Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CSC(=O)N1
Reactant: CNc1cccc(-c2ccc(C=O)cc2)c1
Product: CNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 91.7 %

Procedure:
In a manner similar to Example 1(d), by reacting 2.9 g (13.7 mmol) of 3′-methylaminobiphenyl-4-carbaldehyde with 1.6 g (13.7 mmol) of 2,4-thiazolidinedione, 3.9 g (91%) of the expected product are obtained after trituration in dichloromethane and ether.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Li].IC1C=CC=CC=1C(F)(F)F>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([F:27])([F:26])[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: [Li]c1ccccc1C(F)(F)F
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Agent: FC(F)(F)c1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2C(F)(F)F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-trifluoromethylphenyllithium (˜3 equiv, freshly prepared from 1-iodo-2-trifluoromethylbenzene as in Example 2A), to give (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-trifluoromethyl-phenyl)-methanone. MS (M+H)+: 328.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]([CH3:9])=[C:7]([CH3:8])[C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])c(O)c(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(OCc2ccccc2)c(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
2-Chloro-3,4-dimethyl-6-nitrophenol (6.44 g, 31.9 mmol) was dissolved in dry DMF (105 mL) and flushed with argon. Benzyl bromide (4.17 mL, 35.1 mmol) and K2CO3 (13.24 g, 95.7 mmol) were added. The reaction mixture was stirred at room temperature for 8 h (protected from light) and filtered. Water (5 mL) was added and the solvent was co-evaporated with xylene (2×150 mL) and CH2Cl2 (100 mL). The residue was mixed with CHCl3 (100 mL), filtered and after evaporation of the solvent 10.8 g of crude product remained. Purification by flash column chromatography (SiO2, CHCl3 -Hexane 1:1) gave the title compound (8.44 g). Mp: 74°-75° C.; 1H NMR (DMSO-d6): δ 7.80 (s, 1H), 7.48-7.37 (m, 5H), 5.06 (s, 2H), 2.37 (s, 3H), 2.34 (s, 3H); 13C NMR (DMSO-d6): δ 145.24, 142.22, 142.08, 135.73, 134.73, 129.61, 128.39, 128.37, 128.35, 123.64, 75.74, 19.74, 17.13; MS (EI, 70 eV): m/z (rel.int.) 293/291 (M+, 0.08/0.37), 187/185 (8/24), 91 (100).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:1])[C:3]([NH:29][CH:27]([CH3:28])[CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:5]
Reactant: Cc1ccc(CC(c2ccccc2)C(C)N)cc1
Reactant: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CC(c2ccccc2)C(C)NC(=O)C(C)(C)Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (Reference example 55, 250 mg, 1.04 mmol) and 4-(4-methylphenyl)-3-phenylbutan-2-amine (Reference example 102, 260 mg, 1.04 mmol, mixture of 4 isomers) in CH2Cl2 (5.5 mL) at RT was added diisopropylethylamine (272 μl, 1.56 mmol) followed by PyBOP (649 mg, 1.25 mmol) and the reaction mixture stirred overnight. The reaction was purified by loading the reaction mixture directly onto a silica gel column and eluting from 0-30% EtOAc/hexane to give the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a ZORBAX RxSi column eluting 97% hexane: 3% ethanol at 20 mL/min with retention times of:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C:28]1[C:38]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:42]2[CH2:41][CH2:40][N:39]([C:38]3[C:28]([CH3:27])=[C:29]([CH:35]=[CH:36][CH:37]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:44][CH2:43]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1C
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCOC(=O)c1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c1C

