Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>CN(C)C=O.C(C(C)=O)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[C:29]1([CH2:35][C:36]([O:26][CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:25])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: O=C(Cc1ccccc1)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (7 g) in anhydrous dimethylformamide (75 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (1 g) in anhydrous dimethylformamide (25 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 2 hours. Then, 3.5 g of phenylacetyl chloride is added in the course of 5 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (100 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (30 cc). A solution of oxalic acid (1.1 g) in methyl ethyl ketone (15 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 4.2 g of 3-phenylacetoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 134° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C@H:12]([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:65][O:66][C:67]1[CH:74]=[CH:73][CH:72]=[CH:71][C:68]=1[CH2:69][NH2:70]>CN(C)C=O>[Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C@H:12]([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:70][CH2:69][C:68]1[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=1[O:66][CH3:65])=[O:25])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C[C@H](Cc1ccc2[nH]c(C(=O)O)cc2c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: COc1ccccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
A solution of 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylic acid (Preparation 5, 0.25 g, 0.50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol), hydroxybenzotriazole (75 mg, 0.55 mmol) in N,N-dimethylformamide (5 ml) was treated with triethylamine (0.15 ml, 0.55 mmol) and 2-methoxybenzylamine (0.07 ml, 0.55 mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (20 ml). The organic phase was separated, dried (sodium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5 changing to 90:10, by volume) to give the title compound as a colourless foam (76 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:3]=1.C([Li])CCC.[C:30](=[O:32])=[O:31].Cl>C(OCC)C.C(OCC)(=O)C.O>[F:11][C:10]([F:13])([F:12])[CH2:9][O:8][C:6]1[CH:5]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:3]=[C:2]([C:30]([OH:32])=[O:31])[CH:7]=1
Reactant: FC(F)(F)COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cc(OCC(F)(F)F)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
2-bromo-4-(2,2,2-trifluoroethoxy)-6-[3-(trifluoromethyl)phenoxy] pyridine (9.81 g, 0.0236 mol) was dissolved in about 200 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [16 ml (ca. 1.63 M in hexane solution), 0.0236×1.1 mol]. The obtained mixture was stirred for about 10 minutes. After replacing an interior of the reactor with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 15 ml of a 4 N aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane). The purified product was recrystallized by adding hexane thereto, thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1.[CH3:32][Sn:33]([N:36]=[N+:37]=[N-:38])([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:36]([Sn:33]([CH3:35])([CH3:34])[CH3:32])[N:37]=[N:38][N:12]=3)=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C#N)cc34)cc3cccnc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5nnnn5[Sn](C)(C)C)cc34)cc3cccnc32)cc1
Yield: 84.3 %

Procedure:
A solution of 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5-carbonitrile [100 mg, Reference Example 13(c)] in toluene (10 mL) was treated with trimethyltin azide (56 mg, 0.28 mmol) then heated under reflux for 14 hours. The white precipitate was collected by filtration washed with toluene (10 mL) and then dried to give the title compound (125 mg) as a colourless solid, m.p. 240-243° C. (with decomposition). MS: 633 (MH+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH:11]=[CH:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
