Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6]([CH3:41])([CH3:40])[C:7](=[O:39])[N:8]([CH2:16][CH2:17][CH2:18][N:19]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2=[O:15])=[CH:4][CH:3]=1>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([CH3:41])([CH3:40])[C:7](=[O:39])[N:8]([CH2:16][CH2:17][CH2:18][N:19]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCN(CCCN2C(=O)c3c(ccc(N)c3[N+](=O)[O-])C(C)(C)C2=O)C(=O)OC(C)(C)C)cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCN(CCCN2C(=O)c3c(ccc(N)c3N)C(C)(C)C2=O)C(=O)OC(C)(C)C)cc1OC
Reaction time: 16 h
Yield: 83.5 %

Procedure:
A mixture of tert-butyl [3-(7-amino-4,4-dimethyl-8-nitro-1,3-dioxo-3,4-dihydro-1H-isoquinolin-2-yl)propyl]-[2-(3,4-dimethoxyphenyl)ethyl]carbamate (3.60 g, 6.31 mmol) and 20% Pd(OH)2/C (0.72 g) in EtOH (100 mL) and THF (10 mL) was stirred under H2 (balloon) for 16 h. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40-63μ silica gel, hexane:EtOAc 1:1 to 1:2) to give the title compound (2.85 g, 83% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cnc2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc21
Yield: 83 %

Procedure:
The title compound is prepared from 1-methyl-1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 83% of theory; LC (method 5): tR=1.05 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]=[CH:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([N:27]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])=[CH:25][CH:24]=1
Reactant: Nc1ccc(-c2ccco2)cc1
Reactant: CC(=O)C=CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccco2)cc1
Yield: 24.3 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]pentene-1 4-dione (0.305 g, 1.2 mmol prepared according to the method of J. Med. Chem., 1997, 40, 1619), 4-(2-furyl)aniline (0.35 g, 2 mmol), and p-toluenesulfonic acid monohydrate (0.015 g) in toluene (40 mL) was heated at reflux temperature for 16 hours using Dean-Stark apparatus. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4/1). The resulting solid was recrystallized from CH2Cl2/hexane to give the title compound (0.11 g, 24.3% yield).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]12[CH2:27][C:24]([OH:28])([CH2:25][CH2:26]1)[CH2:23][CH2:22]2.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:20][C:21]23[CH2:27][C:24]([OH:28])([CH2:25][CH2:26]2)[CH2:23][CH2:22]3)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC12CCC(O)(CC1)C2
Reactant: CC(C)(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(NC23CCC(O)(CC2)C3)ncc1C(N)=O
Temperature: 90 °C

Procedure:
4-(tert-Butylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.165 g, 0.606 mmol; synthesis described herein), 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride (0.105 g, 0.644 mmol) and DIEA (0.337 ml 1.931 mmol) were mixed in DMF (8 mL) and heated at 90° C. overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (0-10% methanol in ethyl acetate) to give the desired product. (41 mg, 0.127 mmol, 21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (br. s., 0H) 8.32 (s, 1H) 7.07 (br. s., 1H) 4.88 (br. s., 1H) 1.94-2.14 (m, 2H) 1.61-1.87 (m, 6H) 1.49-1.60 (m, 2H) 1.42 (s, 9H). MS (ESI) m/z 320.0 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=4[Cl:33])=[CH:18][CH:17]=3)=[O:23])[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
As described for Example 136, a mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.131 g of triethylamine and 0.272 g of 2,4-dichlorobenzoyl chloride in 13 ml of dichloromethane is stirred at room temperature for 3 hours. Work-up gives a solid which is crystallized from dichloromethane-hexane to give 0.43 g of crystals, m.p. 199°-201° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:4].C(O)(=O)C.CCOCC>C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N:1]=1
Reactant: NCC(=O)Nc1sccc1C(=O)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: O=C1CN=C(c2ccccc2Cl)c2ccsc2N1