Procedure:
The procedure of step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 87 was used instead of 3,3-diphenylpropyl bromide and the compound prepared in step (a) of Example 53 was used instead of ethyl 3-piperazin-1-yl-benzoate. Thus, ethyl 3-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl]piperazin-1-yl]-2-methylbenzoate was obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:36][C:34]([CH3:37])([O:33][C:31]([NH:30][CH2:29][C:26]1[CH:27]=[CH:28][C:19]([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:25]=1)=[O:32])[CH3:35]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A solution of 1.66 g of benzyl 4-oxopiperidine-1-carboxylate and 1 g of methyl 2-amino-5-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)benzoate obtained in stage 5.1 in 20 ml of DCM is added dropwise at AT to a suspension of 2.04 g of NaBH(OAc)3 in a mixture of 20 ml of DCM and 0.41 ml of AcOH. The mixture is stirred at AT for 15 h 00 and then a further 2.04 g of NaBH(OAc)3 are added. After stirring for 6 h 00, 1.66 g of benzyl 4-oxopiperidine-1-carboxylate are added and the mixture is stirred at AT for 48 h 00. A saturated NaHCO3 solution is added and extraction is carried out with DCM. The organic phase is washed with a saturated NaHCO3 solution and twice with a saturated NH4Cl solution. It is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (40/60, v/v), to give 1.6 g of the expected product.
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:21]([NH2:23])=[O:22])=[C:15]([N+:17]([O-])=O)[CH:16]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.COCCO.[Ni]>[O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:21]([NH2:23])=[O:22])=[C:15]([CH:16]=1)[NH2:17])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: COCCO
Product: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N

Procedure:
33.7 g of 5-phenoxysulfonyl-2-ureidonitrobenzene in 250 ml of methanol and 250 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After uptake of hydrogen is complete, the catalyst is filtered off with suction, washed with dimethylformamide and the solution is evaporated under reduced pressure, induced to crystallize with methanol, and the crystals are filtered off with suction and washed with methanol, melting point 180° C., decomposition.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:7]([Cl:17])=[CH:6][C:3]=1[C:4]#[N:5].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C.N1C=CC=CC=1N>C(O)CCC>[Cl:17][C:7]1[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[N:9][C:2]([NH:27][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1cc(Nc2nc(Cl)c(C#N)cc2Cl)n[nH]1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)c(C#N)cc2Cl)n[nH]1
Temperature: 150 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a 10-ml microwave vessel was added, 2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method 60, 8 mmol), [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine (Method 33, 8 mmol, 97 wt % solution in dioxane), DIEA (0.3 ml, 1.66 mmol), and n-butanol (4 ml). The vessel was then sealed and subjected to microwave heating at 150° C. for 3 hours. After 3 hours, more 2-pyridyl amine (100 mg, 0.69 mmol) was added. The resulting mixture was purified by silica gel chromatography (Biotage Horizon System) using an isocratic system of 15:0.5:0.5% of DCM/EtOAc/MeOH to give 312 mg of the title compound. 1H NMR: 12.04 (br s, 1H), 8.41-8.63 (m, 2H), 7.84 (s, 1H), 7.56-7.71 (m, 1H), 7.40 (dd, J=8.67, 4.14 Hz, 1H), 7.28 (s, 1H), 5.86 (s, 1H), 5.06-5.25 (m, 1H), 2.17 (s, 3H), 1.51 (d, J=7.54 Hz, 3H). MS: Calcd.: 371/373. Found: [M+H]+ 372/374.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([OH:8])[CH:7]=1.Br[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([O:8][CH:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: Oc1cc(I)ccc1OCCN1CCCC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cc(I)ccc1OCCN1CCCC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 0.15 g (0.45 mmol) of 5-iodo-2-(2-pyrrolidin-1-ylethoxy)phenol (Example 33.1c), 52 μL (0.55 mmol) of 2-bromopropane, and 186 mg (1.35 mmol) of potassium carbonate in 2 mL of acetonitrile was stirred for 2 hours at 75° C. The reaction mixture was diluted with water and the aqueous phase exhaustively extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 77 mg (46% of theoretical); C15H22INO2 (M=375.245); calc.: molpeak (M+H)+: 376; found: molpeak (M+H)+: 376; HPLC-MS: 5.86 minutes (method A).
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[NH4+].[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:28])[NH:23][C:22]2=[O:29])=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]>C(O)(=O)C>[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[C:25]([S:3][C:4]#[N:5])=[C:24]([CH3:28])[NH:23][C:22]2=[O:29])=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: N#C[S-]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1SC#N
Temperature: 25 °C

