Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.CCO.C(O)(C(F)(F)F)=O.C(O)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Solvent: CCCO
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 1.20 g, 2.39 mmol) in 10 mL of DCM (CH2Cl2) was added 0.30 mL of EtOH followed by 5.0 mL of TFA. After stirring at RT for 3 h, the mixture was treated with 20 mL of n-propanol and concentrated in vacuo. The residue was triturated with DCM to afford 853 mg (96%) of the title compound as a white solid. 1H-NMR (DMSO-d6; 400 MHz): δ 9.80 (s, 1H), 8.30 (s, 1H), 7.94 (d, 1H, J=8.6 Hz), 7.50 (dd, 1H, J=8.6, 2.3 Hz), 7.39 (d, 1H, J=2.3 Hz), 5.80 (m, 1H), 2.12-2.25 (m, 4H), 1.61-1.77 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C17H15BrN4O, 371.0 (M+H). found 371.0.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:29][S:28](=[O:31])(=[O:30])[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:11]=3[N:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:32]([N:35]=[N+:36]=[N-])(=O)[CH3:33].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:33][C:32]1[NH:35][N:36]=[C:17]([C:16]2[CH:15]=[C:14]([N:12]3[C:11]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=5[S:28](=[O:30])(=[O:31])[CH2:29][C:10]=4[C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[N:13]3)[CH:21]=[CH:20][CH:19]=2)[N:18]=1
Reactant: CC(=O)N=[N+]=[N-]
Reactant: N#Cc1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cccc(-n3nc(C(=O)N4CCOCC4)c4c3-c3ccccc3S(=O)(=O)C4)c2)n[nH]1
Temperature: 110 °C

Procedure:
To a solution of 3-[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]benzonitrile (100 mg, 0.23 mmol) in dry toluene is added acetic azide (34 mg, 0.46 mmol) and K2CO3 (158 mg, 0.115 mmol) under nitrogen. The reaction mixture is heated to 110° C. for 12 h under nitrogen after which it is concentrated under vacuum. The solid residue is purified by Preparative HPLC to afford the title compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.21-8.19 (d, J=7.7 Hz, 1H), 8.03-7.98 (m, 2H), 7.73-7.69 (m, 1H), 7.64-7.56 (m, 3H), 6.92-6.90 (d, J=7.8 Hz, 1H), 4.91 (s, 2H), 3.93 (m, 2H),3.75-3.67 (m, 4H), 3.62-3.61 (m, 2H), 2.37 (s, 3H). MS (ESI+): 491.0. HPLC (max plot) 98.76%; Rt 2.96 min.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.Br[CH:17]([CH3:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C1(OC)C=CC=CC=1>CC(C)=O>[Cl:15][C:14]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]3[C:7]([CH3:9])=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=[C:26]3[N:6]([CH:10]([CH3:11])[CH3:12])[C:5]=2[CH:13]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Cc1nc2cc(Cl)c(Cl)cc2n1C(C)C
Solvent: CC(C)=O
Solvent: COc1ccccc1
Product: Cc1c(-c2ccccc2)cc2n(C(C)C)c3cc(Cl)c(Cl)cc3n12

