Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13](O)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:9]1=[O:22].[Cl:23][C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:18])[C:9]1=[O:22]
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccccc2Cl)C1=O
Reactant: Clc1cccnc1N1CCNCC1
Product: CC(C)S(=O)(=O)N1CC(C(=O)N2CCN(c3ncccc3Cl)CC2)N(c2ccccc2Cl)C1=O

Procedure:
In analogy to example 1, (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 85, step 2) was coupled with 1-(3-chloropyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 526.3 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]([OH:13])[C:11]#[N:12])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:13][CH:10]([C:11]#[N:12])[CH2:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(O)CNc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(C#N)CNc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
7.2 g of 3-(5-bromo-2-pyridinylamino)-2-hydroxypropionitrile was dissolved in 60 mL dichloromethane, and 7.8 mL diisopropyl ethylamine and 6.3 g of 4-toluenesulfonic acid chloride were added thereto, and while the temperature of the mixture was gradually increased to room temperature, the mixture was stirred for 2 hours. An aqueous saturated sodium bicarbonate solution was poured into the reaction mixture which was then extracted with ethyl acetate and washed with brine, then the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 7.64 g of the title compound (yellow oil).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[N:31]#CBr>C(Cl)(Cl)Cl>[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:11]2)[CH2:13][CH2:14]1)#[N:31]
Reactant: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12

Procedure:
A solution of 18.23 g of 1-(2-nitrophenyl)-1'-methylspiro[indoline-3,4'-piperidine] of Example 15 in 100 ml of chloroform is added dropwise over 50 minutes to a rapidly stirred slurry of 11.65 g of potassium carbonate and 8.94 g of cyanogen bromide in 100 ml of chloroform under nitrogen. After heating at reflux for 2.75 hours, the cooled product is washed with 10% sodium hydroxide and water, dried over anhydrous magnesium sulfate and concentrated to yield a crude solid which is chromatographed on silica gel (650 g) using ether-chloroform and is then recrystallized from ether-dichloromethane to yield a solid, mp 148°-150° C. of 1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: [C:1]1([P:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([SH:25])[CH3:24].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]1([P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([S:25][CH2:23][CH3:24])=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCS
Reactant: O=C(O)c1ccccc1P(c1ccccc1)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)c1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
2-(Diphenylphosphanyl)benzoic acid (0.50 g, 1.63 mmol) and DMAP (20 mg, 0.163 mmol) were dissolved in CH2Cl2 (10 mL). Ethanethiol (EtSH, 0.35 mL, 4.89 mmol) was added, and the solution was placed under Ar(g) and cooled to 0° C. DIC (0.25 mL, 1.63 mmol) was added dropwise, and the resulting solution was allowed to warm to room temperature and stirred overnight. The solution was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexanes, to give phosphine 1b as a pale yellow solid (0.43 g, 1.22 mmol, 75% yield).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.[OH-].[K+]>C1COCC1.CO.Cl>[OH:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-4-(1-hydroxyethyl)benzoate (2.00 g, 11.10 mmol) in a mixture of THF (20 mL) and MeOH (10 mL) was added 1 M KOH (13.32 mL, 13.32 mmol). After stirring at room temperature overnight, the solution was diluted with 2 N HCl and extracted with EtOAc (4×). The combined organic layers were dried (MgSO4) and evaporated to give 4-(1-hydroxyethyl)benzoic acid as a colorless solid. 1H NMR (DMSO-d6, 600 MHz) δ 7.86 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 4.75 (q, J=6.5 Hz, 1H), 1.30 (d, J=6.6 Hz, 3H). MS: cal'd 167 (MH+), exp 167 (MH+).
Reaction SMILES: [O:1]([C@@H:9]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][OH:21])=[CH:18][C:13]=2[O:12][CH2:11][C@H:10]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:61]1[CH:62]=[C:63]([CH:69]=[CH:70][CH:71]=1)[C:64]([O:66][CH2:67][CH3:68])=[O:65]>O1CCCC1>[O:1]([C@@H:9]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][O:21][C:70]3[CH:71]=[CH:61][CH:62]=[C:63]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH:69]=3)=[CH:18][C:13]=2[O:12][CH2:11][C@H:10]1[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1c2ccc(CCO)cc2OC[C@H]1Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCCc2ccc3c(c2)OC[C@@H](Cc2ccccc2)[C@@H]3O[Si](C)(C)C(C)(C)C)c1
Yield: 18.9 %