Procedure:
1.86 g of bromine in 10 ml of acetic acid are added dropwise with stirring to 2.1 g of ammonium thiocyanate in 80 ml of acetic acid at 10°-15° C. during 15 minutes. Then 1.5 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 15 ml of acetic acid are added dropwise at 10°-15° C. during 5 minutes, and the reaction mixture is stirred for a further hour at room temperature and thereafter substantially evaporated under reduced pressure. The residue is dissolved in ethyl acetate, the solid material filtered off under suction and the filtrate washed with aqueous sodium bicarbonate solution and thereafter with water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using methylene chloride/ethyl acetate (3:1) as eluent. The product is recrystallized from methylene chloride/diethyl ether. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-5-thiocyanato-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 159°-161° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][CH2:27][C:28]#N.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:28][CH2:27][C:26]#[N:25])[N:8]=1
Reactant: N#CCCN
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(CCC#N)n1
Temperature: 90 °C
Yield: 77.1 %

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 3.50 g, 8.14 mmol), 3-aminopropionitrile (1.79 mL, 24.4 mmol), diisopropylethylamine (2.84 ml, 16.3 mmol) and Na2CO3 (1.73 g, 16.3 mmol) in dry NMP (4 mL) was heated at 90° C. for 8 hours. The reaction was cooled to room temperature, and then partitioned between EtOAc (100 mL) and water (100 mL), and the layers separated. The organic portion was washed with water (100 mL), saturated aqueous NaHCO3 solution (100 ml), brine (100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (SiO2, 0-50% EtOAc in heptane) to furnish 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propanenitrile as a pale yellow foam (2.91 g, 6.28 mmol). LCMS (m/z) 463.1 (MH+), tR=0.98 minute, 1H NMR (CDCl3) δ ppm −0.09 (s, 9H) 0.73-0.85 (m, 2H) 0.99-1.11 (m, 2H) 1.12-1.21 (m, 2H) 1.90-2.05 (m, 1H) 2.75 (t, J=6.7 Hz, 2H) 3.36-3.48 (m, 2H) 3.76 (q, J=6.5 Hz, 3H) 5.50 (br s, 1H) 5.85 (s, 2H) 7.20 (d, J=5.1 Hz, 1H) 8.37 (d, J=5.1 Hz, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a suspension of 7.55 g of magnesium in 50 ml of THF is added dropwise a solution of 50 g of 1-bromo-3,4-difluorobenzene in 100 ml of THF so as to reach and then maintain reflux, and the mixture is left at reflux for 2 hours with stirring. After cooling to rt, a solution of 49 g of 1-benzyl-4-piperidinone in 100 ml of THF is added dropwise and the mixture is then stirred at RT overnight. The reaction mixture is poured onto saturated NH4Cl solution and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. 38.3 g of the expected product are obtained after crystallization from cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16]Br)[CH:9]=[N:10]2.[CH3:19][NH:20][CH3:21].C(O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:20]([CH3:21])[CH3:19])[CH:9]=[N:10]2
Reactant: CNC
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(CBr)cc12
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)Cc1c(Cl)ccc2ncc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (3-bromomethyl-6-chloro-quinolin-5-yl)-acetic acid methyl ester (500 mg, 1.52 mmol) in DMF (10 mL) was added a 33% solution of dimethylamine in ethanol (547 μL, 3.04 mmol). The reaction mixture was stirred for 16 h at room temperature, followed by removal of the solvents in vacuo. The residue was purified by flash column chromatography (silica gel, gradient of CH2Cl2/MeOH 100:0 to 90:10) to afford the title compound as a violet solid (424 mg, 1.45 mmol, 95%). %). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=8.89 (d, J=2.0 Hz, 1H), 8.38 (bs, 1H), 8.00 (d, J=9.1 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 4.36 (s, 2H), 3.69 (bs, 2H), 3.63 (s, 3H), 2.24 (bs, 6H). MS (ES+): 293 (M(C15H735ClN2O2)+H)+.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]([O:18][CH2:19][C@@H:20]3[CH2:24][CH2:23][CH2:22][NH:21]3)[CH:14]=[N:15][C:16]=2[Cl:17])=[CH:5][CH:4]=1.[CH2:25]=O.Cl>C(O)=O>[N:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]([O:18][CH2:19][C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])[CH:14]=[N:15][C:16]=2[Cl:17])=[CH:5][CH:4]=1
Reactant: Clc1ncc(OC[C@@H]2CCCN2)cc1C=Cc1ccncc1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To 5-(2-(4-pyridinyl)ethenyl)-6-chloro-3-(2-(S)-pyrrolidinyl-methoxy)pyridine from Example 33 (110 mg, 0.27 mmol) was added formalin (38%, 3.0 mL) and formic acid (88%, 1.5 mL). The mixture was refluxed for five hours then cooled to room temperature. Hydrochloric acid (36%, 0.3 mL) was added, and the mixture was extracted with Et2O (3×8 mL). The aqueous layer was heated under vacuum to dryness. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3 /MeOH 10:1 to afford an oil (72 mg, 83%). MS (CI/NH3) m/z 330 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.70-2.10 (m, 4H), 2.38-2.40 (m, 1H), 2.51 (s, 3H), 2.65-2.76 (m, 1H), 3.10-3.19 (m, 1H), 3.96-4.10 (m, 2H), 6.96-7.04 (m, 1H), 7.39-7.44 (m, 2H), 7.53 (s, 1H), 7.52-7.60 (m, 1H), 8.05-8.08 (m, 1H), 8.63-8.67 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH2:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1>>[S:9]1[CH:10]=[CH:11][C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH2:4])=[N:8]1
Reactant: BrCc1ccsn1
Reactant: NCCN
Product: NCCNCc1ccsn1

