Azzindani/Open_Reaction_Data huggingface dataset:
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: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)O)c2)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: CCN(C(C)C)C(C)C
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) δ: 8.42 (d, J=7.8 Hz., 1 H), 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: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([O:14][CH:15]([C:17]([O:19]CC)=[O:18])[CH3:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C(O)C>[C:17]([CH:15]([O:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)[CH3:16])([OH:19])=[O:18]
Reactant: CCOC(=O)C(C)Oc1nc(C)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(OC(C)C(=O)O)nn1-c1cccc(Cl)c1

Procedure:
A 3.8 g portion of the compound of Example 17 was refluxed for 4 hours with 1.4 g of potassium hydroxide in 100 ml of ethanol, and the product was collected as shown in Example 22 and recrystallized from ethanol to obtain 2.8 g of the desired product, m.p. 101°-103°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][C:15]1[CH:56]=[CH:55][C:18]([C:19]([N:21]([CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)=[CH:36][CH:35]=4)[N:30]=3)=[CH:25][CH:24]=2)=[O:20])=[CH:17][CH:16]=1)=[O:13].CO.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][C:15]1[CH:56]=[CH:55][C:18]([C:19]([N:21]([CH2:47][C:48]([OH:50])=[O:49])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)[N:30]=3)=[CH:25][CH:24]=2)=[O:20])=[CH:17][CH:16]=1)=[O:13]
Reactant: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71 %

Procedure:
Prepared using General Procedure 9. To a stirring solution of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-65 (55 mg, 0.073 mmol) in THF (2 mL) and MeOH (0.25 mL) was added 1 M LiOH (146 μL, 0.146 mmol). The reaction mixture was stirred at room temperature for 20 h and a precipitate was formed. The mixture was filtered under vacuum and the captured solid washed with diethyl ether (5 mL). The captured solid was under vacuum to provide 36 mg (71%) of 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 457 as a white solid. LCMS-ESI (m/z) calculated for C41H36N4O7: 696; found 697 [M+H]+, tR=9.84 min (Method 9). 1H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 8.22-8.11 (m, 4H), 7.87 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.6 Hz, 4H), 7.51 (d, J=8.0 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 6.94-6.90 (m, 1H), 6.88 (d, J=3.1 Hz, 1H), 6.83-6.78 (m, 1H), 4.81 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.64 (s, 2H), 3.48 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][P-:5]([F:10])([F:9])([F:8])([F:7])[F:6].Cl/[C:12](/[C:18]1[CH:19]=[N:20][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=12)=[CH:13]\[CH:14]=[N+:15]([CH3:17])[CH3:16]>CO>[F:4][P-:5]([F:10])([F:9])([F:8])([F:7])[F:6].[CH3:1][N:2]([CH3:3])/[C:12](/[C:18]1[CH:19]=[N:20][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=12)=[CH:13]\[CH:14]=[N+:15]([CH3:17])[CH3:16]
Reactant: C[N+](C)=C/C=C(\Cl)c1cnn2ccccc12
Reactant: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: CN(C)/C(=C\C=[N+](C)C)c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
Dimethylamine (24.0 mL, 48.0 mmol, 2M in THF) was added in one portion to a suspension of (Z)—N-(3-chloro-3-(pyrazolo[1,5-a]pyridin-3-yl)allylidene)-N-methylmethanaminium hexafluorophosphate (Intermediate 71, 6.07 g, 16 mmol) in CH3OH (40 mL) at r.t. under N2. The resulting solution was stirred at r.t. for 0.25 h then stored in the freezer overnight. Crystals were produced and these were collected, washed with CH3OH at −50° C. and THF, then dried by suction under a stream of N2. Two crops of crystals were collected to give the title compound (5.29 g, 85%) as a beige crystalline solid; m/z: ES+ M+ 244.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:30]([CH3:37])[CH:29]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: COc1ccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4-methoxy-2-methylphenylboronic acid (CAS RN 208399-66-0). Pale yellow sticky solid (67%). MS (ESI): m/z=469.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](=[S:24])[NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25](OC(OCC)CBr)[CH3:26]>Cl.C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]4[S:24][CH:25]=[CH:26][N:23]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: Cl
Solvent: CCO
Product: c1csc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n1
Yield: 15.6 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbothioamide (150 mg, 0.43 mmol), bromoacetaldehyde diethylacetal (67 μL, 0.43 mmol), concentrated hydrochloric acid (5 drops) and ethanol were combined and heated at reflux for 5 hours. The reaction mixture was concentrated in vacuo and partitioned between 10% Na2CO3 (20 mL) and dichloromethane (2×35 mL). The combined organics were dried using Na2SO4, filtered and concentrated in vacuo. The compound was purified using column chromatography using 15 g of silica gel, eluting with dichloromethane:methanol:ammonia (95:5:0.5) to give a cream coloured solid. This was triturated with 3 mL of diethyl ether to give the title compound as a cream coloured solid (25 mg, 16%). 1H NMR (400 MHz, CD3OD) δ7.7 (s, 1H), 7.45 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 4.0 (t, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 2.85-2.75 (m, 6H), 2.6 (m, 2H), 2.4 (m, 2H), 2.03 (m, 2H), 1.9 (m, 4H)
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[C:13]([F:18])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[C:13]=1[F:18]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2ccc(Cl)c(F)c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 197.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 25° C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 93 mg of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=8, 8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 3.58 (m, 1H), 3.25-3.15 (m, 3H), 2.93 (d, J=13 Hz, 1H) 2.75-2.60 (m, 3H), 1.96 (bs, 1H), 1.33 (d, J=8 Hz, 3H). MS calculated for C11H13ClFN+H: 214, observed: 214.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:16][C:15]3=[O:31])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:34]=O>C(O)=O>[CH3:34][N:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)[N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]=[CH2:30])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:16][C:15]1=[O:31]
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(NC3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: C=Cc1ccc(S(=O)(=O)N2CCN(N(C)C3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Yield: 75 %

