Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:27][CH:28]([OH:30])[CH3:29].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.C(OCC)(=O)C.O>[CH:28]([O:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1)([CH3:29])[CH3:27]
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Reactant: CC(C)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(OC(C)C)cc4)no3)cc2C)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 17.6 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 200 mg, 0.44 mmol), 2-propanol (1 ml, 13.06 mmol), copper(I) iodide (8.4 mg, 0.04 mmol), phenanthroline (16 mg, 0.09 mmol) and cesium carbonate (286 mg, 0.88 mmol) was stirred at 100° C. for five hours in a microwave reactor (CEM Discover). The reaction mixture was cooled and water (50 mL) and ethyl acetate (50 mL) was added. The layers were separated and the organic layer was washed with water and brine and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified using preparative HPLC to afford the title compound as a white solid (30 mg, 16%): 1H NMR (400 MHz, CDCl3) 8.12 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 6.97 (d, 2H), 6.79 (s, 1H), 5.41 (s, 2H), 4.63 (sept, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.38 (d, 6H); ES-MS m/z 389 (MH)+, HPLC RT (Method E) 2.67 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[C:3]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15]([C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[O:33])[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1csc2c(CS(=O)c3nc4ccccc4[nH]3)nccc12
Temperature: 0 °C

Procedure:
To a solution of 140 mg (0.433 mmol) of 2-[(3-methoxycarbonylthieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-10) in 6 ml of CHCl3 and 2 ml of MeOH was added 94 mg (1.1 equivalents) of 80% m-CPBA in the ice-water bath of -10° C., and the mixture was allowed to react for 1 hr. at -10° C. The solution was treated with 10 % aqueous sodium sulfite and saturated aqueous NaHCO3 and extracted with CH2Cl2. The extract was subjected to silica gel column chromatography, eluting with CH2Cl2 --MeOH, and the eluate gave 122 mg (Yield : 75.8%) of 2-[(3-carbomethoxythieno[2, 3-c]pyridin-7-yl)methylsulfinylbenzimidazole (Ic-22) as a foamy product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20]([N:12]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:11])[CH2:9][CH3:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: COC(=O)C(=O)Cl
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Temperature: 110 °C
Yield: 87.6 %

Procedure:
A solution of 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (13.0 g, 50.2 mmol) in toluene (150 mL) at 25° C. was treated with methyl chlorooxoacetate (42.86 g, 350 mmol). The reaction mixture was then heated at 110° C. for 16 h. At this time, the reaction mixture was concentrated in vacuo to afford N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester (15.2 g, 87.6%). The material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][Cl:33])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: ClCCCBr
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a suspension of 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol (5.59 g), K2CO3 (7.06 g) in DMF (60 mL) was added 1-bromo-3-chloropropane (6.06 mL) at rt, the mixture was stirred at 40° C. for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (5.80 g, 77.00%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:18][CH2:10][C:9]1[C:2]([Cl:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C#N)c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: N#Cc1cccc(CBr)c1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-3-methylbenzonitrile (6.6 mmol) in 25 mL chlorobenzene was heated to 50° C. when NBS (7.9 mmol) was added. The flask was purged with Ar before AIBN (0.66 mmol) was added at once still at 50° C. The reaction mixture was stirred at 80° C. for 2 h. The solvent was evaporated off, the resulting residue was redissolved in Et2O and washed 3 times with 1N HCl solution and brine. It was dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (85/15) gives the desired compound as white solid.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[N:4]=1>C(O)C>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[N:4]=1
Reactant: N
Reactant: Fc1cc(F)nc(F)n1
Solvent: CCO
Product: Nc1nc(F)cc(F)n1
Yield: 54.9 %

Procedure:
This entailed, in the first stage of the synthesis, absolute ethanol being saturated with ammonia at 0° C., and a solution of 2,4,6-trifluoropyrimidine (II) and ethanol then being added to the solution obtained in this way. It was possible, after elaborate separation of the isomers, to isolate 2-amino-4,6-difluoropyrimidine IVa' in 54.9% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].Br[C:13]1[S:14][C:15]([C:22]2[C:23]([CH3:37])=[N:24][N:25]3[C:30]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:29][C:28]([CH3:36])=[N:27][C:26]=23)=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:13]1[S:14][C:15]([C:22]2[C:23]([CH3:37])=[N:24][N:25]3[C:30]([CH:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[CH:29][C:28]([CH3:36])=[N:27][C:26]=23)=[C:16]([C:18]([F:19])([F:21])[F:20])[N:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3C(F)(F)F)c(C)nn12
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(CC)c1cc(C)nc2c(-c3sc(NCCNC(=O)OC(C)(C)C)nc3C(F)(F)F)c(C)nn12
Temperature: 80 °C
Yield: 94.9 %

