Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][C:18]#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]([CH2:29]CCl)[CH3:28]>>[CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:18][CH2:26][N:27]([CH3:29])[CH3:28])=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCl
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN(C)C

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and dimethylaminoethylchloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][CH2:16][CH2:17][CH2:18]N=C=O>O1CCCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:18][CH2:17][CH2:16][Cl:15])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=NCCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCCCl)CC1
Yield: 97.5 %

Procedure:
A solution of 4-amino-1-t-butoxycarbonylpiperidine (200 mg, 1.0 mmol) in tetrahydrofuran (5 mL) was treated with 3-chloropropyl isocyanate (0.080 mL, 1.0 mmol) overnight. The solvent was evaporated to provide the title compound as a white solid (270 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@@H:9]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:21])[N:7]([CH3:8])[C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Temperature: 60 °C

Procedure:
To a solution of Example 1E (285 mg, 0.98 mmol) in 4.4% HCO2H/MeOH (20 mL) under a nitrogen atmosphere was added Pd(OH)2 on carbon (20%, 40 mg), and the resulting mixture was heated at 60° C. for 16 hours. The mixture was cooled to room temperature and filtered through a layer of diatomaceous earth, the filter pad was washed with extra MeOH (30 mL), and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (30 mL) and washed with 1 M NaOH, then the organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 4.57 (d, J=6 Hz, 1H), 3.03 (m, 2H), 2.87 (m, 1H), 2.79 (s, 3H), 2.76 (m, 1H), 1.99 (m, 1H), 1.79 (m, 1H), 1.46 (s, 9H). MS (DCI+) m/z 201 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13](OC)=[O:14].O.[NH2:19][NH2:20]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13]([NH:19][NH2:20])=[O:14]
Reactant: NN
Reactant: COC(=O)C(C)c1cc2cccnc2cc1F
Solvent: CO
Solvent: O
Product: CC(C(=O)NN)c1cc2cccnc2cc1F
Yield: 100 %

Procedure:
A solution of methyl 2-(7-fluoroquinolin-6-yl)propanoate (756 mg, 3.24 mmol) and hydrazine monohydrate (1.5 mL) in methanol (5 mL) was heated at 50° C. overnight. After cooling, the solvent was removed in vacuo to afford the title compound (756 mg, 100%) which was used without further purification. LCMS (method A): [MH]+=234, tR=3.14 min.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: FC1(F)CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3,3-difluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 438 [M+H]
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:30](O)=[O:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH:30]=[O:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=CO
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C=O)C3)cc1

Procedure:
Compound dx was prepared according to the procedure described in Example 213 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with formic acid. LC-MS: m/z=+425 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:12])[S:5][C:6]=1[CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:12][C:4]1[S:5][C:6]([CH2:7][C:8]([Cl:11])([Cl:9])[Cl:10])=[C:2]([CH3:1])[N:3]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1nc(N)sc1CC(Cl)(Cl)Cl
Product: Cc1nc(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)sc1CC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 46 %

Procedure:
The title compound was prepared according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol, prepared according to Dodinov, A. A et al (1993) Chem. Heterocycl. Comp (Eng. Transl.) 29(8): 955-958) and 2,4,6-trichlorobenzenesulfonyl chloride (140 mg, 0.5 mmol). The solution was allowed to stand at room temperature overnight. The solution was directly loaded on a silica gel column for flash column chromatography, eluted with a mixed solvent of ethyl acetate and hexane (up to 40% v/v) to give a solid product. Crystallization of the product from ethyl acetate and hexane gave the title compound as a white solid (112 mg, 46% yield): mp 228-229° C.; MS m/e 487, 489, 491, 493; Anal. Calcd. (found) for C12H8Cl6N2O2S2: C 29.5 (29.7) % H 1.7 (2.1) % N 5.7 (5.8) %.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.BrC1C=COC=1.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>CCCCCC>[O:6]1[CH:10]=[CH:9][C:8]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:7]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1CCOC1
Agent: Brc1ccoc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccoc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
69.5 ml of a 1.6 molar solution of n-butyllithium in hexane are mixed with 60 ml of absolute tetrahydrofuran. The mixture is cooled to -60° C. and 10 ml of 3-bromofuran are added dropwise at such a rate that the internal temperature does not exceed -50° C.. When the addition is complete, the whole is stirred for 15 minutes at -60° C. and then 33.2 ml of tributyltin chloride are added dropwise, during the course of which the internal temperature is not allowed to exceed -50° C.. When the addition is complete, the reaction solution is allowed to come to -10° C. and is then stirred for one hour at that temperature. The solution is then carefully quenched with water. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulphate. It is filtered off and the solvent is removed in vacuo. The crude product obtained is purified by distillation in a high vacuum. 30.14 g of (3-furanyl)tributylstannane are obtained in the form of a light-yellow oil (boiling point=100°-104° C. at 0.09 torr).
Reaction SMILES: Br.[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2.C([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:32][CH2:31][CH2:30][CH2:29][OH:28])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1CCC(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCC(C)c2cc(-c3csc(C4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 150 mg (0.37 mmol) of 4-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-piperidine hydrobromide and 109 μl (0.74 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N sodium hydroxide solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[O:10]([CH2:15][CH:16]1[CH2:18][O:17]1)[CH2:11][CH:12]1[CH2:14][O:13]1>O>[C:2]1([CH2:1][O:8][CH2:18][CH:16]2[O:17][CH:12]([CH2:14][OH:13])[CH2:11][O:10][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C(OCC1CO1)C1CO1
Agent: [Na]
Solvent: O
Product: OCC1COCC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
108 g of benzyl alcohol (1.0 mole) is stirred under a nitrogen atmosphere at room temperature and 0.4 g of sodium is added to the mixture and stirring continued for 2-1/2 hours. Then 13.1 g of 2,2'-(oxybismethylene)bisoxirane (0.1 mole) is added and the mixture then heated to reflux for 18 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the resulting yellow oil then vacuum distilled through a 10 cm vigreux column. The fraction distilling at 150°-154° @0.4 mm is collected yielding 4.8 g (20%) of the above compound.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1.[CH2:35]1CCC(N=C=NC2CCCCC2)C[CH2:36]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([O:24][C:30](=[O:32])[C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:34][CH:33]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:35][CH3:36]
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCC1Cc2ccc(-c3ncc(OC(=O)c4ccc(F)cc4)cn3)cc2C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.4 %

