Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=O)=[CH:38][CH:37]=1.[NH2:46][C:47]1[CH:51]=[CH:50][O:49][N:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:49]1[CH:50]=[CH:51][C:47]([NH:46][C:43](=[O:45])[CH2:42][C:39]2[CH:38]=[CH:37][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][CH:27]=3)=[CH:41][CH:40]=2)=[N:48]1
Reactant: Nc1ccon1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(CC(=O)Nc4ccon4)cc3)c2cc1OC
Temperature: 60 °C
Yield: 14.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.226 g) and 2-hydroxypyridine N-oxide (0.131 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid (0.2 g), 3-aminoisoxazole (0.064 g), diisopropylethylamine (0.226 g) and DMF (3 ml) at ambient temperature. The resultant mixture was stirred and heated to 60° C. for 16 hours. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetoliitrile as eluent. There was thus obtained the title compound (0.035 g); 1H NMR: (DMSOd6) 3.76 (s, 2H), 3.92 (s, 3H), 3.95 (s, 3H), 6.47 (d, 1H), 6.93 (d, 1H), 7.23 (d, 2H), 7.4 (s, 1H), 7.46 (d, 2H), 7.49 (s, 1H), 8.49 (d, 1H), 8.80 (d, 1H), 11.33 (br s, 1H); Mass Spectrum: M+H+ 406.
Reaction SMILES: [Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.[OH:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][C:24](=[O:26])[O:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1.ClCCl>O1CCCC1>[O:26]=[C:24]1[O:23][N:22]=[C:21]([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH:14]=[O:13])[NH:25]1
Reactant: O=c1[nH]c(-c2cccc(CO)c2)no1
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Yield: 71.9 %

Procedure:
Add pyrdinium chloro chromate (5.22 g, 24.2 mmol) to a solution of 3-(3-hydroxymethyl-phenyl)-4H-[1,2,4]oxadiazol-5-one (3.10 g, 16.1 mmol) in tetrahydrofuran:dichloromethane (125 mL:125 mL) and stir. After 4 hours concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product as a white solid (2.20 g, 72%): 1H NMR (DMSO-d6) δ 7.83 (t, 1H), 8.10-8.17 (m, 2H), 8.35 (m, 1H), 10.09 (s, 1H), 13.15 (bs, 1H).
Reaction SMILES: O1CC[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:9][N:10]1[O:22][C:21]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[S:14][C:13]=2[N:12]=[C:11]1[S:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.C(I)C>C(N(CC)CC)C>[NH2:9][N:10]1[O:22][C:21]2[C:20]3[CH2:19][CH2:18][N:17]([CH2:2][CH3:3])[CH2:16][C:15]=3[S:14][C:13]=2[N:12]=[C:11]1[S:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1
Reactant: NN1Oc2c(sc3c2CCNC3)N=C1SCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCI
Product: CCN1CCc2c(sc3c2ON(N)C(SCCCN2CCN(c4ccc5ccccc5n4)CC2)=N3)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
To 10 ml of tetrahydrofuran, 310 mg of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene trihydrochloride as synthesized in Example 1-59 was added and further 50 mg of ethyl iodide was added. Into this mixture 200 mg of triethylamine was dropped, followed by 3 days' stirring at room temperature. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=10:1) to provide 100 mg (37%) of 3-amino-7-ethyl-2-[3-(4-quinolin-2-ylpiperazin-1-yl)-propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[S:14][CH:15]=[CH:16][C:3]=12.[NH:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1>>[C:8]1([C:6]2[N:5]=[C:4]3[S:14][CH:15]=[CH:16][C:3]3=[C:2]([N:17]3[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)nc2sccc12
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3sccc23)CC1
Temperature: 170 °C
Yield: 33 %

