Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH2:39])=[CH:28][C:27]=2[F:42])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>CCOCC>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:40])(=[O:41])[NH:39][C:46](=[O:47])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[Cl:43])=[CH:28][C:27]=2[F:42])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2=O)c1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3F)c2=O)c1
Yield: 42 %

Procedure:
By the procedure of Example 51, 5-n-butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G) was reacted with 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) followed by trituration with ether afforded a 42% yield of the title compound as a white solid, mp 218°-220° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 753 (M+1)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH2:10][C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2([CH3:15])[CH2:14][O:13][CH2:12]2)[CH:8]=1
Reactant: CC1(CBr)COC1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cn2cc(Br)cn2)COC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
To a suspension of NaH (98 mg, 55% in mineral oil, 2.25 mmol) in DMF (1.2 ml) was added a solution of 4-bromopyrazole (300 mg, 2.04 mmol) in DMF (2 ml). The reaction mixture was stirred at room temperature for 15 minutes before a solution of 3-bromomethyl-3-methyloxetane (404 mg, 2.45 mmol) in DMF (2 ml) was added slowly. The mixture was stirred at room temperature for 1.5 h, then diluted with saturated NaHCO3 solution and extracted with 3 times with EtOAc. The combined organic layers were washed 2 times with water and with brine, dried (Na2SO4) and evaporated. The remaining colorless oil was purified by silica gel chromatography (heptane/EtOAc 80:20-50:50) to obtain the title compound (444 mg, 94%) as colorless oil. MS (EI): 231.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:19][C:6]2=[C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:20])[C:3]1=[CH:21]O.Cl.[NH2:25]O>CCO.O>[CH3:1][C:2]1([CH3:23])[C:3]2[CH:21]=[N:25][O:20][C:4]=2[C:5]2=[C:9]([S:10][CH3:11])[S:8][C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[C:6]2[CH2:19]1
Reactant: NO
Reactant: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)C(=CO)C(C)(C)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1sc(C(=O)N2CCCC2)c2c1-c1oncc1C(C)(C)C2
Temperature: 25 °C

Procedure:
To a solution of 6,6-dimethyl-5-hydroxymethylene-3-methylthio-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (173 mg, 0.49 mmol) in EtOH (4 mL) and water (0.7 mL) was added hydroxylamine hydrochloride (38 mg, 0.54 mmol). The solution was heated at reflux for 2 h then cooled to room temperature and the solvent evaporated. The residue was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer separated, dried (Na2SO4) and evaporated. The residue was triturated with hexane/Et2O and the resultant yellow solid (131 mg, 77%) collected by filtration. mp 114-116° C. C17H2ON20N2S2O2.0.1(H2O) requires: C, 58.29; H, 5.81; N, 8.00%. Found: C, 58.05; H, 5.59; N, 7.65%. 1H NMR (360 MHz, CDCl3) δ1.26 (6H, s), 1.94-1.98 (4H, m), 2.63 (3H, s), 2.90 (2H, s), 3.56-3.67 (4H, m), 8.20 (1H, s). MS (ES+) 349 (M+1).
Reaction SMILES: [CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.ClC(OCC)=O.[CH:19]([NH2:22])([CH3:21])[CH3:20].[Zn:23]>C(#N)C.C(N(CC)CC)C>[Zn:23].[SH:4][CH:5]([CH2:1][CH2:2][SH:3])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:12]
Reactant: O=C(O)CCCCC1CCSS1
Reactant: CC(C)N
Agent: CCOC(=O)Cl
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)NC(=O)CCCCC(S)CCS
Temperature: -65 °C
Reaction time: 1 h