Procedure:
To a stirred solution of the compound of step A (720 mg, 18 mmole) in tetrahydrofuran (10 ml) was added diethylazodicarboxylate (430 μl, 2.5 mmole), triphenylphosphine (710 mg, 2.5 mmole) and ethyl 3-hydroxybenzoate (415 mg, 2.5 mmole). The mixture was refluxed for 3 days, the solvent removed in vacuo and the residue chromatographed (silica gel, 3:1 hexane:ether) to afford 258 mg of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:23]=[C:22]([CH2:24]O)[O:21][N:20]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][CH2:24][C:22]1[O:21][N:20]=[C:19]([O:18][CH2:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH3:5])[CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Thionyl chloride (0.80 ml) was added slowly to a solution of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (2.86 g) in toluene (50 ml) at room temperature, which was stirred for 30 minutes under reflux. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (2.70 g, yield 89%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 105–106° C.
Reaction SMILES: C[O:2][C:3](=[O:47])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([Cl:37])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:38]=[C:39]([CH3:46])[C:40]([C:42]([F:45])([F:44])[F:43])=[CH:41][C:13]2=3)[CH2:7][CH2:6]1.[OH-].[Na+]>CO.O.Cl>[Cl:37][C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:8]2[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:47])=[O:2])[CH2:10][CH2:9]2)[C:13]2[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[C:39]([CH3:46])=[CH:38][C:14]1=2
Reactant: COC(=O)CC1CCC(CN2CCC[C@H](N(Cc3cc(Cl)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCC(CC(=O)O)CC1)CCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.1 mmol) in methanol (1 mL), add 4N sodium hydroxide (0.4 mL). Heat the mixture at 60° C. for 3 h. Dilute the cooled mixture with water and 1N HCl to bring the pH to 6-7 and extract with CH2Cl2 (3×15 mL). Combine the organic layers and wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by chromatography (elution with 5%-20% methanol in EtOAc) to afford the title compound. MS (ES+): 673 (M+H).
Reaction SMILES: [BH4-].[Na+].[I-].[NH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N+:9]([CH3:15])=[CH:10]2>CO.O>[NH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([CH3:15])[CH2:10]2
Reactant: C[n+]1ccc2c(N)cccc2c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCc2c(N)cccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
Sodium borohydride (17.8 g, 0.47 mol) was added portionwise over 2 h to an ice cold solution of 5-amino-2-methylisoquinolinium iodide (18.8 g, 65 mmol) in methanol (1.5 L) and water (60 ml). The mixture was then stirred at 25° C. for 18 h. and concentrated in vacuo. The residue was extracted into water and dichloromethane. The organic layer was dried (Na2SO4) and concentration in vacuo gave the title compound (8.87 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1>C(#N)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[N:23]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
In 100 ml of acetonitrile was dissolved 10 g (0.0567 mole) of 1-benzylpiperazine, and 11.7 g (0.085 mole) of potassium carbonate and 14.8 g (0.068 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added thereto. The mixture was refluxed by heating for 5 hours. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of ethyl acetate : toluene = 1 : 9) to obtain 17.6 g of 4-(4,6-dimethoxy-2-pyrimidinyl)-1-benzylpiperazine as colorless liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: NC1CCCC1
Product: Fc1ccc(-c2ccc3ncnc(NC4CCCC4)c3c2)cc1

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and cyclopentylamine in 78%, using the procedure described example 37 and was characterized by its mass spectrum as follows: MS (m/z): 308 ([M+H]+, 100).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[I:10]Cl.O>CC(O)=O>[CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][C:7]([I:10])=[CH:8][C:3]=2[O:2]1
Reactant: ClI
Reactant: c1ccc2c(c1)OCO2
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 56.7 %