Procedure:
By the procedure of Example 34, ethylenediamine is reacted with 3-bromomethylisothiazole to give N-(3-isothiazolylmethyl)ethylenediamine. This intermediate is heated under reflux with S-methylisothiouronium sulphate in water for 3 hours by the procedure of Example 1 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[N:11]=3)[CH:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1

Procedure:
tert-Butyl {1-[2-(7-chloro-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 139, 308 mg, 0.76 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]([N:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:24][C:23]([CH:33]=O)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:24][C:23]([CH2:33][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Product: Cc1ccc(-c2cc(CNCCN3CCN(c4ccccc4F)CC3)nn2C(C)(C)C)cc1
Yield: 89.4 %

Procedure:
Compound 69 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].I[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1>C(O)C>[CH2:2]([NH:4][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1)[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 74.2 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.1 g (13.4 mmol) of ethylamine hydrochloride, 1.85 g (13.4 mmol) of potassium carbonate and 800 mg (1.34 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 511 mg of ethyl 4′-(3-ethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=148° C., yield=74%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].C[O:10][CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH2:19]([N:22]=C=O)[CH2:20][CH3:21]>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:22][C:11]([C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1)=[O:10])[CH2:20][CH3:21]
Reactant: COCC1(S(N)(=O)=O)CC1
Reactant: CCCN=C=O
Agent: CC(C)(C)NC(=O)O
Product: CCCNC(=O)C1(S(N)(=O)=O)CC1
Yield: 100 %

Procedure:
This compound was obtained in a crude 100% yield according to the procedure described for the synthesis of 1-methoxymethylcyclopropylsulfonylamine tert-butylcarbamate (Step B.1.a) except that 1.10 equivalents of n-propyl isocyanate was used as the electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.10 (m, 2H), 0.51 (m, 2H), 0.67 (m, 1H), 1.10 (m, 2H), 1.49 (s, 9H), 1.62 (m, 2H), 1.87 (d, J=7.0 Hz, 2H).