Procedure:
4.2 g of DL-α-lipoic acid and 2.4 g of triethylamine were dissolved in 50 ml of acetonitrile and cooled down to −65° C. with stirring. To this was gradually added 2.4 g of ethyl chloroformate dropwise. Twenty minutes after the completion of the dropwise addition, 1.5 g of isopropylamine dissolved in 30 ml of acetonitrile was quickly added, and stirring was continued for 30 minutes and, further one hour at room temperature. The solvent was evaporated under reduced pressure, and water was added to the residue and the mixture then was cooled down. Precipitated pale yellow crystals were collected by filtration, dissolved in 60 ml of tetrahydrofuran (THF). To this were added 20 ml of 50% acetic acid aqueous solution and 2.0 g of zinc powder and reaction was allowed for two hours at 50° C. with stirring. Unreacted zinc was separated out by filtration, and the filtrate was concentrated. After addition of water to the residue, precipitated white crystals were collected by filtration. Recrystallized from THF/acetic acid/water gave 5.0 g of the aimed compound. mp. 271-273° C. TLC, Rf=0.89 (n-butanol/acetic acid/water=4/1/2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OC
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(C)c1)OC

Procedure:
A mixture of 3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester and from Step E and 4-(3-bromopropoxy)biphenyl were treated under standard condition I to give the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9](C1C=CC=C(C2C=CC(CC3C(CCCC)=NN4CCCCC=34)=CC=2)C=1C([O-])=O)(C)[CH3:10].BrCC(=O)C>CC(C)=O>[CH3:10][C:9]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:8]=1
Reactant: CCCCc1nn2c(c1Cc1ccc(-c3cccc(C(C)(C)C)c3C(=O)[O-])cc1)CCCC2
Reactant: Nc1ccccn1
Agent: CC(=O)CBr
Solvent: CC(C)=O
Product: Cc1cn2ccccc2n1
Yield: 245.4 %

Procedure:
A mixture of 5 g of 2-amino pyridine and 250 ml of acetone were added at ambient temperature to a mixture of 7.25 g of 1 bromo 2-propanone and 20 ml of acetone and the mixture was refluxed for 30 minutes. Using the procedure of Stage C of Example 22, 5.3 g of the expected product were obtained in the form of an orange oil.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:22]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Yield: 99.8 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (29 mL, 73 mmol), diisopropylamine (9.5 mL, 68 mmol), 4-hydroxyaniline (1.85 g, 17 mmol), and 2,4,5-trifluorobenzoic acid (3 g, 17 mmol) provided 4.5 g of the crude title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][N:36]([CH3:37])[C:4](=[O:6])[CH2:3][CH2:2][OH:1])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CCO
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CCO
Yield: 24 %

Procedure:
The procedure described in Example 1 was repeated using 3-hydroxypropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 24% yield; NMR spectrum (DMSO-d6) 2.13-2.26 (m, 2H), 2.65-2.79 (m, 2H), 3.30 (s, 3H), 3.87-3.97 (m, 2H), 4.13-4.25 (m, 1H), 4.34-4.61 (m, 2H), 5.31 (s, 2H), 7.15 (d, 1H), 7.25 (d, 1H), 7.32-7.39 (m, 2H), 7.53-7.57 (m, 1H), 7.60 (d, 1H), 7.70-7.76 (m, 1H), 7.86-7.92 (m, 2H), 8.42 (s, 1H), 8.61 (d, 1H), 9.70 (s, 1H); Mass spectrum MH+ 508.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH3:18].Cl>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([O:16][CH3:17])=[C:14]([C:5](=[O:7])[CH3:6])[CH:15]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cl)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Cl)cc1C(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A suspension of 2.12 g of AlCl3 in 20 ml of CCl4 is cooled to 0° C. under a nitrogen atmosphere, and a solution of 1.25 g of acetyl chloride in 10 ml of CCl4 is added dropwise. A solution of 2.5 g of 2-chloro-5-methoxytoluene in 10 ml of CCl4 is then added dropwise, and the mixture is left stirring for 2 hours while the temperature is allowed to rise to r.t. The mixture is poured into a mixture of concentrated HCl and ice, the resulting mixture is extracted with DCM, the organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/heptane (70:30; v/v) mixture. 0.68 g of the expected product, m.p.=83° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.O.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[N+:9]([C:4]1[CH:5]=[CH:6][C:7]([NH:15][CH2:14][CH2:13][NH2:16])=[C:2]([Cl:1])[CH:3]=1)([O-:11])=[O:10]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: O
Product: NCCNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 95.1 %