Procedure:
A mixture of 4-chloro-6-phenyl-thieno[2,3-b]pyridine (200 mg, 0.82 mmole) and ethyl isonipecotate (5 mL) is stirred and heated in an oil bath at 170° C. for 6 hours. The reaction mixture is cooled and purified on a preparative tlc plate to give ethyl 1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylate (100 mg, 33% yield) as a colorless oil.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a stirring solution of 695 mg (6.04 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 902 μL (6.47 mmol) of triethylamine and 240 mg (1.97 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.37 g (7.13 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (7.19 mmol) of γ-linolenic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.8 g (79%) of 4-hydroxy-3-[(Z,Z,Z)-1-oxo-6,9,12-octadecatrienyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl.N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Yield: 61.8 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (8.9 g, 39.6 mmol) (as prepared in example 1) was reacted with 14.6 mL (118.8 mmol) of trimethylacetylchloride in dichloromethane (35 mL) and pyridine (9.6 mL) as described in example 2 to yield 7.94 g of the desired compound in 1:1 ratio.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([NH2:64])[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:58]5[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and piperidin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.90 (m, 16 H) 3.16 (br. s., 6 H) 3.32 (s, 3 H) 3.96 (s, 3 H) 4.14 (t, 2 H) 4.48 (quin, 1 H) 7.47 (d, 1 H) 7.49 (s, 1 H) 8.22 (d, 1 H) 8.24 (s, 1 H) 8.47 (br. s., 1 H). [M+H] calc'd for C27H35F2N7O3 544; found 544.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[F:42])=[O:33])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[O:16])[S:14][C:7]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:20][CH2:19][CH2:18][NH:17][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:28]=[CH:29][C:30]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[F:42])=[O:33])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:16]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCNC(=O)OC(C)(C)C)sc34)cc2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCN)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate (488 mg, 0.82 mmol) in 10 ml of dichloromethane was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for one hour and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 400 mg, 99%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].C(N(CC)CC)C.[SH2:17]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:8])=[S:17]
Reactant: COCCOCC(=O)Cl
Reactant: S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCC(O)=S
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A solution of 2-methoxyethoxyacetyl chloride (700 mg.; 4.59 mmoles) in methylene chloride (10 ml.; dried over molecular sieves) was added dropwise at 0°-5° to a stirred solution of triethylamine (0.7 ml.; 508 mg.; 5.04 mmoles) in methylene chloride (20 ml.) which had been saturated at 0°-5° with H2S (ca. 30 min.). The light yellow mixture was stirred at 0°-5° for 30 min. and then at room temperature for 30 min. The mixture was washed with 1 N HCl (10 ml.×2) and then brine. The CH2Cl2 layer was dried (Na2SO4) and evaporated yielding 2-methoxyethoxythioacetic acid (480 mg.; 3.20 mmoles; yield 69.7%) as a light yellow liquid: nmr (CDCl3): δppm 3.42 (3H, s, --OCH3), 3.4-3.9 (4H, m, --CH2CH2 -- ), 4.10 (2H, s, --OCCH2O), 5.0 (1H, br, --COSH); ir (neat): 2550 cm-1 (γS--H), 1770 (γc=o, thio acid).
Reaction SMILES: [Cl-:1].[CH:2]([O:15][C:16]([C:18]1([O:21]/[N:22]=[C:23](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[S:51][CH:52]=2)\[C:24]([NH:26][C@@H:27]2[C:30](=[O:31])[NH:29][C@@H:28]2[CH2:32][N:33]2[N:37]=[C:36]([CH2:38][NH:39][CH2:40][C:41]3[CH:42]=[N+:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[CH:35]=[N:34]2)=[O:25])[CH2:20][CH2:19]1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:61]([O-:64])(O)=[O:62].[Na+]>C(Cl)Cl>[Cl-:1].[CH:2]([O:15][C:16]([C:18]1([O:21]/[N:22]=[C:23](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[S:51][CH:52]=2)\[C:24]([NH:26][C@@H:27]2[C:30](=[O:31])[NH:29][C@@H:28]2[CH2:32][N:33]2[N:37]=[C:36]([CH2:38][N:39]([CH2:40][C:41]3[CH:42]=[N+:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[C:61]([O:64][C:3]([CH3:8])([CH3:4])[CH3:2])=[O:62])[CH:35]=[N:34]2)=[O:25])[CH2:19][CH2:20]1)=[O:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[n+]1cccc(CNCc2cnn(C[C@H]3NC(=O)[C@H]3NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)n2)c1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C[n+]1cccc(CN(Cc2cnn(C[C@H]3NC(=O)[C@H]3NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)n2)C(=O)OC(C)(C)C)c1

