Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[C:16]1([C:22]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[C:8]([C:5]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:7][C:2]([N:25]2[CH2:24][CH2:23][C:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]2)=[CH:3][CH2:4]1)#[N:9]
Reactant: N#CC1(c2ccccn2)CCC(=O)CC1
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccccc2)CCN(C2=CCC(C#N)(c3ccccn3)CC2)CC1
Yield: 45 %

Procedure:
A mixture of 4.5 parts of 4-oxo-1-(2-pyridinyl)cyclohexanecarbonitrile, 5.2 parts of ethyl 4-phenyl-4-piperidinecarboxylate, 1 part of 4-methylbenzenesulfonic acid and 225 parts of methylbenzene is stirred and refluxed overnight using a water-separator. The reaction mixture is evaporated and the residue is crystallized from 2-propanol, yielding 4.5 parts (45%) of ethyl 1-[4-cyano-4-(2-pyridinyl)-1-cyclohexeneyl]-4-phenyl-4-piperidinecarboxylate; mp. 160° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])[CH2:21][N:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[CH2:21][N:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[CH:10][CH:9]=1
Reactant: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(c2ccc(N)cc2)CC1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.11 g) (59%) of 1-[4-(4-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 10.54 (s, 1H), 7.52 (d, 2H, J=8.5 Hz), 7.20 (d, 2H, J=8.5 Hz), 4.10 (s, 2H), 3.34-3.37 (m, 2H), 2.97-3.12 (m, 3H), 2.85 (s, 6H), 1.88-1.91 (m, 2H), 1.69-1.78 (m, 2H).
Reaction SMILES: [O:1]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([CH:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)#[N:16].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.N>O>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]2[C:28]3[C:27](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:17]([CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[C:15](=[O:1])[NH:16]2)=[CH:36][CH:35]=1
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CN1CCN(CCC(C#N)c2ccccc2)CC1
Agent: N
Solvent: O
Product: CN1CCN(CCC2C(=O)NC(c3ccc(Cl)cc3)c3ccccc32)CC1
Temperature: 80 °C

Procedure:
50 ml of 85 % polyphosphoric acid and 50 g of phosphorus pentoxide were mixed and 0.1 mole of 1-cyano-1-phenyl-3-(1-methyl-piperazine-4-yl)-propane was added. The reaction mixture was heated to 80°C and 0.04 mole of 4-chlorobenzaldehyde was added. The whole was heated for 1 hour to 100°C and 0.04 mole of 4-chlorobenzaldehyde was added. After a further hour at 100°C the mixture was poured into 1 liter of water and the pH value was adjusted to 10 by means of concentrated ammonia. The crystal magma was filtered off with suction and recrystallized from ethanol. M.p.: 201°-205°C (oxalate)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:16]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:11][CH3:12]
Reactant: Clc1nc[nH]c1Cl
Reactant: CCBr
Reactant: BrCCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.[Br:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].[CH2:31]([N:33]([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1)[CH3:32]>C(OCC)(=O)C.C(N(CC)CC)C.ClCCl>[Br:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:33]([CH2:31][CH3:32])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1
Reactant: CCN(CCCC(=O)O)c1cccc(C)c1
Reactant: Nc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CCCC(=O)Nc1ccccc1Br)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg), 1-hydroxy-7-azabenzotriazole (106 mg), dichloromethane (2 ml), 2-bromoaniline (134 μl), and triethylamine (162 μl) were added to the compound (100 mg) obtained in Step 2, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (56 mg).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][CH3:11])[C:3]([OH:23])=[O:2]
Reactant: CNc1ccc(C(=O)OC)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-benzoic acid methyl ester in 3 ml of MeOH:water/3:1, 14 mg of lithium hydroxide monohydrate were added and the reaction was stirred at RT for 16 h. The solution was acidified with half-concentrated hydrochloric acid and the solvent was evaporated. The crude acid was subjected to the subsequent amide coupling without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][C:10]([CH3:12])=O.C[Si]([C:17]#[N:18])(C)C>C(#N)C.[Cl-].[Zn+2].[Cl-]>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:10]([CH3:12])([CH3:9])[C:17]#[N:18])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)=O
Reactant: Nc1cncc(Br)c1
Reactant: C[Si](C)(C)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(C)(C#N)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
3-Amino-5-bromopyridine (Aldrich, 5.0 g, 28.9 mmol), acetone (6.37 ml, 87 mmol), Zinc chloride (0.5 M in THF) (11.56 ml, 5.78 mmol) were combined in acetonitrile (150 ml) and cooled to 0° C. The reaction was stirred for 10 min and trimethylsilylcyanide (10.46 ml, 78 mmol) was added dropwise. The reaction was heated to 85° C. in an oil bath with a reflux condensor. The reaction was monitored by LCMS and at 2 hrs the reaction was 80% complete. The reaction was cooled to room temperature and additional acetone (1.2 mL) and trimethylsilylcyanide (3 mL) added. The reaction was allowed to stir 18 hrs at 85° C. The reaction mixture was concentrated to reduce the volume by 50% and mixture poured into brine (100 mL). The pH was adjusted to 7.5 with aq. NaHCO3 and the product extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and resulting solution filtered thru a pad of silica. The filtrate was concentrated and the residue purified by silica gel chromatography, Biotage SNAP 100 g, eluting with EtOAc/isohexane (0-100%) to give 6.42 g, 93% yield of the desired product as an off-white solid, I-4a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.C(OCC)C.C(O)(=O)C>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][CH:26]([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:2]([Cl:1])[CH:3]=3)[CH2:7][CH2:8]2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in 1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g) followed by NaBH(OAc)3 (1.81 g) and acetic acid (0.37 g). After 18 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO4 and concentrated. Purification by silica chromatography (dichloromethane:methanol 92:8) gave the sub-title product (1.97 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:14]([S:11]([C:4]1[CH:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])(=[O:13])=[O:12])[CH3:15]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)c1cc(Cl)cc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCS(=O)(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 150 °C
Yield: 96 %

