Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:27][C:23]1[CH:22]=[C:21]([C@@H:19]([OH:20])[CH2:18][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:30])=[CH:3][CH:4]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CNc1ccc(CCN(C[C@H](O)c2cccc(Cl)c2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of tert-butyl [2-(4-aminophenyl)-ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (1.75 g) and formaldehyde (37% w/w solution in water, 390 μl) in 1,2-dichloroethane (20 ml) was added sodium triacetoxyborohydride (1.23 g), and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The resulting mixture was poured into a mixture of 1N sodium hydroxide and chloroform, and the mixture was stirred for 20 minutes. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl](2-[4-(methylamino)phenyl]ethyl]carbamate (550 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]=O)=[CH:38][CH:37]=1)[OH:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:42][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22](=[O:23])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:3]=2)=[CH:40][CH:41]=1)[OH:35])[CH3:31]
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)C(O)c1ccc(C=O)cc1
Product: CCOC(=O)C(O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-hydroxy-acetic acid ethyl ester according to the procedure of step 1, Example 66. MS (ES) m/z 585.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[CH:10]=[C:9]([S:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)(=[O:13])=[O:12])[CH:8]=[C:7]1[C:19]([OH:21])=O.CN(C)C=O.S(Cl)(Cl)=O.Cl.[Cl:36][C:37]1[S:41][C:40]([NH2:42])=[N:39][CH:38]=1>ClC(Cl)C.ClCCl.O.N1C=CC=CC=1>[Cl:36][C:37]1[S:41][C:40]([NH:42][C:19]([C:7]2[N:6]([CH2:5][C:4]3[CH:22]=[CH:23][C:24]([F:25])=[C:2]([F:1])[CH:3]=3)[CH:10]=[C:9]([S:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)(=[O:13])=[O:12])[CH:8]=2)=[O:21])=[N:39][CH:38]=1
Reactant: O=C(O)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Cl)s1)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Temperature: 80 °C

Procedure:
To a solution of 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid (D1-3) in dichloroethane was added catalytic amount of dimethylformamide and thionyl chloride at 0-5° C. Reaction mixture was heated at 80° C. for 6 hrs and concentrated in inert atmosphere, resulting residue was dissolved in dichloromethane and was added drop wise to mixture of pyridine (1 ml) and 5-chloro-thiazol-2-ylamine hydrochloride at 0° C. The reaction was maintained at 40-50° C. overnight. Water was added to reaction mixture and extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated to afford 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid (5-chloro-thiazol-2-yl)-amide (D1).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14]O)=[C:9]([CH3:16])[CH:8]=[CH:7][CH:6]=1>O1CCCC1.ClCCl>[Cl:4][C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][NH:3][CH2:1][CH3:2])=[C:9]([CH3:16])[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(Cl)c1NCCCO
Reactant: CCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNCCCNc1c(C)cccc1Cl
Yield: 54.3 %

Procedure:
A mixture of a 2.0 M solution of ethylamine in tetrahydrofuran (139.5 mL) and the hydrobromide salt of Example 12, Step A (9.5 g) was stirred at ambient temperature under nitrogen for 48 hours. The tetrahydrofuran was removed in vacuo and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 95:5 to 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.4 g, 54.3%) as a yellow oil, which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])=[O:24])[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)c1cccc(N)c1
Product: CCOC(=O)c1cccc(NC(=O)C2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 94.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and m-ethoxycarbonylaniline (200 mg, 1.2 mmol) to give 410 mg of the title compound (94%): mp 262°~265° C.; 1H NMR (270 MHz, DMSO-d6) δ12.2 (br, 1H), 10.60 (s, 1H), 8.23 (bs, 1H), 7.81 (d, 1H, J=8.0 Hz), 7.67 (d, 1H, J=8.0 Hz), 7.47 (t, 2H, J=8.0 Hz), 7.22 (bs, 1H), 7.19 (bs, 1H), 5.29~5.34 (m, 1H), 4.30 (q, 2H, J=7.1 Hz), 2.85 (dm, 1H, J=16.8 Hz), 2.50~2.82 (m, 2H), 2.03~2.20 (m, 1H), 1.30 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(N(C(C)C)CC)(C)C>CC#N>[Br:13][CH2:14][CH2:15][CH2:16][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: BrCCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Temperature: 25 °C