Alternately, the PGE1 -type compound is transformed to a bis-trifluoroacetate, for example by reaction with trifluoroacetic anhydride in the presence of pyridine in a solvent at 0° to 5° C., and thereafter contacted with a low-boiling alcohol (preferably b.p. below 110° C.) with a tertiary amine to form a PGA1 -type compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].Cl.[NH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(C(C)C)C(C)C)C>CC(N(C)C)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)CNc1cccc(Br)c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 1-bromo-3-fluoro-2-nitrobenzene (10.25 g, 46.6 mmol; Ark Pharm, Inc., Libertyville, Ill.), ethyl 2-aminoacetate hydrochloride (6.50 g, 46.6 mmol; Aldrich), and N-ethyl-N-isopropylpropan-2-amine (24.35 ml, 140 mmol) in DMA (116 ml) was heated to 80° C. for 5 h. The mixture was diluted with DCM (400 ml), added to a separatory funnel, and washed with water (4×200 ml) before the organic layer was separated, dried over Na2SO4, and concentrated to give ethyl 2-((3-bromo-2-nitrophenyl)amino)acetate (210b, >99% yield) as a yellow oil (contaminated with DMA). MS (ESI, pos. ion) m/z: 303.0/305.0 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:19][C:20]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:24][C:21]=1C#N.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(O)=O>[F:19][C:20]1[CH:21]=[CH:24][C:25]([C:34]#[N:35])=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([C:10](=[O:12])[C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:32][CH2:33]2)[CH:27]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N#Cc1ccc(N2CCNCC2)cc1F
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)N2CCN(c3cc(F)ccc3C#N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 13.6 mg (0.05 mmol) 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid, 15.7 mg (0.06 mmol) 2-Fluoro-4-piperazin-1-yl-benzonitrile (Org. Proc. Res. Dev. 1999, 460), 17.9 mg (0.06 mmol) TBTU and 43 ul (0.25 mmol) DIPEA in 1 ml DMF was stirred for 16 h at room temperature. After addition of 100 ul formic acid the mixture was subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 10.6 mg (33%) of the title compound. MS (m/e): 457.2 (MH+, 100%)
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18].C(=O)(O)[O-].[Na+]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:23]=[CH:24][CH:25]=1)#[CH:18]
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: C#Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: C#Cc1cccc(Nc2ncnc3cnc(F)cc23)c1
Yield: 98.8 %

Procedure:
A suspension of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (93) (6.64 g, 40.2 mmol), thionyl chloride (150 mL) and a catalytic amount of DMF (5 drops) was stirred under reflux for 30 min to give a homogeneous mixture which was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-ethynylaniline (6.56 g, 44.2 mmol) and dry DMA (40 mL). The reaction mixture was then stirred at room temperature for 40 min before a 5% solution of sodium bicarbonate (500 mL) was added and the resultant mixture was stirred at room temperature for 15 min. The solid was collected by filtration and washed several times with water and then hexane, respectively. The solid was then dried under vacuum over silica gel to give N-(3-ethynylphenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (164) (10.5 g, 99%), mp 225-227° C.; 1H NMR δ [(CD3)2SO] 10.06 (s, 1H), 8.96 (s, 1H), 8.74 (s, 1H), 8.28 (poorly resolved d, J=0.6 Hz, 1H), 8.10 (t, J=1.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.32-7.27 (m, 1H), 4.22 (s, 1H). Anal. Calcd for C15H9BrFN4: C, 68.18; H, 3.43; N, 21.20%. Found C, 67.80; H, 3.50; N, 20.81%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=[O:4].[I-].[K+].C(N(CC)CC)C.Cl.[F:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=1>C(#N)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:2][C:3]([NH:5][C:6]3[CH:15]=[CH:14][C:9]4[NH:10][C:11](=[O:13])[O:12][C:8]=4[CH:7]=3)=[O:4])[CH2:36][CH2:37]2)=[CH:38][CH:39]=1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)oc2c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2[nH]c(=O)oc2c1
Yield: 26.1 %

Procedure:
A mixture of 0.91 g (4 mmol) of 2-chloro-N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide, 0.7 g (4 mmol) of potassium iodide, 1.2 ml (8 mmol) of triethylamine, 0.7 g (3 mmol) of 4-(4-fluoro-benzyl)-piperidine hydrochloride and 50 ml of acetonitrile is refluxed for 20 hours. The reaction mixture is concentrated and 30 ml of water and 30 ml of chloroform are added to the residue. The organic layer is separated and the water phase is extracted three times with 10 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 adsorbent (Merck) and chloroform methanol=97:3 as eluent to yield 0.3 g (26%) of the title compound. Melting Point: 232-234° C. (diethylether)