Procedure:
0.70 g (3.0 mM) of 2-octyl-5-(5-hydroxypyrimidine-2-yl)indan, 0.42 g (3.0 mM) of 4-fluorobenzoic acid, 0.62 g (3.0 mM) of DCC, 0.02 g of 4-dimethylaminopyridine and 20 ml of methylene chloride were mixed and stirred for 7 hours at room temperature to precipitate N,N'-dicyclohexaurea. The N,N'-dicyclohexylurea was recovered by filtration and washed with dichloromethane to be added to the filtrate. The resultant dichloromethane solution was evaporated into a residue under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.70 g of 2-decyl-5-[5-(4-fluorobenzoyloxy)pyrimidine-2-yl]indan (Yield: 66.0%). ##STR299##
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][C:26]([F:32])=[C:27]([F:31])[CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[CH:28][C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Reactant: CC1Cc2cc(F)c(F)cc2N1
Agent: [Na+]
Product: CC1Cc2cc(F)c(F)cc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 47.7 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 80 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 51 mg of (+)-2-methyl-5,6-difluoro-2,3-dihydro-1H-indole (reference example 3a). After silica column purification: eluent 98/02 dichloromethane/methanol, 55 mg of 5-fluoro-2-[2-((−)-5,6-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:17])[CH3:16]
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: CC(C)N
Product: CC(C)Nc1nc2ccccc2n2ccnc12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with isopropylamine according to a procedure that is similar to that followed in example 3 there is obtained 4-isopropylaminoimidazo[1,2-a]quinoxaline. m.p. (DSC)=102.7° C. (onset); IR (KBr): 3230, 2966, 1559 cm-1 ; 1H-NMR (DMSO-d6): δ8.55 (1H,s), 8.2÷7.95 (1H,m), 7.6÷7.4 (2H,m), 7.4÷7.2 (3H,m), 4.5 (1H,m), 1.25 (6H,d); UV (EtOH): λmax =227, 244, 285, 297, 318, 332 nm. Elementary analysis for C13H14N4 (m.w. 226.28): calcd. C 69.00, H 6.23, N 24.76%; found C 69.17, H 6.70, N 25.05%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](O)=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([S:10][C:11]([F:13])([F:12])[F:14])[CH:7]=[C:8]2[N:9]=1
Reactant: O=C(O)c1sccc1Cl
Reactant: CNc1ncc(SC(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(-c2sccc2Cl)nc2cc(SC(F)(F)F)cnc21
Temperature: 90 °C
Reaction time: 10 h
Yield: 89.3 %

