulphanilyl fluoride (1 g, 5.7 mmol), 3-amino-2,2-dimethylpropan-1-ol (884 mg, 8.6 mmol) and triethylamine (0.876 ml, 6.3 mmol) in butan-1-ol (20 ml) was heated at reflux for 24 hours. The volatiles were removed by evaporation and residue was purified by chromatography on silica gel to give the title compound. NMR: 0.72 (s, 6H), 2.52 (d, 2H), 3.08 (d, 2H), 4.40 (t, 1H), 7.19 (t, 1H), 7.60 (s, 1H), 7.64 (d, 2H), 7.96 (d, 2H), 8.40 (s, 1H), m/z 259 (MN)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:35][CH3:36])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=O)[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:13]>>[CH2:35]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:36]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 9.4 %

Procedure:
5-bromo-1,3-dihydroindol-2-one (0.47 g, 2.2 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (0.75 g) to give 0.11 g (42%) of the title compound as an orange solid.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH2:7][C:8]#[N:9]>N1C=CC=CC=1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:7][C:8]#[N:9]
Reactant: COc1ccccc1C(O)(CC#N)c1ccccc1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=CC#N)c1ccccc1OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Thionyl chloride (4.5 mL) was added to a stirred suspension of beta-hydroxy-beta-(2-methoxyphenyl)-2-methoxybenzenepropanenitrile (13.45 g) in dry pyridine (70 mL) maintained at 10° C. during the addition. The reaction was stirred at room temperature for 2 hours, then was diluted with ice-water and extracted with dichloromethane. The organic extract was washed with 3N HCl (1×150 mL; 1×20 mL) and brine and then was dried (MgSO4) and evaporated. The residue was crystallized from isopropanol-hexane to provide 9.0 g of 3,3-bis(2-methoxyphenyl)-2-propenenitrile, mp 99°-100° C. Recrystallization of a portion from the same solvents afforded the analytical sample, mp 100.5°-101.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:10]1[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH2:11]1
Reactant: Cc1ccc(C2CN(C(=O)OC(C)(C)C)C2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2CNC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 126-2 (37 mg, 0.15 mmol) in DCM (4 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 2 h. The solvent was removed by rotary evaporation, followed by three cycles of dilution with DCM and evaporation to provide 126-3 that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:20][CH3:21])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Reactant: CCN
Product: CCNc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Yield: 99 %

Procedure:
was synthesized from 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine and ethylamine in 99% yield, as a white solid which was characterised as follows: MS (m/z): 303 ([M+H]+, 100).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:4]1[CH2:9][CH2:10][N:5]([CH2:6][CH2:7][OH:8])[CH2:2][CH2:3]1
Reactant: OCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CCOCC1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 2-bromoethanol (27.9 g, 223 mmol), morpholine (40 g, 459 mmol) and K2CO3 (48.4 g, 350 mmol) in CH3CN (30 mL) was refluxed for 3 h. The mixture was then cooled to rt and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (24.40 g, 83%), which was used for next step without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:30][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccncc3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccncc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.90 g of 4,5-bis(4-methoxyphenyl)-2-(4-pyridylthio)imidazole in 100 ml of dichloromethane. The mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is recrystallized from ethanol/ether, thus producing 3.41 g of 4,5-bis(4-methoxyphenyl)-2-(4-pyridylsulfinyl)imidazole, mp 170°-171°.
Reaction SMILES: [C:1]([N:3]1[CH2:6][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:4]1)#[N:2].Cl.[NH2:32][OH:33].CCN(C(C)C)C(C)C>C(O)C>[OH:33][N:32]=[C:1]([N:3]1[CH2:4][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:6]1)[NH2:2]
Reactant: NO
Reactant: Cc1ccc(-c2noc(C3CN(C#N)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(-c2noc(C3CN(C(N)=NO)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 78 °C

Procedure:
A stirring mixture of N-(5-(5-(1-cyanoazetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (82) (50 mg, 0.125 mmol), hydroxylamine HCl (13 mg, 0.188 mmol) and DIEA (44 uL, 0.250 mmol) in ethanol was heated at 78° C. for 2 hours. The solvent was concentrated and dried under high vacuum. Crude N-(5-(5-(1-(N′-hydroxycarbamimidoyl)azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (83) was used in the next step without further purification. MS m/z 433.17 (M+1)+.