Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(N(CC)CC)C.N1CCOCC1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:11]=[C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[NH:13]2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cc1nc2ccccc2[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Product: O=C(C=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 25 °C

Procedure:
3-Fluorobenzoyl chloride was added to a mixture of 2-methylbenzimidazole, triethylamine and dioxane, followed by heating under reflux for 3 hours and cooling to room temperature. Morpholine was added, followed by stirring under heat at 70° C. for 1 hour and work-up to obtain 1-(3-fluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone.
Reaction SMILES: [N:1]1([C:7]2C=CC(NC(C3C(C4C=CC(C(F)(F)F)=CC=4)=CC=CC=3)=O)=CC=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32]([O-:35])([O-])=[O:33].[Na+].[Na+].BrC(C1C=CC=CC=1)C(OC)=O>CN(C=O)C>[N:1]1([CH2:7][C:32]([OH:35])=[O:33])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: COC(=O)C(Br)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CN1CCNCC1

Procedure:
A mixture of intermediate (2) (0.019 mol) and Na2CO3 (0.019 mol) in DMF (125 ml) was stirred. Methyl 2-bromo-2-phenylacetate (0.019 mol) was added dropwise. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated. The residue was stirred in DCM and washed with water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was stirred in DIPE. The precipitate was filtered off, dried and separated by high performance liquid chromatography over Chiralcel OD (eluent:hexane/EtOH 70/30) in its enantiomers. The desired fractions were collected and the solvent was evaporated, yielding 1-piperazineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1A)-(intermediate 33) after crystallisation from 2-propanol, and 1-piperazineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1B)-(intermediate 34) after crystallisation from 2-propanol.
Reaction SMILES: BrC1C=CC(N(C)C(N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)=O)=CC=1.C(N1CCNCC1)(OC(C)(C)C)=O.[CH3:65][N:66]([C:109]1[CH:114]=[CH:113][C:112]([N:115]2[CH2:120][CH2:119][NH:118][CH2:117][CH2:116]2)=[CH:111][CH:110]=1)[C:67]([N:69]1[C:73]2[N:74]=[C:75]([N:103]3[CH2:108][CH2:107][O:106][CH2:105][CH2:104]3)[N:76]=[C:77]([C:78]3[CH:79]=[N:80][C:81]([N:84](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:82][CH:83]=3)[C:72]=2[CH2:71][CH2:70]1)=[O:68]>>[CH3:65][N:66]([C:109]1[CH:110]=[CH:111][C:112]([N:115]2[CH2:116][CH2:117][NH:118][CH2:119][CH2:120]2)=[CH:113][CH:114]=1)[C:67]([N:69]1[C:73]2[N:74]=[C:75]([N:103]3[CH2:108][CH2:107][O:106][CH2:105][CH2:104]3)[N:76]=[C:77]([C:78]3[CH:79]=[N:80][C:81]([NH2:84])=[N:82][CH:83]=3)[C:72]=2[CH2:71][CH2:70]1)=[O:68]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3ccc(N4CCNCC4)cc3)cn2)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3ccc(Br)cc3)cn2)cc1
Product: CN(C(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21)c1ccc(N2CCNCC2)cc1
Yield: 67 %

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (4-bromo-phenyl)-methyl-amide (121 mg) obtained in Step B in Example 1-D-160 instead of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide, and N-Boc-piperazine (60 mg) instead of 2-piperazin-1-yl-ethanol, in the same manner as Step C in Example 1-D-153, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid methyl-(4-piperazin-1-yl-phenyl)-amide was obtained. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-161) as a yellow solid (56.1 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.C(N([CH2:27][CH3:28])CC)C.[O:29]=[C:30](Cl)[O:31]C(Cl)(Cl)Cl.C(O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([C:30]([O:31][CH2:27][CH3:28])=[O:29])[N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2c(-c3ccccc3)cn3c2CCC3)cc1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2n1CCC2
Reaction time: 12 h

Procedure:
7-(4-Chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (Example 21 b, 1.5 g, 5.1 mmol), dissolved in THF (10 ml), is treated with triethylamine (0.7 ml, 0.51 g, 5 mmol). A solution of diphosgene (0.5 g, 2.5 mmol), dissolved in THF (5 ml), is added dropwise to this solution at RT, it is stirred for 12 h, ethanol (abs., 3 ml, 2.37 g, 51 mmol) and triethylamine (0.7 ml, 0.51 g, 5 mmol) are added, and the mixture is stirred at RT for a further 72 h. The reaction mixture is concentrated in vacuo, and the residue is crystallized from EtOH and dried.
Reaction SMILES: [Cl:1][CH2:2][CH3:3].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[Cl-:1].[CH2:9]([N+:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1)[CH3:8]
Reactant: CCCl
Reactant: c1ccncc1
Product: CC[n+]1ccccc1
Product: [Cl-]
Yield: 83.4 %