Procedure:
Prepared in an anologous manner to example 85, step 4 using 3-((((2-(((2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)amino)methyl)-1-methylpyridin-1-ium chloride (50 mg, 0.058 mmol), Boc-anhydride (0.027 mL, 0.115 mmol), NaHCO3 (satd aq, 1.22 mL) and DCM (1.15 mL). LCMS: Rt=0.99 min, m/z=921.3 (M+) Method 2m_acidic.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>>[NH2:17][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCCOCn1cc(Cl)c2c(Cl)ncnc21
Product: Nc1ncnc2c1c(Cl)cn2COCCO
Temperature: 135 °C
Reaction time: 10 h

Procedure:
4,5-Dichloro-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d] pyrimidine (7b, 0.07 g) was covered with methanolic-ammonia (20 mL) and heated in a sealed reaction vessel at 135 degrees C. for 10 hours. The solvent was evaporated in vacuo to give a thick syrup. This syrup was subjected to column chromatography and elution of the silica gel column (20×3 cm) with 5% MeOH in CHCl3 furnished colorless needles of 10, after evaporation of the appropriate UV absorbing fractions; 0.04 g. (66.6%), mp 149-150 degrees C. 1H-NMR (DMSO-d6): δ 8.14 (s, 1, C2-H), 7.56 (s, 1, C6-H), 6.92 (bs, 2, exchangeable with D2O, NH2), 5.49 (s, 1, N7-CH2), 4.64 (bs, 1, exchangeable with D2O, OH), 3.43 (m, 4, CH2): UVλmax nm (ε× 104) (pH 7) 214 (2.5), 278 (1.3); (pH 1) 233 (2.8), 280 (1.3); (pH 11) 227 (1.4), 278 (1.3).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][C:18](=[O:22])[CH:19](Br)[CH3:20]>CN(C=O)C.CC(=O)OCC>[CH3:16][O:17][C:18](=[O:22])[CH:19]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:20]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccccc1C=O
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 91.5 %

Procedure:
A mixture of 2-hydroxy-benzaldehyde (1 g; 8.19 mmol; 1 eq.), K2CO3 (3.4 g; 24.6 mmol; 3 eq.) and 2-bromo-propionic acid methyl ester (3.42 g; 20.5 mmol; 2.5 eq.) in DMF (50 mL) was stirred at 120° C. for 45 minutes then diluted with EA. The solution was washed with water (3×) then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (15% to 33% EA in cyclohexane) afforded the title compound (1.56 g, 91%) as a colourless oil. HPLC (max plot) 96.3%; Rt 3.18 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH3:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl.C1(C)C=CC=CC=1>[O:24]1[CH:14]([CH2:13][O:12][C:11]2[CH:17]=[CH:18][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=2)[CH:15]1[CH3:16]
Reactant: C/C=C/COc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1OC1COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
A solution of trans-4-[4-(tert-butoxycarbonyl)phenoxy]-2-butene (3.10 g, 12.48 mmol) in dry dichloromethane (50 ml) was treated at 22° C. with 3-chloroperoxybenzoic acid (4.30 g, 24.9 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The mixture was then diluted with toluene, washed with 5% sodium thiosulfate, saturated sodium bicarbonate and brine. After drying (sodium sulfate), evaporation of the solvent gave an oil that was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (95:5) gave 3.16 g (96%) of the title material as an oil which solidified upon standing: bp 85-90° C./0.05 torr (bulb to bulb, air bath temperature); mp 47-48° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:8][C:9](=O)[CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:13]=2[N:12]=1)C>C(OCC)(=O)C>[O:8]=[C:9]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:35])([F:36])[F:34])=[O:26])[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:13]=2[N:12]=1
Reactant: CCOC(=O)Cc1nc2c(C(=O)OC)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(CC(=O)N3CCCC3)nc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (1 mL) was added to methyl 2-(2-ethoxy-2-oxoethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylate (80 mg), and the solution was stirred at 70° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, and washed with brine. The ethyl acetate layer was concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (74 mg) as white powder.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[CH3:14][O:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:5][C:2]([NH:1][S:18]([CH2:17][CH2:16][O:15][CH3:14])(=[O:20])=[O:19])([CH3:6])[C:3]#[N:4]
Reactant: COCCS(=O)(=O)Cl
Reactant: CC(C)(N)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a stirred mixture of 10 g (0.12 mole) 2-amino-2-methyl-propionitrile and 12.1 g (0.12 mole) triethylamine in about 200 ml methylene chloride cooled by an ice bath, 18.8 g (0.12 moles) 2-methoxyethane sulfonyl chloride (the product of Example 19) in 15 ml methylene chloride were added dropwise. The reaction mixture was then stirred at room temperature over the weekend. The reaction mixture was washed three times with equal amounts (about 200 ml) water, dried over magnesium sulfate, filtered and stripped to give an oil. The oil was recrystallized from ethyl ether/petroleum ether to give 15.0 g of the above-identified product, melting point 58°-60° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: ClCCCCBr
Reactant: O=C(Nc1cccnc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N(CCCCCl)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.1 %