Procedure:
4-Chloro-2-(ethylsulfonyl)-6-methyl-benzonitrile (0.43 g, 1.77 mmol), morpholine (0.46 ml, 5.31 mmol) and potassium carbonate (0.32 g, 2.30 mmol) are taken up in N-methyl-2-pyrrolidone (3 ml) in a sealed tube and the resulting mixture is heated at 150° C. for 2 d. The mixture is then diluted with water (6 ml) and extracted with ethyl acetate (3×10 ml). The organic layer is washed with water (2×10 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 2-(ethylsulfonyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.50 g, 1.70 mmol, 96%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][N:8]=1.[N+:14]([O-])([OH:16])=[O:15]>O>[NH2:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: Nc1nccc(=O)[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ncc([N+](=O)[O-])c(=O)[nH]1
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (2.4 mL) was added to 2-amino-3,4-dihydropyrimidin-4-one (1 g, 9.0 mmol). The mixture was stirred and cooled in ice bath before dropwise addition of concentrated nitric acid (0.56 mL). The mixture was stirred at RT for 30 min before being heated at 70° C. for 2 hr. The mixture was allowed to cool to RT and was slowly added to water (10 mL), cooled in an ice bath. The resultant precipitate was collected by suction filtration, washed with diethyl ether (5 mL) and then thoroughly dried under high vacuum to give the title compound: 1H NMR (250 MHz, DMSO) δ 7.18 (1H, br. s.), 8.61 (1H, br. s.), 8.81 (1H, s); LC-MS: m/z=+156.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([NH:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.N1NC(=O)C=CC=1.Cl.[F:36][C:37]([F:52])([F:51])[C:38]1[CH:50]=[CH:49][CH:48]=[CH:47][C:39]=1[O:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([NH:15][CH2:16][C:17](=[O:19])[N:44]2[CH2:43][CH2:42][CH:41]([O:40][C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[C:37]([F:36])([F:51])[F:52])[CH2:46][CH2:45]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1ccnn(Cc2ccccc2)c1=O
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: BrCc1ccccc1
Agent: Cl
Agent: O=c1cccn[nH]1
Product: O=C(CNc1ccnn(Cc2ccccc2)c1=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Yield: 30 %

Procedure:
Compound 48 is prepared from (2-benzyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-acetic acid (obtained following the operating mode for 4e using benzyl bromide to alkylate nitrogen 2 of pyridazinone) and from intermediate 1a in base form, following synthesis method 2 (yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=1
Reactant: Cc1cc(CCCO)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(CCCBr)ccc1Cl
Yield: 89.6 %

Procedure:
Compound 67-2 (2.49 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.90 g) and N-bromosuccinimide (2.64 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.99 g) as a colorless oil.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[S:17][C:16]2[C:11](=[N:12][CH:13]=[CH:14][C:15]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=3[F:36])=[O:27])=[C:21]([F:37])[CH:20]=2)[CH:10]=1)=[O:8])C.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:37][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:7]([NH:6][CH2:5][CH:4]=[O:3])=[O:8])[S:17][C:16]=12
Reactant: CCOC(CNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCC=O)sc34)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (300 mg, 0.53 mmol) in 10 ml of THF was added 2 ml of 2M HCl. The mixture was heated under nitrogen at 60° C. for 4 hours, cooled to room temperature, and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 250 mg, 96%.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]1[CH:26]=[CH:25][C:11]([C:12](OC2C=C(F)C(C#N)=C(F)C=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OCC1C=CC(C(O)=O)=CC=1)CCCC.S(Cl)([Cl:45])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:6][CH2:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([Cl:45])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOCc1ccc(C(=O)Oc2cc(F)c(C#N)c(F)c2)cc1
Reactant: O=S(Cl)Cl
Agent: CCCCCOCc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCOCc1ccc(C(=O)Cl)cc1

Procedure:
Preparation of 3,5-difluoro-4-cyanophenyl 4-(pentyloxymethyl)benzoate (in the formula (1), R=C5H11, l=1, m=1, n and o=both, 0; A1 =1,4- phenylene group, Z1 =--COO--, X=CN, and Y1 and Y2 =both, F) (Compound No. 1)) 4-(Pentyloxymethyl)benzoic acid. (1.6 g, 7.1 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(pentyloxymethyl)benzoyl chloride.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[C:8]([C:7]1[C:6]([CH3:10])=[C:5]([CH:11]([OH:12])[CH2:13][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]2[CH2:27][OH:28])[CH:4]=[CH:3][C:2]=1[F:1])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1c(C2CO2)ccc(F)c1C#N
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Temperature: 150 °C