Procedure:
192 g (1mole) of 3,4-dichloro-nitrobenzene is added to 810 cm3 (10 moles) ethylene diamine hydrate. The reaction mixture is heated at reflux for 4 hours and then poured into 2.5 liters of ice water. Drying yields 205 g of 4-nitro-2-chloro-N-(β-aminoethyl) aniline which, after recrystallization in absolute ethanol, melts at 116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O[C:13]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:14]=1[CH:15]=O.C1(P(Cl)(Cl)=O)C=CC=CC=1.C(N(CC)CC)C>ClCCCl>[CH3:24][O:23][C:19]1[C:20]([O:21][CH3:22])=[C:13]2[C:14]([CH:15]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9](=[O:11])[O:10]2)=[CH:17][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: Cc1ccccc1CC(=O)O
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccccc3C)c(=O)oc2c1OC

Procedure:
A mixture of 2-methylphenyl acetic acid (0.60 g), 2-hydroxy-3,4dimethoxy-5-nitro-benzaldehyde (0.91 g), PhPOCl2 (0.60 ml) and triethyl amine (1.7 ml) were reacted in 1,2-dichloroethane as described in example 4. Yield: 0.68 g.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: N[C@H](CO)Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Yield: 79 %

Procedure:
2 g (8.8 mmol) of 3-benzoylbenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 2.5 g (79%) of the product were obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:7]1([NH:6][CH2:2][C:3]([NH2:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=O)CCl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)CNc1ccccc1
Yield: 9.6 %

Procedure:
The mixture of 2-chloroacetamide (3.1 g), aniline (3.1 g), K2CO3 (4.5 g) and KI (1 g) in acetonitrile (50 mL) and water (10 mL) was stirred at room temperature for overnight. The solvent was evaporated to about 20 ml under vacuum and the residue was poured into water (40 mL). The solution was extracted with ethyl acetate (3×20 mL), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 0.48 g of 2-phenylamino-acetamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:12][C:13]#[CH:14]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:14][C:13]#[CH:12])[CH2:4][CH2:3]1
Reactant: C#CCBr
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
A solution of 1-methylpiperidin-4-ol (1.15 g, 10.0 mmol) in dry THF (5 mL) was added drop wise to a suspension of NaH (60% dispersion in mineral oil, 0.400 g, 10.0 mmol) in dry THF (5 mL) at 0° C. The reaction was kept at the same temperature for 15 min then stirred at room temperature for 1 h. 3-Bromoprop-1-yne (0.75 mL, 10.0 mmol), was slowly added and the mixture was stirred at room temperature for 16 h. After solvent removal, the residue was taken up with DCM (50 mL), washed with water (50 mL), dried over sodium sulfate and purified by flash chromatography on silica gel (DCM/MeOH/TEA 90/10/0.1) to afford the title compound (0.140 g, 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[Br:25])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)CC1C=CC=CC=1.[CH3:41][S:42]([CH2:44][S:45][CH3:46])=[O:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[C:44](\[S:42]([CH3:41])=[O:43])/[S:45][CH3:46])=[CH:19][C:18]=3[Br:25])=[CH:14][CH:15]=2)=[CH:27][CH:28]=1
Reactant: CSCS(C)=O
Reactant: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CS/C(=C/c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1)S(C)=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
N-(4-chlorophenethyl)-4-(2-bromo-4-formylphenoxy)benzamide (1.6 g, 3.5 mmol) was diluted with THF (10 mL) followed by the addition of N,N,N-trimethyl(phenyl)methanaminium hydroxide (0.79 ml, 1.7 mmol) and methylsulfinyl(methylthio)methane (0.87 g, 7.0 mmol). The reaction was stirred at 70° C. for 2 hours. The reaction mixture was loaded directly onto a silica gel column and eluted with DCM:MeOH (98:2) to yield (Z)-N-(4-chlorophenethyl)-4-(2-bromo-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)benzamide (1.9 g, 96% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[O:23][C:22]([C:24](OC)=[O:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[NH3:38]>CO>[NH2:38][C:24]([C:22]1[O:23][C:19]([S:16]([N:14]2[C:13]([C:28]3[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=3)=[C:12]([F:35])[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:15]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1)=[O:25]
Reactant: N
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Solvent: CO
Product: CN(Cc1cn(S(=O)(=O)c2ccc(C(N)=O)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of methyl 5-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}-2-furoate (443 mg) in methanol (5 mL) was added 8 mol/L ammonia methanol solution (1 mL) at room temperature and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a pale-yellow oil (yield 330 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:14]
Reactant: CI
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 2-methyl-3-nitrophenol (15.3 g, 100 mmol) in DMF (150 mL) was added sodium hydride (60% in mineral oil, 2.6 g, 110 mmol) at 0° C. and the mixture was stirred for 30 minutes at room temperature. Methyl iodide (28.4 g, 200 mmol) was added and the mixture was heated to 80° C. for 5 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 times 100 mL). The combined ethyl acetate phases were dried over sodium sulphate and concentrated under vacuum to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc=5:1). Evaporation afforded the title compound as a yellow solid (14.4 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=O.COCCO[AlH2-]OCCOC.[Na+].O.Cl>C1(C)C=CC=CC=1>[CH2:25]([CH:22]1[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([CH:3]=[O:2])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)[CH2:24][CH2:23]1)[CH2:26][CH3:27]
Reactant: CCCC1CCC(CCc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(CCc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Temperature: -40 °C