Procedure:
To a solution of N-hydroxyphthalimide (2.0 g) and 1,3-dibromopropane (2.49 ml) in 50 ml of dry CH3CN was added diisopropylethylamine (4.27 ml). The mixture was stirred at room temperature. After 4 hours the volatiles were removed in vacuo. The residue was triturated with Et2O to provide 2.53 g of while solid, homogeneous by TLC.
Reaction SMILES: [CH:1]([C@H:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[S:21])[NH:5]1)([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC.[CH3:43][Si:44]([CH3:63])([CH3:62])[CH2:45][CH2:46][O:47][C:48]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]/[CH2:58][C:59](O)=[O:60])=[O:49].P([O-])(O)(O)=O.[K+]>ClCCl>[CH:1]([C@H:4]1[C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[S:21])[N:5]1[C:59](=[O:60])[CH2:58]/[CH:57]=[CH:56]/[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][NH:50][C:48](=[O:49])[O:47][CH2:46][CH2:45][Si:44]([CH3:43])([CH3:63])[CH3:62])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1NC(=S)OC1(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOC(=O)NCCCCC/C=C/CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@@H]1N(C(=O)C/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)C(=S)OC1(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 63.9 %

Procedure:
(S)-4-Isopropyl-5,5-diphenyl-oxazolidine-2-thione (2.3 g, 8.28 mmol) was suspended in dichloromethane (17.5 mL), and the mixture was then cooled to 0° C. in an ice bath. Dimethylaminopyridine (97 mg, 0.794 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.00 g, 10.4 mmol) were added and the mixture was then stirred for 25 minutes. To this suspension was added a solution of (E)-9-(2-trimethylsilanyl-ethoxycarbonylamino)-non-3-enoic acid (2.50 g, 7.92 mmol) in dichloromethane (17.5 mL). After stirring at 0° C. for 7.5 hours, an aqueous solution (50 mL) of 10% potassium dihydrogen phosphate and dichloromethane (40 mL) were added and the mixture was separated. The organic layer was washed with a saturated aqueous solution (40 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 3.01 g (5.06 mmol, yield 64%) of 2-trimethylsilanyl-ethyl [(E)-9-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-9-oxo-non-6-enyl]-carbamate.
Reaction SMILES: [CH2:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>[OH-].[Na+].C(O)C.[Pd]>[C:4]1([CH2:3][CH2:2][CH2:1][NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(NCC=Cc2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCCCc2ccccc2)cn1

Procedure:
3 g of 5-cinnamylamino pyridine-2-carboxylic acid are dissolved in 50 ml of 0.5 N aqueous sodium hydroxide containing 1 ml of ethanol and the solution is hydrogenated over 0.5 g of 10% palladium on charcoal at atmospheric pressure and room temperature. After the hydrogen uptake has ceased, the mixture is filtered and the filtrate acidified with hydrochloric acid. The solution is extracted with ethyl acetate, the extract washed with water, dried, evaporated and the residue crystallized from methanol, to yield the 5-(3-phenylpropylamino)-pyridine-2-carboxylic acid melting at 167°-169°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[C@@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(=O)N[C@@H]1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-N-(pyrrolidin-3-yl)acetamide. MS(m/e): 428.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C1COCC1>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([CH:17]=[O:18])=[CH:7][N:6]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (151; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at −78° C. The reaction mixture was stirred at this temperature for 1 h. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at −78° C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6-methylnicotinaldehyde 152 (5.0 g, 72%).
Reaction SMILES: C(OC(=O)N[C@@H](CC1C=CC=CC=1)[C@@H](O)[CH2:10][C@H:11]([C:13](=O)[NH:14]CCC(C)(C)C)[CH3:12])(C)(C)C.C(N)C(C)C.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=1)[C:43]([NH:45][C@H:46]([C@@H:54]1[CH2:58][C@@H:57]([CH3:59])[C:56](=[O:60])[O:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])([CH3:38])[CH3:37]>>[CH2:47]([C@H:46]([NH:45][C:43](=[O:44])[C:42]1[CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=[C:40]([O:39][CH:36]([CH3:37])[CH3:38])[CH:41]=1)[C@@H:54]([OH:55])[CH2:58][C@H:57]([C:56](=[O:60])[NH:14][CH2:13][CH:11]([CH3:12])[CH3:10])[CH3:59])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Solvent: CC(C)CN
Product: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(OC(C)C)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from isobutylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: C([C:3]1[C:14]([Cl:15])=[C:13]([OH:16])[C:6]2[N:7]=[C:8]([C:10]([OH:12])=[O:11])[O:9][C:5]=2[CH:4]=1)C.O>C(O)(=O)C>[Cl:15][C:14]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[N:7][C:6]=2[C:13]=1[OH:16]
Reactant: CCc1cc2oc(C(=O)O)nc2c(O)c1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1nc2c(O)c(Cl)ccc2o1