Procedure:
To a stirred solution of 21.6 parts of 4-fluoro-N-(3-pyridinyl)benzamide in 235 parts of N,N-dimethylformamide were added portionwise 5.76 parts of a sodium hydride dispersion 50% at <25° C. under nitrogen atmosphere. After stirring for 1.5 hours at room temperature, the mixture was cooled to 0° C. and 27.8 parts of 1-bromo-4-chlorobutane were added. The reaction mixture was stirred for 3 hours at 60° C. After cooling, the whole was poured into 1000 parts of ice water and the product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 7.4 parts (24.1%) of N-(4-chlorobutyl)-4-fluoro-N-(3-pyridinyl)benzamide as a residue (int. 67).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 84.2 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (2.62 g, 5.68 mmol), pyrrolidine (808 mg, 11.36 mmol, 2.0 eq), triethylamine (575 mg, 5.68 mmol, 1.0 eq); and sodium iodide (85 mg, 0.56 mmol, 0.1 eq) in anhydrous DMF (28 mL) was stirred at 55° C. for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aq. brine (3×), dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude was triturated from MeOH, filtered, and washed with cold MeOH and ether to provide 2.16 g (84.2%) of the desired product as a white solid. 1H-NMR (DMSO-d6) 8.54 (s, 1H), 7.89 (s, 1H), 7.80 (d, 1H), 7.58 (s, 1H), 7.36 to 7.30 (m, 5H), 7.14 (d, 1H), 6.59 (s, 1H), 5.65 (s, 2H), 2.90 (t, 2H), 2.48 to 2.39 (m, 6H), 1.87 to 1.83 (m, 2H), 1.67 to 1.64 (m, 4H); LC-MS [M+H]+=452, RT=2.14 min.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[OH-].[K+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]=[CH:27]OCC)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH:27]=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:3]2[N:4]=[CH:5][NH:6][C:2]=2[CH3:1])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CCOC=NS(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]cnc1CSCCN=CNS(=O)(=O)c1ccc(Cl)cc1
Yield: 61.9 %

Procedure:
To a solution of 2.44 g of 2-[[(5-methyl-1H-imidazole-4-yl)methyl]thio]ethanamine (prepared according to British Pat. No. 1,338,169) in 50 ml of methanol, 13.3 ml of 1.45M methanol potassium hydroxide are added at 0° C. To the resulting solution, 2.47 g of ethyl N-p-chlorobenzene-sulphonylformimidate are added at room temperature and stirring. The mixture is kept under stirring for 1 hour at room temperature, then filtered off and the solvent is removed by distillation at reduced pressure. The formed residue is purified by dissolving in 50 ml of ethyl acetate and 25 ml of water. Then, it is acidulated with 3N hydrochloric acid till pH2. The organic phase is cast aside and the aqueous phase is basified in the presence of 50 ml of ethyl acetate with 1N sodium hydroxide till pH8. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness. 2.3 g (oily product) of N-p-chlorobenzene-sulphonyl-N'-[2 -[[(5-methyl-1H-imidazole-4-yl)methyl]thio]ethyl]formamidine are obtained.