Procedure:
Vitride (3.3M in toluene, 19 mL, 62.7 mmol) was added with syringe to a flask filled with Argon gas, adjusted to 0° C., and morpholine (5.5 ml, 62.7 mmol) was added slowly dropwise with syringe. Then, toluene (31 ml) was added dropwise with syringe to produce vitride solution. 63 ml of a solution including 4-{4-[2-(4-propyl-cyclohexyl)-ethyl]-phenyl}-cyclohexane carboxylic acid methyl ester (2.3 g, 6.27 mmol) obtained in Example 5-2 in toluene a solution was added to another flask filled with argon gas, and vitride solution was added slowly dropwise at −70° C. for 30 minutes. Then, the solution was stirred with maintaining −30 to −50° C. for 6 hours and water was added very slowly dropwise to the flask. After reaction, 1M HCl was slowly added to the flask to neutralize the reaction solution. White precipitate was filtered under reduced pressure and the filtrate was extracted by toluene (20 ml×three times). The organic layer was collected, washed by distilled water (10 ml×two times), dried with anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane:ether=5:1, Rf=0.32) to produce 0.96 g (45%) of trans-4-{4-[2-(4-propyl-cyclohexyl)ethyl]phenyl}cyclohexane carbaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][N:12]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[NH:8]1[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:11]#[N:12])[C:3]=2[CH:10]=[CH:9]1
Reactant: CN1CCCC1=O
Reactant: Brc1cncc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cncc2[nH]ccc12
Temperature: 100 °C
Yield: 85.1 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine (1.0 g, 5.08 mmol) in NMP (20 mL) under an argon atmosphere was added Zn(CN)2 (1.19 g, 10.15 mmol) and Pd(PPh3)4 (0) (590 mg, 0.51 mmol). The mixture was heated at 100° C. for 18 h. The reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (1:1) to afford 618 mg (85.1%) of 1H-pyrrolo[2,3-c]pyridine-4-carbonitrile as yellow solid. MS (ESI): m/z=144.3 [M+1]+.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: N#Cc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(C#N)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 4-iodo-benzonitrile (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.00 (s, 1H), 7.93 (d, 1H), 7.74-7.76 (m, 2H), 7.35-7.51 (m, 9H), 7.10 (t, 1H), 6.56-6.72 (m, 2H), 6.35 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.CCOC(C)=O>[Pd].CO>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:19])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Reaction time: 24 h

Procedure:
A round bottom flask equipped with a stir bar was charged with N-(2-aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide 8 (300 mg, 1.1 mmol), 10% Pd/C (˜150 mg), EtOAc (24 mL) and MeOH (6 mL). The mixture was purged with H2 (3× evacuation and back-fill cycles) then allowed to stir under an H2 balloon. After 24 h, TLC and LCMS indicated that the starting material was completely consumed. The mixture was filtered through a pad of Celite, washing with MeOH and CH2Cl2. Recrystalization from MeOH/CH2Cl2 afforded 5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 9 as a pale yellow crystalline solid.