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:14][CH3:15])[CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)[CH3:3].[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]1[CH2:8][CH2:9][CH:5]([N:4]([CH2:2][CH3:3])[CH2:14][CH3:15])[CH2:6]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCN(CC)C1CCN(CC(=O)O)C1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CCN(CC)C1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Yield: 48.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-(diethylamino)pyrrolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 109, (2S)-3-(benzyloxy)-2-(2-(3-(diethylamino)pyrrolidin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (21.7 mg, 48.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.87 (d, 1H), 7.61 (d, 2H), 7.29 (m, 5H), 7.21 (t, 2H), 7.03-6.98 (m, 4H), 4.71 (m, 1H), 4.52 (s, 2H), 3.76-3.67 (m, 2H), 3.31 (m, 1H), 3.15 (m, 1H), 3.03 (m, 1H), 2.69-2.58 (m, 3H), 2.48 (m, 5H), 1.88 (m, 1H), 1.55 (m, 1H), 0.92 (t, 6H). MS (EI) for C32H39FN4O4. found 563.7 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH:11]([CH3:13])[CH3:12]>>[CH:11]([C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9])([CH3:12])[CH3:10]
Reactant: Cc1ccnc(N)c1N
Reactant: CC(C)C(=O)O
Product: Cc1ccnc2nc(C(C)C)[nH]c12

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and isobutyric acid (0.19 ml, 2 mmol) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (20:1) to give the pure product (0.25 g, 72%) as a tan colored solid.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[F:10][CH:11]([F:41])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[N:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[N:32][C:33]([C:36](O)([CH3:38])[CH3:37])=[N:34][CH:35]=3)[C:27]([F:29])=[CH:28][C:23]2=[N:22][C:21]=1[CH3:40]>O1CCCC1>[F:41][CH:11]([F:10])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[N:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[N:32][C:33]([C:36]([F:7])([CH3:37])[CH3:38])=[N:34][CH:35]=3)[C:27]([F:29])=[CH:28][C:23]2=[N:22][C:21]=1[CH3:40]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1nc2cc(F)c(-c3cnc(C(C)(C)O)nc3)cn2c1Cc1ccccc1OC(F)F
Solvent: C1CCOC1
Product: Cc1nc2cc(F)c(-c3cnc(C(C)(C)F)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
DAST (0.04 mL, 0.34 mmol) was added to a solution of Example 173 (0.1 g, 0.23 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature under N2 gas. The mixture was stirred at room temperature for 2 h, quenched with water (5 mL) and poured onto saturated aqueous NaHCO3 solution (10 mL). The crude residue was extracted with EtOAc (3×10 mL), dried (MgSO4) and concentrated in vacuo. The resulting light yellow glass was purified by chromatography on silica (Biotage, 10 g cartridge), eluting with 0 to 100% EtOAc in heptanes. The resulting crude off white gum was further purified by preparative HPLC (preparative method C, neutral) to give the title compound (0.031 g, 31%) as a pale orange glass. δH (500 MHz, CDCl3) 8.80 (d, J 1.4 Hz, 2H), 7.79 (d, J 7.0 Hz, 1H), 7.37 (d, J 10.6 Hz, 1H), 7.30-7.27 (m, 1H), 7.17 (d, J 7.9 Hz, 1H), 7.11 (t, J 7.5 Hz, 1H), 6.90 (dd, J 7.7, 1.2 Hz, 1H), 6.62 (t, J 73.6 Hz, 1H), 4.29 (s, 2H), 2.52 (s, 3H), 1.83 (d, J 21.7 Hz, 6H). Method D HPLC-MS: MH+ m/z 445, RT 2.24 minutes.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:8]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CO>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[N:21][C:22]#[N:23])[N:8]=1
Reactant: CSC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CCN(CC)CCN
Solvent: CO
Product: CCN(CC)CCNC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine (0.2 g.), N,N-diethylethylenediamine (0.5 ml.) and methanol (2 ml.) was heated under reflux for 24 hours and then evaporated to dryness. Water was added to the residue, the mixture extracted with ethyl acetate and the ethyl acetate extract dried and evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-[2-diethylaminoethyl]guanidino)propylthio]pyrimidine (0.08 g.), characterised as the bis hydrogen maleate, m.p. 76°-80° after recrystallisation from acetone.