Procedure:
Add (2-amino-ethyl)-carbamic acid tert-butyl ester (0.5 mL, 506 mg, 3.2 mmol) to a solution of 3-(2-bromo-4-trifluoromethyl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (100 mg, 0.22 mmol) and triethylamine (0.3 mL, 222 mg, 2.2 mmol) in methanol (1 mL). Evaporate off the methanol and heat to 80° C. overnight. Cool the reaction to room temperature and concentrate under vacuum. Purify the resulting residue by column chromatography, eluting with 10-50% ethyl acetate in CH2Cl2, to give the title compound (0.11 g, 97%). ES/MS m/z 527.2 (M+1)+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[C:11]([C:14]1[CH:32]=[C:17]2[C:18]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[N:16]2[N:15]=1)([CH3:13])[CH3:12]>C(Cl)(Cl)Cl>[F:7][C:11]([C:14]1[CH:32]=[C:17]2[C:18]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[N:16]2[N:15]=1)([CH3:13])[CH3:12]
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)(C)O)nn12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)(C)F)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
DAST (27.9 mg) was added dropwise to a solution of the compound of Example 242 (21.9 mg) in chloroform (5.0 mL) and the mixture was stirred at 0° C. for 30 min. Subsequently, the reaction was quenched by adding a saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform (30 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=1:3→ :4) to afford the title compound as a colorless powder (16.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20](SC)=[N:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[N:30]#[C:31][NH2:32]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:32][C:31]#[N:30])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10]
Reactant: N#CN
Reactant: CSC(=Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1
Solvent: C1CCOC1
Product: N#CN=C(Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1

Procedure:
A solution of methyl 2-[(2-aminophenyl)carbamoyl]-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbimidothioate obtained in step IV (1 eq), cyanamide (10 eq) in very small quantity of THF was heated at reflux temperature for 15 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to afford the title compound.
Reaction SMILES: I[CH:2]([C:12]([F:15])([F:14])[F:13])[CH2:3][C:4]([F:11])([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([SnH](CCCC)CCCC)CCC>>[F:10][C:4]([F:11])([CH2:3][CH2:2][C:12]([F:13])([F:15])[F:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)(F)CC(I)C(F)(F)F
Agent: CCCC[SnH](CCCC)CCCC
Product: CCOC(=O)C(F)(F)CCC(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
The compound ethyl 4-iodo-2,2,5,5,5-pentafluoropentanoate prepared from above experiment (86.5 g, 0.25 mol) was added dropwise into a well-stirred tributyltin hydride liquid (75.5 g, 0.26 mol). The reaction temperature was controlled at below 30° C. with external cooling during the process. After addition was complete, the mixture was stirred at 50° C. for 2 hr. The product was isolated by distillation, 42.0 g (76.4% yield) of product was obtained as a clear, colorless liquid, bp. 38-39° C./10 mm Hg. 1H NMR (500 MHz, CDCl3): δ 4.35 (q, J=7 Hz, 2H), 2.35 (m, 4H), 1.38 (t, J=7 Hz, 3H); 19F NMR (282.75 MHz, CDCl3): −67.3 (m, 3F), −107.5 (m, 2F).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(bromomethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (87%) as a colorless solid: mp 137-138° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.6 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.13 (m, 3H), 7.07-7.00 (m, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q, 2JC-F=30.8 Hz), 127.6, 126.8, 126.4 (q, 5JC-F=5.8 Hz), 124.4 (q, 1JC-F=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1). Anal. Calcd. for C25H18F3NO4: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.16; H, 4.11; N, 3.07.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[CH:32](O)[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:35])([CH3:36])[CH:32]([N:10]5[CH2:9][CH2:8][CH:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[CH2:12][CH2:11]5)[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(N3CCC(c5ccccc5)CC3)C(C)(C)O4)CC2)cc1
Yield: 45 %

Procedure:
Using 4-phenylpiperidine and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 57. Yield 45%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[C:13]([C:15]1[N:19]([CH3:20])[C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C:15]1[N:19]([CH3:20])[C:18]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:12])=[CH:17][CH:16]=1)#[N:14]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: NS(=O)(=O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(N)(=O)=O)cc1F
Reaction time: 16 h
Yield: 17.6 %