Procedure:
Liquified chloroethane was mixed with 10% excess chilled pyridine, sealed in the Parr pressure reaction apparatus and heated for 3 hrs. at 120° C. The resulting white, extremely hygroscopic crystals were washed three times with anhydrous ether and dried. This procedure gave a 83.4% yield of crystals, mp 116°-118° C., (lit, mp 118°-120° C.). NMR, δ1.75 (t, 3 protons), δ5.18 (q, 2 protons), δ8.20 (t, 2 protons), δ8.60 (t, 1 proton), δ9.90 (d, 2 protons).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH3:13])[N:7]=1)=[O:5].[CH3:15][Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH3:13])[N:7]=1)(=[O:5])[CH3:15]
Reactant: C[Mg]Br
Reactant: CCc1cc(C(=O)N(C)OC)nn1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C(C)=O)nn1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
N-Methoxy-N-methyl-5-ethyl-1-methylpyrazole-3-carboxamide (2.9 g) in dry tetrahydrofuran (100 ml), under argon was cooled to -20 ° C. and treated with methylmagnesium bromide (9.8 ml of a 3M solution in ether). A precipitate was initially formed that re-dissolved on complete addition. The reaction mixture was stirred at 0° C. for 2 h. and then poured into saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate and the combined organic phases washed with brine, dried over anhydrous magnesium sulphate and concentrated to a brown oil. The crude product was purified by silica gel chromatography eluting with 50% ethyl acetate/hexane to give the title compound as a pale brown oil, (1.97 g, 88%); (Found: M+, 152.0950. C8H12N2O requires M 152.0950); nmax (CH2Cl2) 1693. 1472, 1376 and 1352 cm-1 ; dH (CDCl3) 1.28 (3H, t, J7.4 Hz), 2.54 (3H, s), 2.61 (2H, q, J7.4 Hz), 3.84 (3H, s) and 6.56 (1H, s).
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].C[N:13]1[C:17](=O)[CH2:16][CH2:15][CH2:14]1.[C:19]1([C:31](Cl)=[O:32])[CH:24]=[C:23]([C:25](Cl)=[O:26])[CH:22]=[C:21]([C:28](Cl)=[O:29])[CH:20]=1>N1C=CC=CC=1>[CH:1]1([NH:9][C:31]([C:19]2[CH:24]=[C:23]([C:25]([NH:9][CH:1]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:26])[CH:22]=[C:21]([C:28]([NH:13][CH:17]3[CH2:16][CH2:15][CH2:14][CH2:3][CH2:2][CH2:1][CH2:8]3)=[O:29])[CH:20]=2)=[O:32])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCCC1=O
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Reactant: NC1CCCCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(NC1CCCCCCC1)c1cc(C(=O)NC2CCCCCCC2)cc(C(=O)NC2CCCCCCC2)c1
Temperature: 5 °C

Procedure:
4.20 g (33 mmol) of cyclooctylamine and 0.1 g of dry LiCl are added under inert atmosphere to 70 ml of dry NMP and 15 ml of dry pyridine and cooled to 5° C. Then, 2.39 g (9 mmol) of 1,3,5-benzenetricarboxylic acid trichloride are added. The reaction mixture is heated to 75° C. and stirred. After 2 hours the reaction mixture is added to 300 ml of ice water. Customary work-up (recrystallization from N,N-dimethylformamide) gives 1,3,5-benzenetricarboxylic acid tris(cyclooctylamide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]Br)=[CH:5][CH:4]=1.[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH2:14][C:13]([NH:12][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([CH3:30])[CH3:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(N)COC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCNC(C)(C)COC(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared as described in Example 1 using 4-methoxyphenethyl bromide and 2-amino-1-diphenylmethoxy-2-methylpropane (see Preparation 1). The title compound was obtained as a colourless oil (378 mg, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([F:15])[CH2:12][N:11]([C:16](OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC1[CH:41]=[CH:40][N:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43]>[Pd].CO>[F:15][C@H:13]1[CH2:12][N:11]([C:16]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[N+:42]([O-:44])=[O:43])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-fluoropiperidine-1-carboxylate (1 eq) in 28 methanol was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 1 hours. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 33 mL of isopropanol and DIPEA (2.5 eq) and 4-chloro-3-nitropyridine (1.5 eq) were added. The reaction mixture was stirred at 80° C. for 2 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 150 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (5% methanol in EtOAc:hexanes=1:1) to yield tert-butyl(3S,5R)-5-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (90%). LC/MS (m/z): 341.1 (MH+). HPLC: Rt: 2.12 min.
Reaction SMILES: [CH2:1]([NH:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)Cl>[CH2:13]([O:12][N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:22]([NH:21][CH3:20])=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCNOCc1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CCCCCCCCCCN(OCc1ccccc1)C(=O)NC
Reaction time: 2 h
Yield: 83 %