Procedure:
A mixture of 0.50 g of N2-methyl-5-trifluoromethylthiopyridine-2,3-diamine, 0.44 g of 3-chloro-thiophene-2-carboxylic acid, 0.51 g of EDCI hydrochloride, 30 mg of HOBt and 5 ml of pyridine was stirred at 90° C. for 10 hours. Water was poured into the cooled reaction mixture, and the deposited precipitate was filtered. The filtrate was applied to a silica gel column chromatography to obtain 0.7 g of 2-(3-chlorothiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine.
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[S:15][C:16]([CH2:19][OH:20])=[CH:17][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][C:22]1([CH3:32])[C@@H:24]([CH:25]=[C:26]([Br:28])[Br:27])[C@H:23]1[C:29](Cl)=[O:30].Cl>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:32])[C@@H:24]([CH:25]=[C:26]([Br:27])[Br:28])[C@H:23]1[C:29]([O:20][CH2:19][C:16]1[S:15][C:14]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:18][CH:17]=1)=[O:30]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3 ml of pyridine were added dropwise at 5° C. to a solution of 2.1 gof the product of Step B in 50 ml of benzene and 3.5 g of (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylic acid chloride and the mixture was stirred at 20° C. for 8 hours and was poured into aqueous 2N hydrochloric acid. The decanted organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 95-5 benzene-ethyl acetate mixture to obtain 1.45 g of (2-phenoxy-5-thiazolyl)-methyl (1R3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH3:30])[C:14]=3[C:5]=2[CH:4]=1
Reactant: CI
Reactant: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)NCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)N(C)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
9-methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (500 mg, 1.36 mmol) was dissolved in N,N-dimethylformamide (10 ml), added with sodium hydride (140 mg, 2.04 mmol) at 0° C. After stirring for 30 minutes, iodomethane (0.13 ml, 2.04 mmol) was added and the resulting mixture was stirred for 3 hours at 0° C. After completion, the mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (445 mg, yield: 90%, white solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][C:6]1[N:5]=[C:4]([C:9]#[N:10])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1cccnc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)nc1C#N

Procedure:
A solution of 3-methoxy-pyridine-2-carbonitrile from Example 13b in CCl4 is treated with N-bromosuccinimide (1 equiv.) and catalytic 2,2-azobisisobutyronitrile and is heated at reflux for 18 h. The reaction mixture is evaporated, the residue is taken into ethyl acetate, washed with 5% Na2CO3 (aqueous), 5 % Na2S2O3 (aqueous), dried over MgSO4 and evaporated to give 6-bromo-3-methoxy-pyridine-2-carbonitrile.
Reaction SMILES: C[Si]([I:5])(C)C.C(OC([N:16]1[CH2:23][C:22]2[O:21][C:20]([CH3:24])=[N:19][C:18]=2[CH2:17]1)=O)C1C=CC=CC=1>C(#N)C>[IH:5].[CH3:24][C:20]1[O:21][C:22]2[CH2:23][NH:16][CH2:17][C:18]=2[N:19]=1
Reactant: Cc1nc2c(o1)CN(C(=O)OCc1ccccc1)C2
Reactant: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1nc2c(o1)CNC2
Product: I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.6 mL trimethylsilyliodide was added to 400 mg 2-methyl-4,6-dihydro-pyrrolo[3,4-d]oxazole-5-carboxylic acid benzyl ester in 30 mL acetonitrile. The reaction was stirred 4 h at RT. The solvent was removed to give 390 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][N:29]3[Si](C(C)C)(C(C)C)C(C)C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.CN(C=O)C.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)C1C=CC=CC=1C1C=CC=CC=1N(C)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: Nc1ccc(Br)cc1C(=O)c1cccnc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: CN(C)c1ccccc1-c1ccccc1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cccc3[nH]ccc23)cc1C(=O)c1cccnc1
Temperature: 120 °C

Procedure:
To (2-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.120 g, 0.43 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (0.210 g, 0.52 mmol) in 1 mL of dioxane and 0.5 mL of DMF was added chloro(di-2-norbornylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) and 2M aqueous K3PO4 (0.5 mL, 1 mmol). The resulting reaction mixture was heated at 120° C. for 1 h. Ethyl acetate was then added to the reaction mixture and the organic phase was washed with water and brine, dried, filtered and concentrated. The crude product was purified by preparative TLC to afford [2-amino-5-(1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone. 1H NMR (400 MHz, CD3OD): δ 8.82 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.47 (dd, J=7.8, 5.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.21 (d, J=3.2 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.97-6.93 (m, 2H), 6.48 (d, J=3.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH3:36][O:37][C:38]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1)=[O:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:44][C:43]3[CH:42]=[CH:41][C:40]([C:38]([O:37][CH3:36])=[O:39])=[CH:47][CH:46]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(Cn2c(=O)n(C3CCN(c4ncnc5cc(OC)c(OC)cc45)CC3)c(=O)c3cc([N+](=O)[O-])ccc32)cc1
Yield: 26 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-methoxycarbonylbenzyl bromide was used in place of methyl iodide. As a result, 101.2 mg (yield: 26%) of Compound 13 was obtained as pale yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17]>COCCOC>[F:17][C:16]([F:19])([F:18])[C:12]([C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][CH:10]=1)=[O:13]
Reactant: O=Cc1cnc(-c2ccccc2)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C(c1cnc(-c2ccccc2)s1)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution (0.15 M) of 2-phenyl-1,3-thiazole-5-carbaldehyde (1.0 eq.) and CsF (0.2 eq.) in DME was treated with CF3SiMe3 (1.5 eq.) and then stiffed for 3 h at RT. The reaction mixture was quenched by adding 1N HCl and stirred for 30 min. The mixture was diluted with EtOAc, the organic phase was separated, washed with sat. aq. NaHCO3 solution and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded the product as an yellow oil. MS (ES+) C11H8F3NOS requires: 259, found: 260