Procedure:
Ethyl 5-chloro-4-hydroxybenzoxazole-2-carboxylic acid is dissolved in glacial acetic acid and water (5:1) and the solution refluxed for 4 hours. This is cooled and the resulting solid collected and washed with water to give 5-chloro-4-hydroxybenzoxazole-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO.O>[OH:17][N:16]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:7][CH:8]=1
Reactant: NO
Reactant: COC(=O)COc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.3 %

Procedure:
A solution of methyl-(4-formylphenoxy)acetate (100 g, 0.515 mol) in methanol (500 mL) was cooled to 0-5° C. To this was added a solution of hydroxylamine hydrochloride (54 g) and sodium acetate (64 g) in water (500 mL) drop-wise and stirred at rt for 6 h. The reaction mixture diluted with water and filtered off the solid. The solid was washed with water and dried under vacuum to give the title compound (80 g, 74%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].[NH2:28][CH2:29][C@@H:30]1[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH2:29][C@H:30]2[CH2:31][CH2:32][C:33](=[O:35])[NH:34]2)=[O:15])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Reactant: NC[C@H]1CCC(=O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NC[C@H]2CCC(=O)N2)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (110 mg, 0.30 mmol), (R)-5-(aminomethyl)pyrrolidin-2-one (52 mg, 0.46 mmol), HOBT (62 mg, 0.46 mmol), and HBTU (174 mg, 0.46 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N-((5-oxopyrrolidin-2-yl)methyl)nicotinamide (91.6 mg, 67%). LRMS (M+H+) m/z 458.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:2]=1.[CH3:12][N:13]([C:15]1C=CC=C[N:16]=1)C>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:12]2=[N:13][C:15]#[N:16])[CH:2]=1
Reactant: NCCNCc1cccnc1
Reactant: CN(C)c1ccccn1
Solvent: CC#N
Product: N#CN=C1NCCN1Cc1cccnc1

Procedure:
7.56 g of N-pyrid-3-ylmethylethylenediamine, 7.31 g of dimethyl-N-cyanothioiminocarbonate and 20 mg of dimethylaminopyridine in 50 ml of acetonitrile are heated at reflux for 3 hours. The product crystallises out when the mixture has cooled. The resulting crystals are filtered off and washed with ether, yielding the title compound of formula ##STR6## having a melting point of 126.5°-128.5° C. (compound No. 1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([F:26])[CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(Cl)cc1F
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1OC
Yield: 90.7 %