Reaction SMILES: C(OC([NH:6][N:7]=[C:8]([CH2:18][S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)C.[S:27](Cl)(Cl)=O>ClCCCl>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][S:10][C:9]1[S:27][N:6]=[N:7][C:8]=1[CH2:18][S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CCSCC(CSCCC(=O)OCC)=NNC(=O)OCC
Solvent: ClCCCl
Product: CCOC(=O)CCSCc1nnsc1SCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of the hydrazone (7.2 g, 17.6 mmol) in 1,2-dichloroethane (20 mL) was added thionyl chloride (3.9 mL, 53 mmol) at 0° C. and stirred overnight at room temperature. The mixture was concentrated to a volume of 10 mL, diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and then concentrated to dryness, affording 6.47 g of 5-[(2-ethoxycarbonylethyl)thio]-4-[(2-ethoxycarbonylethyl)thiomethyl]-1,2,3-thiadiazole. 1H NMR (CDCl3) δ 1.2-1.3 (m, 6H), 2.60 (t, 2H, J=7), 2.68 (t, 2H, J=7), 2.77 (t, 2H, J=7), 3.24 (t, 2H, J=7), 4.07 (s, 2H), 4.1-4.2 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([N:48]=[C:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>ClCCl>[Cl:41][C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:10]3[C:9]([CH2:8][O:7][C:6]4[CH:32]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[CH3:33])=[C:18]4[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]4[CH3:19])=[CH:12][CH:11]=3)=[C:24]([O:30][CH3:31])[CH:25]=2)=[O:50])[CH:45]=[CH:46][CH:47]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)Nc2cccc(Cl)c2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 20.3 mg, 0.0451 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), then triethylamine (13.6 μL, 0.0977 mmol) and 3-chlorophenyl isocyanate (6 μL, 0.05 mmol) were added to the mixture successively. After the reaction mixture was stirred for 1 hour at room temperature, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.4 mg) as a colorless solid. (Yield 82%)
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>C1COCC1>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc3ccccc3c2)oc1C

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dimethylfuran, 2-(bromomethyl)naphthalene and 1.6M n-BuLi/hexanes in THF. 1H NMR (DMSO-d6) δ 1.89 (s, 3 H), 2.15 (s, 3 H), 4.08 (s, 2 H), 5.95 (s, 1 H), 7.40 (d, 1 H), 7.45-7.57 (m, 2 H), 7.77 (s, 1 H), 7.83-7.91 (m, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])=[CH:5][CH:4]=1.O(C1C=CC(C(C2C=CC(OC#N)=CC=2)(C)C)=CC=1)[C:26]#[N:27].CS(C)=O.CCN(CC)CC>[Cl-].[Na+].O>[CH3:24][C:19]1[C:18]([C:10]2[N:11]([C:26]#[N:27])[C:12]3[C:17]([C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: CC(C)(c1ccc(OC#N)cc1)c1ccc(OC#N)cc1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2c(-c3c(C)noc3C)n(C#N)c3ccccc23)cc1
Temperature: 120 °C

Procedure:
4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (37 mg, 0.12 mmol) and 2,2-bis-(4-cyanatophenyl)propane (0.6 eq) were mixed in a vial. 1.8 ml DMSO and Et3N (3 eq) were added and the mixture was heated at 120° C. in microwave. 2,2-bis-(4-cyanatophenyl)propane (5.7 eq) and Et3N (40 eq) were added and the mixture was heated at 150° C. for 25 min in microwave. Brine was added and the aqueous layer was extracted with EtOAc 6×. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was taken up in DCM, filtered through cotton wool and purified on silica (EtOAc/n-Heptane 1:9-2:8). 25.7 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was obtained as a yellowish solid.