Procedure:
To 2.57 g of 5,6-dichloro-1-isopropyl-2-methylbenzimidazole were added 1.52 ml of α-bromopropiophenone and 1 ml of anisole, and the mixture was heated for 2 hours on a steam bath. Then, to the mixture was added 50 ml of acetone. A produced crystals were separated from the mixture through filtration, then to the crystals were added 40 ml of 2% aqueous solution of sodium carbonate, and the resulting mixture was heated for 80 minutes on a steam bath. After the mixture was allowed to stand for cooling, produced crystals were separated from through filtration. The crystals were then washed with water to obtain 6,7-dichloro-4-isopropyl-1-methyl-2-phenylpyrrolo[1,2-a]benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[O-]CC.[Na+].[C:29](#[N:32])[CH:30]=[CH2:31]>C(O)C>[C:29]([CH2:30][CH2:31][O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:32]
Reactant: C=CC#N
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)c1c(C=NOCCC#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
In a manner similar to that employed in Example 12 an ethanol solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime was reacted with sodium ethoxide and acrylonitrile to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(2-cyanoethyl)oxime. Compound 28, as the 85 percent (by weight) component of a mixture containing 8 percent of the oxime starting material. Mass spectrometric analysis of the product indicated the following: MS m/e=453 (M+).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:29][CH:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH:30]([S:32]([NH:35][C:24]([C:23]1[CH:22]=[CH:21][C:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])=[CH:28][CH:27]=1)=[O:26])(=[O:34])=[O:33])([CH3:31])[CH3:29]
Reactant: CC(C)S(N)(=O)=O
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (198 mg) was added to a stirred mixture of 4-(t-butoxycarbonyl)benzoic acid (195 mg), 2-propanesulfonamide (98 mg) and 4-dimethylaminopyridine (126 mg) in dichloromethane (3.7 ml). The mixture was stirred overnight, diluted with ethyl acetate, washed (1N HCl, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography, eluting with acetone:hexanes (75:25), to afford the product (193 mg): TLC, Rf =0.64, acetone:hexanes (75:25): MS, m/e=356(M+29), 330(M+3), 329(M+2), 328(M+1), 272, 223, 222, 205, 204, 166.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][N:2]1C(OC(C)(C)C)=O.[Cl:17][C:18]1[C:23](N2CCNCC2)=[CH:22][C:21]([C:30]#[N:31])=[CH:20][C:19]=1[NH:32][C:33]1[N:38]=[C:37]([N:39]([CH:49]2[CH2:51][CH2:50]2)CC2C=CC(OC)=CC=2)[C:36]2=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:35]2[N:34]=1>>[Cl:17][C:18]1[C:23]([N:7]2[CH2:6][CH2:5][C:4]3([CH2:1][NH:2][CH2:3]3)[CH2:9][CH2:8]2)=[CH:22][C:21]([C:30]#[N:31])=[CH:20][C:19]=1[NH:32][C:33]1[N:38]=[C:37]([NH:39][CH:49]2[CH2:51][CH2:50]2)[C:36]2=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:35]2[N:34]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC3(CC2)CNC3)c1

Procedure:
The title compound was prepared from tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate using a method to prepare Intermediate 11 and method analogous to that used to prepare Example 1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]2[CH2:17][O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CO.C(OC)=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]([OH:16])[CH2:17][N:18]=[N+:19]=[N-:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCCCCOCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC=O
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCC(O)COCCCCCCc1ccccc1
Yield: 95 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 4 g of 6-phenylhexyloxymethyloxirane (prepared as described in Preparation 61), 5.5 g of sodium azide, 100 ml of an 8:1 by volume mixture of methanol and water and 25 ml of methyl formate were used, to give 4.5 g of the title compound as a pale yellow oil having an Rf value of 0.39 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH:28]=[CH:29][C:30]#[N:31])[C:16]=3[N:15]=2)[C:5]1=[O:32])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH2:28][CH2:29][C:30]#[N:31])[C:16]=3[N:15]=2)[C:5]1=[O:32])([CH3:2])[CH3:3]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(C=CC#N)cccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CCC#N)cccc21
Yield: 73.6 %

Procedure:
A mixture of 3-[2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-acrylonitrile (100 mg, 0.234 mmol) and 10% Pd-C (10 mg) in THF (2 mL) and methanol (25 mL) was rocked in a Parr shaker under a hydrogen atmosphere (50 psi) for 15 hrs. The catalyst was removed by filtration and the filtrate purified by flash chromatography (eluent hexane:ethyl acetate 1:1) to afford 3-[2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-propionitrile (74 mg, 74%) as a white solid:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]([C:29]([NH2:31])=[O:30])=[N:19][N:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:14]=3[C:13]2=[O:32])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].Cl.Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40].CC(C)([O-])C.[K+]>C(O)C.[Pd].C1COCC1>[CH3:4][C:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]([C:29]([NH2:31])=[O:30])=[N:19][N:20]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[C:14]=3[C:13]2=[O:32])=[CH:10][CH:11]=1)([CH3:5])[CH2:1][N:2]1[CH2:35][CH2:36][CH2:37][CH2:38][C:39]1=[O:40]
Reactant: O=C(Cl)CCCCBr
Reactant: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(C(C)(C)C#N)cc2)CC3)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(C(C)(C)CN4CCCCC4=O)cc2)CC3)cc1
Reaction time: 1 h