Procedure:
To a solution of 1,2-methylenedioxybenzene (24.4 g, 0.20M) in AcOH (30 ml) was added ICl (40 g, 0.250M) in AcOH (50 ml) at room temperature over 0.5 hour. The reaction mixture was stirred for an additional three hours, then poured into H2O and extracted twice with ether. The organic extracts were washed with NaHSO3, saturated NaHCO3, H2O, dried (MgSO4), and evaporated in vacuo. The product was distilled under vacuum at 70° C. to give 3,4-methylenedioxyiodobenzene as a pale orange liquid (28.1 g, 57% yield). NMR (CDCl3) δ 5.85 (s, 2H, O--CH2 --O), 6.50 (d, 1H, J=8 Hz, H6), 7.10 (m, 2H, J=8 Hz, J=2 Hz, H2 and H5); MS: 248 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](Cl)=[O:32]>C1COCC1>[CH3:28][N:29]([CH3:34])[CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:32]
Reactant: CN(C)CC(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)CN(C)C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 2-(dimethylamino)acetyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.28-1.38 (m, 2H) 2.24 (bs, 2H) 2.90 (s, 6H) 4.21 (s, 2H) 6.79 (s, 1H) 7.58 (t, J=7.58 Hz, 1H) 7.76 (d, J=8.59 Hz, 2H) 7.79-7.90 (m, 4H) 8.10 (d, J=8.34 Hz, 1H) 9.89 (s, 1H) 10.94 (s, 1H); ESI-MS: m/z calc'd for C25H27N5O2S 461.58. found 462.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-(2-(dimethylamino)ethyl)cyclohexyl)amino)quinolin-3-yl)ethanone (63 mg, 0.15 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.225 mmol) to afford the desired product (7.3 mg, 9.7%) as a yellow solid. NMR (500 MHz, DMSO) δ 10.69 (d, J=8.0 Hz, 1H), 8.92 (s, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.6, 2.1 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.66 (s, 2H), 4.21-4.12 (m, 1H), 2.65 (s, 3H), 2.48-2.41 (m, 2H), 2.28 (s, 3H), 2.23-2.16 (m, 2H), 1.88-1.81 (m, 2H), 1.51-1.38 (m, 5H), 1.23-1.12 (m, 2H). ESI MS m/z 500 [C27H31Cl2N3O2+H]+; HPLC>99% (AUC), tR=11.40 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Se]=[O:13]>C(OCC)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2ncccc2c1
Reactant: O=[Se]
Solvent: CCOC(C)=O
Product: O=Cc1ccc2ncccc2c1
Temperature: 220 °C
Yield: 54.9 %

Procedure:
A mixture of 6-methylquinoline (5.72 g, 40.0 mmol) and selenium oxide (4.44 g, 40.0 mmol) was heated to 220° C. for 1 h. After cooling down the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with brine, dried over MgSO4. Evaporation of solvents provided a solid, which was recrystalized from ether-hexane (1:1) mixture to give 6-quinolinecarboxaldehyde (3.45 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=[O:14])[C:6]=2[CH:15]=1>C1C=CC=CC=1.[Rh].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1
Reactant: O=C(O)c1cc(=O)c2cc(F)ccc2o1
Agent: [Rh]
Solvent: c1ccccc1
Solvent: CO
Product: O=C1CC(C(=O)O)Oc2ccc(F)cc21
Reaction time: 0.25 h

Procedure:
(+)-2,3-O-isopropyliden-2,3-dihydroxy-1,4-bis(diphenylphosphyno)butane (120 mg, 0.0240 mmol) was added to a solution of dichloro-bis-[(1,3)-cyclooctadiene]-dirhodium(I) (59.2 mg, 0.0120 mmol) in dry benzene (0.5 ml) under argon atomosphere and the mixture was stirred for 15 minutes to prepare an optical active rhodium catalyst. The benzene solution (catalyst) was added to a suspension of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (1.00 g, 4.80 mmol, obtained in Example 5) in methanol (30 ml) under argon atmosphere. Gaseous phase was changed for H2, and the mixture was stirred for 24 hours under H2 (4 kg/cm2) at 40° C.
Reaction SMILES: [CH:1]1([C:4]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])[CH3:5])[CH2:3][CH2:2]1.CC(C(C1C2C(=C(CS(C)=[O:53])C=CC=2)NC=1)C1C=CC(C(F)(F)F)=CC=1)CC#N>>[CH:1]1([C:4]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:53])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(CC#N)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 217 mg (94% purity, 0.61 mmol) of the compound from Example 96 in analogy to the synthesis of the compound from Example 91. 212 mg (99% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[C:8]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: N#C[S-]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-(bromoacetyl)benzonitrile (7.72 g, 34.5 mmol) and potassium thiocyanate (3.35 g, 34.5 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 4.39 g (63.0% (2 steps)) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN(C)C(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
To a solution of 4-amino-N,N-dimethyl-benzamide (3.5 g, 0.0213 mol), TEA (2.15 g, 0.0213 mol) in DCM (50 mL) was added 4-bromophenyl isocyanate (5.07 g, 0.0256 mol). The reaction mixture was stirred at room temperature for 12 h. The white solid was obtained and was filtered and dried to afford the title compound [6.8 g, 88%]; LC-MS (ESI): Calculated mass: 361.0; Observed mass: 362.0 [M+H]+ (RT: 0.17 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3ccccn3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in toluene (2 ml), then thereto are added 2-tributylstannylpyridine (105 μl) and tetrakis(triphenylphosphine)palladium (16 mg), and the mixture is stirred at 100° C. under nitrogen flow overnight. After allowing to cool to room temperature, 10% aqueous potassium fluoride solution is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a 10% aqueous potassium fluoride solution and a saturated brine successively, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyridin-2-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (138 mg). MS (m/z): 661 [M+H]+