Procedure:
6-Fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile (12.0 g, 67.7 mmol) and (S)-4-N—BOC-2-hydroxymethylpiperazine (22.0 g. 102 mmol) were suspended in ethanol (100 mL) then heated in a microwave apparatus for 30 minutes at 150° C. The reaction mixture was cooled and evaporated dryness. The residue was purified by MPLC chromatography through a 330 g Redi-sep column eluting with 5% MeOH/95% EtOAc solvent system to yield the title compound. LC-MS: M+1=394.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12]=O)[CH:5]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][CH2:28][CH2:27][C:26]2=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12]=[C:27]2[C:26](=[O:33])[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:24]=3)[O:29][CH2:28]2)[CH:5]=1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Reactant: COC(=O)c1ccc(OC)c(C=O)c1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1ccc(OC)c(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
19.1 g (98.3 mmol) of 3-formyl-4-methoxybenzoic acid methyl ester (from Example 37) were added to a room temperature suspension of 25.0 g (98.3 mmol) of 6-benzyloxychroman-4-one and 8.21 mL (98.3 mmol) of pyrrolidine in 350 mL CH3OH. After stirring 20 hours at room temperature, the reaction mixture was filtered, washed two times with CH3OH and the precipitate dried under vacuum to give 33.93 of the title product as a yellow powder. Mp: 167°-169° C. 80% yield. 1H NMR (300 m Hz, CDCl3): δ3.93 (s, 3H); 3.91 (s, 3H); 12 aromatic resonances δ6.8→8.1.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=2[N:17]=1.C(N(CC)C(C)C)(C)C>CC#N>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1
Reaction time: 0.33 h

Procedure:
A mixture of the hydrochloride salt from step (b) above (0.564 g, 2.4 mmol), 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.27 g, 1.22 mmol, Example 1c) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol, Aldrich) in MeCN (1 mL) was subjected to microwave irradiation at 180° C. with stirring for 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexane, to give the title compound as a white solid. M.p. 208-210° C. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[C:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[C:27](Cl)[N:26]=[C:25]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:24]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CN1C(=O)N(C)CCC1>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]2[C:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[C:27]([O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])[N:26]=[C:25]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:24]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCC#CCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCC#CCO
Temperature: 25 °C
Yield: 16.2 %

Procedure:
To a suspension of 675 mg of NaH in 45 ml of DMF and 5 ml of DMPU was added 4.85 g of 2-butyne-1,4-diol. The mixture was stirred at room temperature until evolution of gas had ceased. Then 1.5 g of 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide was added and the resulting mixture was heated to 95° C. and stirred for 5 days. Eventually, the mixture was pourred into 150 ml of 10% aqueous citric acid and extracted three times with 150 ml of ethyl acetate. The organic layers were washed with water and brine, dried over MgSO4 and evaporated. The resulting residue was purified by column chromatography on silicagel eluting with hexane:ethyl acetate 1:1 to give 265 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a beige foam along with 1.13 g of the starting material 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide. LC-MS: tR=5.39 min, [M+1]+=583.41, [M−1]−=581.35.
Reaction SMILES: [CH3:1][C@@H:2]([C@H:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)/[CH:8]=[CH:9]\[CH3:10])[C:3]([O:5][CH3:6])=[O:4].ClB(Cl)Cl.CSC.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:7](/[CH:8]=[CH:9]\[CH3:10])[C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:16][CH:15]=1
Reactant: C/C=C\[C@@H](c1ccc(OCc2ccccc2)cc1)[C@H](C)C(=O)OC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C/C=C\[C@@H](c1ccc(O)cc1)[C@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A reaction mixture of (2S,3R,Z)-methyl 3-(4-(benzyloxy)phenyl)-2-methylhex-4-enoate 41.2 (0.45 g, 1.4 mmol), trichloroborane (0.99 g, 8.5 mmol) and dimethylsulfane (0.53 g, 8.5 mmol) in DCM (10.0 mL) was stirred at 0° C. for 5 minutes and then at room temperature for 7 hours. A saturated solution of sodium bicarbonate was added slowly at 0° C. to reach a pH of 6.5. EtOAc was added, and the organic layer was washed with brine (2×25 mL) and dried with Na2SO4. The product was purified by reverse phase HPLC to give the title compound (41.3) as the major product in a ratio of 95:5. 1H NMR (500 MHz, CDCl3) δ ppm 1.21 (d, J=6.85 Hz, 3H) 2.77 (td, J=6.97, 2.93 Hz, 1H) 3.47-3.50 (m, 3H) 3.82 (m, 1H) 5.50-5.65 (m, 2H) 6.71-6.80 (m, 2H) 7.08 (d, J=8.56 Hz, 2H). MS ESI (pos.) m/e: 235.1 (M+H)+.