Procedure:
According to general procedure B, 4-bromo-3-fluorobenzenesulfonamide (150 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorobenzenesulfonamide (29 mg, 18%) was provided after purification. MS (ESI) m/z 279. HPLC purity 100.0% at 210-370 nm, 8.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:14])(=[NH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[CH:18][CH:17]=1>C1C=CC=CC=1.CCCCC>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:13][C:7](=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[S:24])=[CH:18][CH:17]=1
Reactant: CCCCCC(=N)N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCC
Product: CCCCCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 42 but using 3.4 g. sodium in 300 ml. dry acetone, 22.5 g. hexanamidine hydrochloride, and 25.9 g. 4-chlorophenyl isothiocyanate in 150 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(hexanimidoyl)-2-thiourea, m.p. 100°-102°C. (from benzene-n-pentane); hydrochloride (21 g.), m.p. 175°C. (from acetonitrile).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22]([C:24]1[CH:25]=[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:28]([Br:30])[CH:29]=1)=O)C.CCOC(C)=O>C1COCC1>[CH2:1]([NH:13][C:22]([C:24]1[CH:25]=[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:28]([Br:30])[CH:29]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of dodecyl amine (3.22 g, 17.64 mmol) in 50 mL anhydrous THF was added n-BuLi (7.05 mL, 17.64 mmol) dropwise. When the addition was complete, the mixture was stirred for 10 min at 0° C. then at room temperature for 30 min. This lithiated amine was added dropwise to a cooled (0° C.) solution. of 5-bromo-3′-chloro-6-(2-hydroxy-ethoxy)-biphenyl-3-carboxylic acid ethyl ester (2.5 g, 5.78 mmol) in 40 mL anhydrous THF via cannula. The reaction was stirred for 10 min at 0° C. when the addition was complete then at room temperature overnight. Then the reaction mixture was heated to 35° C. for 1 hour then more n-BuLi was added (0.7 mL, 1.75 mmol). The reaction. was then worked up as in Step 2 of Example 135. There yielded 2.5 g, 80% of a yellow oil as desired product after flash chromatography (25% EtOAc:75% Hexanes) on silica gel.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[C:20](=[O:28])[C@@H:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:18][C@H:17]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[C:16]=2[CH:45]=1.C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH2:22][C:23]([CH:24]=[O:25])([CH3:26])[CH3:27])[C:20](=[O:28])[C@@H:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:18][C@H:17]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[C:16]=2[CH:45]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CO)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)C=O)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
Dimethyl sulphoxide (1.61 g, 20.6 mmol) was added dropwise to a solution of oxalyl chloride (1.31 g, 10.3 mmol) in dichloromethane (75 ml) at -60° C. The mixture was stirred until gas evolution had ceased. Ethyl trans-7-chloro-5-(1-naphthyl)-1-(2,2-dimethyl-3-hydroxypropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (4.6 g, 9.4 mmol), dissolved in dichloromethane (30 ml), was added dropwise over a period of 5 min. at -60° C., and stirring was continued for further 15 min. The mixture was quenched with triethylamine (4.73 g, 46.8 mmol) before allowing to warm to room temperature. Addition of water, separation of the organic layer and repeated extraction of the aqueous layer with dichloromethane was followed by drying of the combined organic layers with MgSO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (dichloromethane/methanol 99:1) to give the title compound (4.62 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:22](SC)=[N:23][C:24]#[N:25])[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[N:30][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[NH:23][C:24]#[N:25])[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: NCc1ccncc1
Reactant: CSC(=NC#N)N1CCN(C2c3ccc(Cl)cc3N(C)Cc3cccnc32)CC1
Product: CN1Cc2cccnc2C(N2CCN(C(=NCc3ccncc3)NC#N)CC2)c2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
Methyl 4-(8-chloro-6,11-dihydro-6-methyl-5H-pyrido[3,2-c][1]benzazepin-11-yl)-N-cyano-1-piperazinecarboximidothioate (105 mg) and 4-aminomethyl-pyridine (0.45 ml) were heated at 80° C. in a sealed vial allowing escape of gases. Ice-water was then added, and the resulting tan solid was chromatographed on silica gel to afford the desired product, 107 mg; HRMS, FAB: calcd. 487.2125; found 487.2141.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]1[O:14][CH2:13]1>CN(C=O)C>[OH:14][CH2:13][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.7 g of indole in 500 ml of DMF were treated with 4 g of sodium hydride dispersed in mineral oil. After 1 hour the mixture was cooled in an ice bath and 10 ml of ethylene oxide were added. The mixture was allowed to warm to room temperature and was then stirred for 2 hours. The solvent was evaporated and the residue was treated with 50 ml of water and neutralized with 2M hydrochloric acid. The product was extracted into dichloromethane, the solvent was evaporated and the residue was chromatographed with ethyl acetate/petroleum ether to give 7.6 g of 1-(2-hydroxyethyl)indole.
Reaction SMILES: S(Cl)(Cl)=O.FC(F)(F)C(O)=O.[CH3:12][O:13][C:14]1[C:15]([O:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20].C[N:37](C=O)C>>[CH3:12][O:13][C:14]1[C:15]([O:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19]([NH2:37])=[O:20]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Reactant: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 50 °C

Procedure:
Thionyl chloride (15 ml) and DMF (0.05 ml) were added to 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzoic acid trifluoroacetate (7.54 g, 16.6 mmol). The mixture was heated at 50° C. for 1 hour, the excess thionyl chloride was removed by evaporation and by azeotroping with toluene (x2). The resulting solid was suspended in THF (200 ml) and ammonia was bubbled through the mixture for 30 minutes. The precipitate was removed by filtration, washed with THF and discarded. After concentration of the filtrate by evaporation, the product crystallised and was collected by filtration to give 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide (5.25 g, 93%yield) as light yellow crystals which were used without further purification.