Procedure:
To 6-[4-(1-cyano-1-methylethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (0.17 g, 0.39 mmol) was hydrogenated at 40 psi in ethanol with 0.5 mL conc. HCl and 10% palladium on carbon (25 mg) for 72 h. The reaction was filtered and concentrated. To the amine in THF (5 mL) at 0° C. was added 5-bromovaleryl chloride (99 mg, 0.5 mmol) and TEA (1 mL) and the reaction was stirred 1 h. To the reaction was added potassium t-butoxide (0.24 g, 1.9 mmol) and the reaction was stirred 24 h. The reaction was quenched with water and extracted with ethyl acetate and dried (MgSO4). Purification by HPLC and freeze-drying afforded 15 mg (7.5%). Mass Spec (M+H)+ 516.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: NC1CCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNC2CCCC2)c1
Yield: 42.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-((cyclopentylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), cyclopentanamine (0.043 g; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.024 g (42%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.Cl[CH2:18]Cl.CO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][CH3:18])=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: ClCCl
Reactant: COc1cc(F)ccc1-c1cnncc1N
Solvent: CO
Product: CNc1cnncc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 1, intermediate a, from 5-(4-fluoro-2-methoxy-phenyl)-pyridazin-4-ylamine and using a gradient of dichloromethane:methanol (100:0 to 90:10) for the chromatographic purification. Brown oil (5%). MS (ESI+): m/z=234.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH:14]=[CH:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1cnc2ccccc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
The 3-bromoquinoline (300 g, 1.44 mmol), ethyl acrylate (168 g, 1.68 mmol), palladium(II) acetate (32.3 g, 144 mmol), tetrabutylammonium bromide (478 g 1.44 mol), and sodium bicarbonate (483.9 g, 5.76 mol) were combined in a 5-L round-bottom flask with overhead stirring and 3 L dimethyl formamide (anhydrous). The reaction mixture was heated to 90° C. with heating mantle. After 30 minutes, 3-bromoquinoline was not detected by HPLC. The reaction was cooled to room temperature with an ice bath, and 2.65 L of ethyl acetate was added. The organic layer was washed with 1500 mL H2O. The aqueous layer was extracted with 4×1 L of 1:1 toluene/ethyl acetate; the combined organic layers were then washed with 6×1 L brine, then evaporated to give 217.4 g (65% of desired product).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][CH:11]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:12]([O:14]CC1C=CC=CC=1)=[O:13]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH:11]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:12]([OH:14])=[O:13]
Reactant: Nc1ccccc1C=CCC(C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: Nc1ccccc1CCCC(C(=O)O)N1C(=O)c2ccccc2C1=O

Procedure:
A solution of benzyl 5-(2-aminophenyl)-2-phthalimido-4-pentenoate (10.7 g) in ethanol (500 ml) is hydrogenated at atmospheric pressure with 10-palladium on charcoal (2 g) until uptake ceases. The catalyst is filtered off and the filtrate evaporated under reduced pressure. The residue is triturated with ethyl acetate to give 5-(2-aminophenyl)-2-phthalimidopentanoic acid, mp 258°-260° C., used without further purification in the next synthetic step.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][OH:30]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH2:29][OH:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCBr
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (100 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and 3-bromo-1-propanol (0.1 ml, 1 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (149 mg, yield 62%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl.Cl[C:6]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[O:24])[CH:12]=2)[N:7]=1>CO>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[C:6]([O:2][CH3:1])[CH:15]=[C:14]3[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: C[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 80 °C
Yield: 62 %