Procedure:
150 g (0.51 mol) of 2-aminoacetylamino-3-(o-chlorobenzoyl)-thiophene are dissolved in 2.5 liters of absolute ethanol and 250 ml of glacial acetic acid are added. The solution is heated to reflux with stirring until the reaction has ended (about 5 hours) as indicated by thin-layer chromatography (eluant: ether). The solvent is removed under a vacuum and the product taken up in 2 liters of methylene chloride. The methylene chloride solution is shaken out with dilute aqueous sodium bicarbonate solution, washed with water and evaporated. The product is brought to crystallization, treated with 150 ml of methylene chloride, refluxed and left to crystallize in a refrigerator. After filtration under a vacuum and treatment with ice-cold methylene chloride, pure 5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one is obtained in the form of bright-yellow crystals, melting point 221°-223° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[N:7]#[C:8][Br:9]>O>[BrH:9].[CH3:4][C:3]1([CH3:5])[NH:6][C:8]([NH2:7])=[N:1][CH2:2]1
Reactant: CC(C)(N)CN
Reactant: N#CBr
Solvent: O
Product: Br
Product: CC1(C)CN=C(N)N1
Temperature: 25 °C

Procedure:
To a solution of 15 g (0.17 mol) of 1,2-diamino-2-methylpropane in 150 ml of water at 0° C., was added 18 g (0.17 mol) of cyanogen bromide portionwise and the temperature was allowed to warm to room temperature during 4 h.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH:26]=[CH:25][C:24]3=[O:34])[CH2:17][CH2:16]2)[NH:5][C:6]2[C:7]=1[O:8][CH2:9][C:10](=[O:12])[N:11]=2.C([O-])(O)=O.[Na+].[H][H]>CO.[Pd]>[ClH:1].[F:33][C:30]1[CH:31]=[C:32]2[C:27]([CH:26]=[CH:25][C:24](=[O:34])[N:23]2[CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([NH:14][CH2:13][C:4]3[NH:5][C:6]4[C:7]([O:8][CH2:9][C:10](=[O:12])[N:11]=4)=[CH:2][N:3]=3)[CH2:16][CH2:17]2)=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: O=C1COC2=C(Cl)N=C(CNC3CCN(CCn4c(=O)ccc5ccc(F)cc54)CC3)NC2=N1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=C1COC2=CN=C(CNC3CCN(CCn4c(=O)ccc5ccc(F)cc54)CC3)NC2=N1
Yield: 16 %

Procedure:
To a solution of 4-chloro-2-[({1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-1H-pyrimido[5,4-b][1,4]oxazin-7(6H)-one (see Example 124(j) for a preparation) (67 mg, 0.13 mmol) in methanol (3 mL) was added NaHCO3 (40 mg) followed by 10% palladium over carbon catalyst (30 mg). The resulting mixture was stirred at room temperature under 1 atm of hydrogen (balloon) for 24 h. The reaction mixture was filtered through a nylon filter and the crude residue was purified by chromatography (silica gel) using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (10 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:13]([CH3:23])[N:12]=[C:11]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH2:10]2)=[CH:5][CH:4]=1.CS(C)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[C:13]([CH3:23])[N:12]=[C:11]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(C)N=C(N3CCN(c4ccccc4)CC3)CC2c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1ccc(-c2cc(N3CCN(c4ccccc4)CC3)nc(C)c2-c2ccc(OC)cc2)cc1
Yield: 69 %

Procedure:
7 g (15 millimol) of 4,5-bis-(4-methoxyphenyl)-6-methyl-2-(4-phenylpiperazino)-3,4-dihydropyridine were suspended in 150 ml of analytically pure dimethylsulphoxide, whilst stirring, and 1.7 g (15 millimol) of potassium tert.-butylate were added to the suspension. The mixture was stirred in a closed vessel until a clear, orange-red coloration had formed. The reaction solution was then stirred in an open reaction flask for 1 hour. After the reaction solution had been neutralised with glacial acetic acid, the colourless precipitate which had separated out was filtered off under suction, washed with methanol and dried in vacuo to obtain 4,5-bis-(4-methoxyphenyl)-6-methyl-2-(4-phenylpiperazino)-pyridine.
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=4)[N:22]=[CH:21][C:20]=3[Cl:31])[CH2:13]2)C=CC=CC=1.[OH-].[K+].O>CO>[Cl:31][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][C@@H:12]([CH2:11][NH2:10])[CH2:13]1)=[N:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2
Reactant: COc1ccc2ncc(Cl)c(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2ncc(Cl)c(CCN3CC[C@@H](CN)C3)c2n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A solution of phenylmethyl[((3S)-1-{2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (1.0 g, 2.2 mmol) in MeOH (30 mL) was treated with 40% KOH (15 mL, 107 mmol) and heated at 100° C. for 3 h. The MeOH was stripped off at reduced pressure and the residue was treated with water. The product was extracted into CHCl3 and the combined organic phases were dried (K2CO3) and filtered. Purification of silica gel provided the product as a light brown oil (0.36 g, 51%): LC/MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11](Br)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=c1c2[nH]c(Br)nc2n(CC2CC2)c(=O)n1CC1CC1
Product: O=c1c2[nH]c(N3CCCCC3)nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
The title compound was prepared from 1,3-di-cyclopropylmethyl-8-bromo xanthine (1.2 g, 0.0037 mol) and piperidine (0.79 g, 0.009 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]2=[O:16])=[C:4]([F:17])[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[F:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[O:13])[C@H:11]([CH3:14])[C@H:10]([CH3:15])[C:9]1=[O:16]
Reactant: [H][H]
Reactant: CC1=C(C)C(=O)N(c2ccc(Cl)cc2F)C1=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: C[C@@H]1C(=O)N(c2ccc(Cl)cc2F)C(=O)[C@@H]1C
Reaction time: 5 h