Procedure:
Purification by chromatography on silica gave t-butyl N-benzyloxy-N-decylcarbamate as a colorless oil (8.39 g, 79% yield). To a solution of this urethane (7.0 g) in methylene chloride (15 ml) at room temperature under nitrogen was added trifluoroacetic acid (15 ml). After 30 minutes, the solution was evaporated at 40° C. lN NaHCO3 was added and solid Na2CO3 was added to bring the pH to 9. The mixture was extracted twice with methylene chloride, and the combined extracts were dried (MgSO4), filtered, and evaporated to give decyl-N-benzyloxyamine as a colorless oil (5.0g g, 100% yield). To a stirred solution of this amine (4.92 g, 18.8 mmol) in methylene chloride (30 ml) at room temperature under nitrogen was added methyl isocyanate (1.2 ml). After two hours, the reaction mixture was evaporated and triturated with cold pentane to give N-benzyloxy-N-decyl-N'-methylurea as a white solid (4.98 g, 83% yield). This urea (745 mg) was dissolved in ethanol (10 ml) under nitrogen at room temperature, and ammonium formate (0.8 g) was added. After 20 minutes, 10% palladium on carbon (0.25 g) was added. After stirring for two hours, the reaction mixture was filtered through celite and evaporated. Water was added, and the resulting solid was collected by filtration. Recrystallization from isopropanol gave the title compound as a white solid (420 mg, mp 96°-97° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:21][CH:22]=1)[CH2:12][CH2:13][CH3:14]
Reactant: C#Cc1ccc(N)nc1N
Reactant: CCCCOCc1ccc(CC(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOCc1ccc(Cc2cc(-c3ccc(N)nc3N)on2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.3 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (14.6 mg, 0.11 mmol) described in Manufacturing Example 13-1-3 and 4-butoxymethyl-phenyl-acetohydroximoyl chloride (28 mg, 0.11 mmol) described in Manufacturing Example 4-1-4 in tetrahydrofuran was added triethylamine (31 μL, 0.22 mmol), which was stirred for 4 hours at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) and then purified again by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (6.7 mg, 13%) as a trifluoroacetic acid salt.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11]>C(NC(C)C)(C)C.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.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: COc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: COc1cncc(C#Cc2ccc(F)cc2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 59.2 %

Procedure:
Dissolve 3-bromo-5-methoxypyridine (1.0 g, 5.35 mmol) in diisopropylamine (17 mL) and toluene (10 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium (0.200 g, 0.16 mmol). Heat at 60° C. and add 1-ethynyl-4-fluorobenzene (642 mg, 5.35 mmol) and copper (I) iodide (20 mg, 0.11 mmol). After 20 h, concentrate, and purify using silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes, to give the title compound (720 mg, 60%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[CH3:29][C:30]1[CH:34]=[CH:33][S:32][C:31]=1[CH2:35][NH2:36].C1COCC1.C(Cl)(Cl)Cl.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[Br:24][C:22]1[CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH2:7])=[NH:9])[S:11][C:12]=2[S:26][CH3:27])(=[O:16])=[O:17])[CH:19]=[N:20][C:21]=1[NH:36][CH2:35][C:31]1[S:32][CH:33]=[CH:34][C:30]=1[CH3:29]
Reactant: Cc1ccsc1CN
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cnc(NCc2sccc2C)c(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 3-methylthiophene-2-methylamine (0.016 g, 0.133 mmol), THF [2 mL]. The reaction vessel was sealed and heated to 70° C. for 18 hours, cooled to room temperature and concentrated in vacuo. Chromatography of crude material (10%–25% EtOAC/Hx) yielded the intermediate which was dissolved in a solution of chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound. ESI-MS (m/z): Calcd. for C18H18BrN3O2S4: 517.52 (M+H); found 516.9, 518.9.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:25]([O:16][C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[C:3](=[CH:4][C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=3)[C:2]([F:1])=[CH:15][C:14]=2[CH:13]=1)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(O)ccc12
Product: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(OC(=O)CCCCC)ccc12