Procedure:
NaOMe, 30% methanol (300 ml) was added to a mixture of intermediate (55) (0.127 mol) in methanol (285 ml) and the mixture was stirred at 80° C. for one night. The precipitate was filtered off, washed with ethanol and dried. The product (44.8 g, 87%) was taken up in DCM and the layers were separated. The organic layer was dried (MgSO4), filtered off and evaporated till dryness, yielding 32.3 g (62%) of (4-chlorophenyl)[4-(3-chlorophenyl)-2-methoxy-6-quinolinyl]-methanone (intermediate 56).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[OH:22])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[CH3:23][SH:24]>O1CCCC1>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:2]1([S:24][CH3:23])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: COc1ccc(O)c(C2(Cl)Sc3ccccc3N(C)C2=O)c1
Reactant: CS
Solvent: C1CCOC1
Product: COc1ccc(O)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
2-Chloro-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (12.3 g, compound No. 3) is added to a mixture of 30% aqueous methyl mercaptan solution (26 ml) and tetrahydrofuran (50 ml). The mixture is stirred for 1.5 hours at room temperature and concentrated in vacuo. The separated crystals are collected by filtration to give 10.0 g (78.3%) of the titled compound.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C[Si](C)(C)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[O:15])=[CH:10][CH:9]=1>C1COCC1.C1(C)C=CC=CC=1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=2)([OH:15])[CH:1]=[CH2:2])=[CH:17][CH:18]=1
Reactant: C=C[Mg]Cl
Reactant: C[Si](C)(C)Oc1ccc(C(=O)c2ccc(Br)cc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Eb) 30.2 ml of 15% vinylmagnesium chloride solution in THF are added dropwise at 0° C. to a solution of 5.58 g of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone in 80 ml of toluene. The mixture is stirred at 0° C. for 2 h., then at room temperature for 2 h., subsequently hydrolyzed with 40 ml of ammonium chloride solution and extracted with methylene chloride. The extracts are dried, evaporated and purified over silica gel with toluene-acetone as the eluent. There are obtained 2.8 g of (RS)-4-[1-(4-bromophenyl)-1-hydroxy-allyl]-phenol, MS: m/e 304 (M+H+, 1Br).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:24])([CH3:23])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[OH:22])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:24])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[O:22][S:33]([CH3:32])(=[O:35])=[O:34])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCC1C(O)CC1CO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
2-(2-((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl)-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)cyclobutanol (160 mg, 0.43 mmol) from Step B was dissolved in 2 mL of methylene chloride and the resultant solution was cooled to 0° C. Triethylamine (120μL) was added, followed by 36 μL of methanesulfonyl chloride. After stirring the reaction mixture for 30 min at 0° C., it was concentrated in vacuo and the residue was purified on a silica gel column eluted with 10% ethyl acetate in hexane to give 180 mg (89% yield) of the title compound.; MS DCI-NH3M/Z: 447 (M+H)+, 464 (M+NH4)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH:22]([CH3:24])[CH3:23])[CH2:8][C@H:9]([OH:21])[C@@H:10]([N:18]=[N+]=[N-])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH:22]([CH3:24])[CH3:23])[CH2:8][C@H:9]([OH:21])[C@@H:10]([NH2:18])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)N=[N+]=[N-])C(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C

Procedure:
21.3 g (0.06 mol) of 5(S)-azido-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoic acid n-butylamide in 240 ml of methanol are hydrogenated for 2 hours in the presence of 5 g of 10% palladium-on-carbon. The reaction mixture is filtered, concentrated in a rotary evaporator, and the residue is recrystallised from hexane: m.p. 88.5°-90°; [α]D -27.2°±0.9° (c=1.1, CHCl3).
Reaction SMILES: C([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:11]([C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[CH3:25]O>[Pd]>[CH3:25][O:23][C:21]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH:12]1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:22]
Reactant: CO
Reactant: O=C(O)C1=C(c2ccc(F)cc2)CN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Product: COC(=O)C1CCNCC1c1ccc(F)cc1
Yield: 94 %

Procedure:
A mixture of 3.6 g (1.03 mmol) 1-Benzyl-5-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid (Bioorganic & Medicinal Chemistry Letters 2003, 2513-2518); hydrochloride, 16.6 mL HCl in methanol (1.25 N) in 250 mL methanol was stirred at room temperature over night. Further 16.6 mL HCl in methanol (1.25 N) was added and the mixture was stirred at 70° C. and subsequently hydrogenated with H2 over 360 mg Pd/C (10%) for 44 h at room temperature. The mixture was filtered off and evaporated to dryness to yield 2.3 g (94%) of the title compound as colorless oil. MS (m/e): 238.1 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([NH2:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Br:14])[CH3:2].[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Br:14])[NH:15][C:20](=[O:21])[CH2:19][C:18](=[O:22])[CH3:17])[CH3:2]
Reactant: CCOC(=O)C[C@@H](N)c1ccc(F)cc1Br
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](NC(=O)CC(C)=O)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A 500 mL round-bottom flask charged with 31D (13.3 g, 41 mmol) in 200 mL of DCM and TEA (22.8 mL, 3 equiv.) was added diketene (31E, 8.81 mL, 50% in DCM). The reaction was stirred at ambient temperature until completion (2 h, determined by LCMS). The reaction mixture was washed with 1 N NaHSO4, brine, dried over Na2SO4 and concentrated in vacuo to afford Compound 31F as a yellow solid (15.3 g, 99%). ESI-MS: m/z 374.0 (MH+).