Procedure:
A mixture of 7.5 g (0.03 mol) of N-(4-chloro-2-fluorophenyl)-2,3-dimethylmaleic acid imide and 400 mg of platinum oxide (PtO2) is hydrogenated with hydrogen in 75 ml of ethyl acetate at room temperature under normal pressure. After about 5 hours, the reduction is complete. The catalyst is then filtered off and the filtrate is concentrated in vacuo. 7.6 g (99% of the theoretical yield) of cis-N-(2-fluoro-4-chlorophenyl)-2,3-dimethylsuccinimide in the form of a yellowish oil which is uniform in a thin-layer chromatogram remain as residue.
Reaction SMILES: [C:1](O)(=O)[C:2]#[CH:3].[ClH:6].Cl.Br[C:9]1[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=1>C(O)CO>[Cl:6][CH:3]=[CH:2][C:1]1[NH:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][C:11]=2[N:16]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: Cl
Reactant: C#CC(=O)O
Solvent: OCCO
Product: ClC=Cc1nc2ccccc2[nH]1

Procedure:
Reaction of the propiolic acid KK2 with 4-bromobenzene-1,2-diamine dihydrochloride KK3 in refluxing ethylene glycol gives chlorovinylbenzimidazole KK4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH3:31])=[CH:25][CH:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:31])[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:12])=[CH:25][CH:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Reactant: CNCc1ccc(-c2ccc(OC)c(Br)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CN(C)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
1-methyl-1H-indole-3-carbonyl chloride (16.3 mmol), prepared in the previous step, in 50 mL of methylene chloride was added under nitrogen dropwise to a solution of N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N-methylamine (5.00 g, 16.3 mmol), prepared in step 5 of Example 6, and triethylamine (2.3 mL, 16.3 mmol) in 200 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 20 h. The reaction was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (7.4 g, 98%) as a white solid foam, MS (ESI) m/z 463 [M+H]+. Elemental Analysis for C25H23BrN2O2. Calc'd: C, 64.80; H, 5.00; N, 6.05 Found: C, 62.88; H, 4.92; N, 5.61
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH2:21]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([F:40])[C:32]=1[F:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:21]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=3)=[N:6][CH:7]=2)=[C:33]([F:40])[C:32]=1[F:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Reactant: CCCCCCCCCCc1ccc(B(O)O)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCc1ccc(-c2cnc(-c3ccc(OCCCCCC)nc3)nc2)c(F)c1F
Yield: 39.2 %

Procedure:
The reaction of 2 mmol of 5-bromo-2-(6-hexyloxypyridin-3-yl)pyrimidine, 2 mmol of 4-decyl-2,3-difluorophenylboronic acid, 4 mmol of sodium carbonate and 0.02 mmol of tetrakis(triphenylphosphine)palladium(0) in 8 ml of toluene, 3 ml of ethanol and 3 ml of water is carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using ethyl acetate as eluent and is recrystallized from acetonitrile, giving 0.4 g (39%) of colorless crystals, X 96 SA 127 I.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:21].C1COCC1.[F:30][C:31]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]2[C:32]=1[C:33](=[O:53])[C:34]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)=[CH:35][NH:36]2.[C:54]([CH:57](O)[CH2:58][NH-:59])([OH:56])=[O:55]>O>[F:30][C:31]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]2[C:32]=1[C:33](=[O:53])[C:34]([C:45]1[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=1)=[CH:35][NH:36]2.[C:54]([CH:57]([Cl:21])[CH2:58][NH-:59])([OH:56])=[O:55]
Reactant: [NH-]CC(O)C(=O)O
Reactant: ClC(Cl)(Cl)Cl
Agent: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: [NH-]CC(Cl)C(=O)O
Temperature: 25 °C