Procedure:
From 9-fluoro-7-octylphenanthren-2-ol by reaction with hexanoyl chloride.
Reaction SMILES: C(N)(=O)C1C(=CC=CC=1)C(N)=O.[CH2:13]([N:20]1[C:25](=[O:26])[C:24]2[CH:27]=[N:28][CH:29]=[CH:30][C:23]=2[N:22]=[C:21]1[CH:31]([N:35]([CH2:45][CH2:46][CH2:47][N:48]1C(=O)C2C(=CC=CC=2)C1=O)[C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)[CH:32]([CH3:34])[CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.NN>CCO>[NH2:48][CH2:47][CH2:46][CH2:45][N:35]([C@@H:31]([C:21]1[N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:25](=[O:26])[C:24]2[CH:27]=[N:28][CH:29]=[CH:30][C:23]=2[N:22]=1)[CH:32]([CH3:34])[CH3:33])[C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1.[NH2:48][CH2:47][CH2:46][CH2:45][N:35]([CH:31]([C:21]1[N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:25](=[O:26])[C:24]2[CH:27]=[N:28][CH:29]=[CH:30][C:23]=2[N:22]=1)[CH:32]([CH3:34])[CH3:33])[C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1
Reactant: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3ccncc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NC(=O)c1ccccc1C(N)=O
Agent: NN
Solvent: CCO
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ccncc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Product: Cc1ccc(C(=O)N(CCCN)[C@@H](c2nc3ccncc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 5 °C

Procedure:
Alternative Preparation of Formula I where R1, R3 and R4 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; R7 is 3-Amino-propy; R8 is —C(O)—R9 where R9 is p-Methyl-phenyl-; W, Y and Z are —C═; and X is —N═: A phthalamide-protected precursor to Formula I, N-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[4,3-d]pyrimidin-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide (300 mg, 0.488 mmol) and anhydrous hydrazine (98 mg, 3.06 mmol) in EtOH (12 mL) is refluxed for 3.0 h. The reaction is cooled to 5° C. and a precipitate is filtered off. The filtrate is concentrated in vacuo and purified by flash chromatography (silica gel, 90:9:1 methylene chloride:methanol:ammonium hydroxide as eluent) to provide the title compound, N-(3-amino-propyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[4,3-d]pyrimidin-2-yl)-2-methyl-propyl]-4-methyl-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH:10]1[O:12][CH2:11]1.[NH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1>C(O)(C)C>[C:21]([C:20]1[CH:24]=[CH:25][C:17]([O:16][CH2:15][CH2:14][NH:13][CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:18][CH:19]=1)(=[O:22])[NH2:23]
Reactant: NCCOc1ccc(C(N)=O)cn1
Reactant: Clc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: NC(=O)c1ccc(OCCNCC(O)COc2ccccc2Cl)nc1

Procedure:
9.2 g of 3-(2-chloro-phenyloxy)-1,2-epoxy-propane are added to a solution of 9.0 g of 6-(2-aminoethoxy)-nicotinic acid amide in 200 ml of isopropanol and the mixture is heated under reflux for 4 hours. After evaporating off the solvent under reduced pressure, 1-[2-(5-carbamoyl-2-pyridyloxy)-ethyl-amino]-3-(2-chloro-phenoxy)-2-propanol is obtained; its hydrochloride melts at 202°-204° C. after recrystallisation from methanol.
Reaction SMILES: C([CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18]2[S:19][CH:20]=[C:21]([S:23]([CH3:25])=[O:24])[N:22]=2)[C:10]1=[O:26])[C:6]([O-:8])=[O:7])(C)(C)C.C(Cl)Cl>C(C(O)=O)(F)(F)F>[CH3:25][S:23]([C:21]1[N:22]=[C:18]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH2:5][C:6]([OH:8])=[O:7])[C:10]2=[O:26])[S:19][CH:20]=1)=[O:24]
Reactant: CS(=O)c1csc(-n2c(=O)n(C(C(=O)[O-])C(C)(C)C)c3ccccc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1

Procedure:
(±)-tert-Butyl {3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step D (100 mg, 0.254 mmol) was dissolved in CF3CO2H (3 mL) and CH2Cl2 (3 mL) and the mixture was stirred at ambient temperature for 3 h, then concentrated in vacuo to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: [CH:1]1([CH2:18]C2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:2]1.O.[C-]#[N:32].[Na+].C[N:35]([CH:37]=O)C>>[CH:1]1([CH2:18][C:37]#[N:35])[CH2:5][CH2:4][CH:3]([CH2:6][C:7]#[N:32])[CH2:2]1
Reactant: [C-]#N
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC2CCC(Cc3cc(C)ccc3S(=O)(=O)[O-])C2)c1
Agent: [Na+]
Solvent: O
Product: N#CCC1CCC(CC#N)C1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
Cyclopentane-1,3-diylbis(methylene)bis(4-methylbenzenesulfonate) 1-21 (1 equivalent) was taken in DMF:H2O mixture (3:1) and sodium cyanide (6 equivalents) was added and stirred at 150° C. for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was quenched with water, extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified to afford the desired product I-22.