Procedure:
A mixture of 2.0 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 1.46 g of 4-chloro-2-fluoroaniline, 0.925 g of pyridine hydrochloride, and 125 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 2.61 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 139-141° C.; mass spectrum (electrospray, m/e): M+H 357.9.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].C(N(CC)CC)C>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(Cl)Cl>[C:1]([O:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(=O)NCCCO
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCNC(C)=O
Temperature: -72 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
184.0 g (1.76 mol) of methacryloyl chloride were added dropwise in the course of 2 hours to an initial mixture, cooled to -72° C., consisting of 206.2 g (1.76 mol) of N-(3-hydroxypropyl)-acetamide, 750 ml of methylene chloride, 228 g (2.25 mol) of triethylamine and 250 mg of 2,6-di-tert.butyl-4-methylphenol. The mixture was stirred for a further 2 hours at -52° C. and the precipitated pale precipitate was then filtered off with suction at 0° C. The filtrate was subjected to aqueous work-up and the product was dried and, after concentrating on a rotary evaporator, distilled first at 100° C., and then the residue at 130° C. (in each case 0.1 mm Hg). 174.1 g (53% of theory) of 3- acetamidopropyl methacrylate were obtained in the form of a colorless oil.
Reaction SMILES: N=C=N.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[CH3:23][N:24]([S:53]([CH3:56])(=[O:55])=[O:54])[C:25]1[C:30]([CH2:31][NH:32][C:33]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][N:36]=[C:35]([NH:43][C:44]3[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=3)[C:47]([OH:49])=O)[N:34]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CC[N:59]([CH:63]([CH3:65])[CH3:64])C(C)C.C1(N)CC1>C(#N)C>[CH:63]1([NH:59][C:47](=[O:49])[C:46]2[CH:50]=[CH:51][CH:52]=[C:44]([NH:43][C:35]3[N:34]=[C:33]([NH:32][CH2:31][C:30]4[C:25]([N:24]([CH3:23])[S:53]([CH3:56])(=[O:54])=[O:55])=[N:26][CH:27]=[CH:28][CH:29]=4)[C:38]([C:39]([F:42])([F:40])[F:41])=[CH:37][N:36]=3)[CH:45]=2)[CH2:65][CH2:64]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)O)c2)ncc1C(F)(F)F)S(C)(=O)=O
Agent: N=C=N
Agent: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)NC3CC3)c2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
A polymer supported carbodiimide (PS-CDI) (0.326 mmol) was allowed to swell in acetonitrile (volume of 500 μL). The resultant suspension was treated with 10 (100 mg, 0.164 mmol) and DIEA (29 μL, 0.164 mmol). The resultant solution was then treated with cyclopropylamine (19 μL, 0.164 mmol). The resultant suspension was then mixed on a shaker plate for 16 hours. The mixture was then filtered, and the solids washed with 10% MeOH in chloroform. The combined filtrates were concentrated under reduced pressure, and the resultant residue was purified over silica (99:1:0.1 CHCl3:CH3OH:NH4OH) to provide 11 as a white foam. Yield: 14.3 mg, 16%. LC Ret. Time (standard)=2.1 min., m/z 536.2 (MH+); 1H NMR (CD3OD) : 8.42 (d, J=7.8 Hz., 1H), 8.20 (s, 1 h), 7.97 (t, J=7.8 Hz., 1H), 7.81 (d, J=7.8 Hz., 1H), 1.68 (d, J=7.8 Hz., 1H), 7.39-7.34 (m, 2H), 7.26 (t, J=7.8 Hz., 1H), 4.94 (s, 2H), 3.23 (s, 3H), 3.14 (s, 3H), 2.82 (m, 1H), 0.79 (m, 2 h), 0.60 (m, 2H) ppm. FAK IC50: 0.00186 μM
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CN2C(=NCCC2)C1.[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH:31](Br)C)[N:30]=1>CC#N>[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:30]=1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Reactant: CC(Br)c1csc(Br)n1
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 568.6 %

Procedure:
To a cooled (0° C.) stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.7 g, 3.44 mmol, 1.0 eq.) in 25 ml of MeCN, was added dropwise DBN (0.42 g, 3.44 mmol, 1.0 eq.). The reaction was stirred for 5 mins before addition of 2-bromo-4-(1-bromoethyl)-1,3-thiazole (0.86 g, 3.2 mmol, 0.93 eq.) portionwise. The mixture was stirred for further 5 mins before removal of the cooling bath and continued at ambient temperature. LCMS after 2 h would indicate reaction complete. MeCN was evaporated and the residue was purified by chromatography on silica gel to yield N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (6.9 g, 79% yield, 9:1 mixture of stereoisomers).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.O>C1(C)C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: Clc1ccc(Br)cn1
Reactant: C1CNCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 130 °C
Yield: 79.7 %

Procedure:
A mixture of piperazine (107 g, 1.24 mol) and 2-chloro-5-bromopyridine (30 g, 156 mmol) in toluene (150 mL) was heated at 130° C. for 2 hours, The reaction mixture was cooled to room temperature and toluene (400 mL) and water (200 mL) were added. The organic phase was isolated and the aqeuous phase was extracted once with toluene (100 mL). The collected organic phases were washed with water (150 mL) and brine (100 mL), dried over magnesium sulphate and evaporated to dryness in vacuo to give 30.1 g (80%) of 1-(5-bromopyridin-2-yl)-piperazine.