Procedure:
Triphenyl phosphine (2.47 g, 9.8 mmol) and carbon tetrachloride (1.4 g, 9.1 mmol) were added to a THF solution (30 ml) of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydro-quinoline-2-carboxy-(2-hydroxyethyl)amide (3.0 g, 7.24 mmol) and heated under reflux for 2 hours. The mixture was cooled to room temperature, and water was then added thereto, followed by extraction with dichloromethane. The thus-obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=100:0→20:1). The purified material was concentrated to dryness under reduced pressure, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide (1.8 g, yield: 58%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[CH2:11][C:12]([CH3:17])(C)[C:13]([OH:15])=[O:14].F[C:19](F)(F)[C:20](O)=O.N[C@@H]1CCC[C@@H]1C(OCC)=O>>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[C@@H:11]1[CH2:20][CH2:19][CH2:17][C@@H:12]1[C:13]([OH:15])=[O:14]
Reactant: CC(C)(CN1C[C@@H]2CNCCN2C1=O)C(=O)O
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=O)[C@H]1CCC[C@H]1N
Product: O=C(O)[C@H]1CCC[C@H]1N1C[C@@H]2CNCCN2C1=O

Procedure:
Compound 50-A was prepared in analogy to compound Q in Example 19 by using ethyl (1S,2R)-2-aminocyclopentanecarboxylate trifluoroacetic acid salt (compound 50-B) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
Reaction SMILES: [CH3:1][S:2]S(C)(=O)=O.[N+](C1C=CC=CC=1)([O-])=O.[S:16]1[CH:20]=[CH:19][N:18]2[CH:21]=[N:22][CH:23]=[C:17]12.Cl>Cl[Ti](Cl)Cl.ClCCl>[CH3:1][S:2][C:23]1[N:22]=[CH:21][N:18]2[CH:19]=[CH:20][S:16][C:17]=12
Reactant: c1cn2cncc2s1
Reactant: CSS(C)(=O)=O
Agent: Cl[Ti](Cl)Cl
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: CSc1ncn2ccsc12
Reaction time: 0.33 h

Procedure:
To 200 ml of dichloromethane cooled at 0° C., 35 ml of trichlorotitanium and 40 g of methyl methanethiolsulfonate were added and the mixture was stirred at the same temperature for 20 min. The mixture was added dropwise to 1 L of nitrobenzene containing 26 g of imidazo[5,1-b]thiazole at 5 to 10° C. and stirred at the same temperature for five hr. The reaction was stopped by adding 400 ml of 0.5N hydrochloride, followed by filtration to remove insolubles. The mixture was washed with 200 ml of dichloromethane and 200 ml of water. The organic layer was removed and the aqueous layer was washed with 800 ml of dichloromethane twice. After the pH of the aqueous layer was adjusted to 4.0, the extraction three times with dichloromethane. The organic layer was dried and the solvent was removed to give 19.8 g of 7-Methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[S:31]1[CH:35]=[C:34]([C:36]([NH:38][NH2:39])=O)[N:33]=[N:32]1>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:36]([C:34]3[N:33]=[N:32][S:31][CH:35]=3)=[N:38][N:39]=[C:26]2[CH2:25]1)=[O:23]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1csnn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2csnn2)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Triethyloxonium tetrafluoroborate (363 mg, 1.908 mmol) was added to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(505 mg, 1.735 mmol) in dry dichloromethane (DCM) (4.2 ml). The reaction mixture was stirred at room temperature 45 mins—until everything was dissolved. 1,2,3-Thiadiazole-4-carbohydrazide (300 mg, 2.082 mmol, commercially available from e.g. Apollo) was added and the resulting mixture was stirred at room temperature for 3 h. DCM was evaporated and the residue was dissolved into 1-butanol (4.2 ml). The reaction mixture was stirred at reflux for 19 h. The mixture was washed with ethyl acetate and washed with water (2×25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and dried under reduced pressure. The crude product was purified by flash chromatography (DCM−10% MeOH in DCM). The residue was triturated with Et2O and then dried under vacuum at 50° C. for 2 days. The resulting solid was triturated with n-hexane and dried at 50° C. under vacuum 20 h to afford the desired product in 4.71 mg, as a white solid.