Procedure:
1-{[1-(4-pyridinyl)-4-piperidinyl]amino}-4-(4-vinylbenzenesulfonyl)-2-piperazinone (180 mg) was dissolved in a 37% aqueous solution of formaldehyde (11 ml and formic acid (5 ml) and refluxed for 2 hours. The reaction mixture was cooled and made alkaline by adding an aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ether to obtain the title compound (139 mg, 75%) as colorless crystals.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][C:17]=2[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[CH2:10][C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CO.[Li+].[OH-]>O>[C:1]1([S:7][CH2:8][C@H:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:24])(=[O:25])[NH2:23])=[CH:18][C:17]=2[S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A 100 ml flask was charged with (R)-methyl 4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoate (INTERMEDIATE 7, 7.5 g, 14.63 mmol) and THF (117 ml), MeOH (39 ml) and water (39 ml) were added sequentially. LiOH (1.05 g, 43.9 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the volatiles, and cooled to 0° C. An aqueous solution of HCl (1N) was added dropwise to the solution and the resulting mixture was filtered. The filter cake was dried under high vacuum at 60° C. to provide the title product (6.8 g, yield: 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH:25][S:12]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:14])=[O:13])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1cc(Br)cc2cnccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(Br)cc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 7-bromo-isoquinoline-5-sulfonyl chloride (16.3 g, 35.5 mmol) in CH2Cl2 (200 mL) is added in small portions to a stirred solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (6 mL, 37.9 mmol) and pyridine (2.79 mL, 34.5 mmol) in CH2Cl2 (100 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature overnight. The mixture is diluted with another 100 mL CH2Cl2, washed with saturated aqueous NaHCO3 (150 mL) solution, dried, filtered and concentrated. The dark oil is subject to column chromatography (Biotage 75 short; eluted with 10-20% CH3CN/CH2Cl2+0.2% NEt3) to give the title compound as a white solid. ESIMS: m/z 430 [(M+H)+, 79Br], 432 [(M+H)+, 81Br].
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1)[CH3:6])[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1.C(Cl)[Cl:74]>>[ClH:74].[ClH:74].[CH2:1]([N:5]([CH2:7][C:8]1[S:12][C:11]([C:13]([NH:49][C@@H:50]([CH2:64][C:65]2[CH:66]=[C:67]([F:72])[CH:68]=[C:69]([F:71])[CH:70]=2)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=2)=[O:15])=[CH:10][CH:9]=1)[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)Cc1ccc(C(=O)O)s1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: ClCCl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)Cc1ccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)s1
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution 5-([butyl(methyl)amino]methyl)thiophene-2-carboxylic acid (171 mg, 0.75 mmol) and N,N-diisopropylethylamine (250 μL, 1.43 mmol) in methylene chloride (5.0 mL) is added HBTU (285 mg, 0.75 mmol) and the reaction stirred for 0.5 h. To this is added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method in EXAMPLE SP-272 (306 mg, 0.75 mmol) in methylene chloride (5.0 mL) containing N,N-diisopropylethylamine (250 μL, 1.43 mmol). The reaction mixture is then stirred at room temperature overnight. The reaction mixture is diluted with methylene chloride, washed with saturated sodium bicarbonate, and brine. The organic layer is then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 95:5 chloroform/methanol) gives the title compound as the free base. The solid is dissolved in methanol (1 mL) and treated with hydrochloric acid (1.0 M diethyl ether). The resulting precipitate was collected by filtration to provide the title compound. ESI MS m/z 544.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:34])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[CH3:34])=[CH:33][CH:32]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCCOc1ccc(N)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(F)cncc2F)s1
Product: CN(C)CCCOc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(F)cncc3F)s2)cc1

Procedure:
Prepared according to the procedure described for example 44 from 5-((3,5-difluoropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (25 mg, 0.79 mmol) and 4-(3-(dimethylamino)propoxy)aniline (26.7 mg, 0.79 mmol). The title compound was obtained as a solid (12 mg, 15%). MS m/z: 495.10, [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[NH:16][C:15](=[O:24])[N:14]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]3=[O:30])[CH:9]=1)=O.C([NH2:33])=O.C[O-].[Na+]>CN(C)C=O>[CH3:29][S:26]([NH:25][N:14]1[C:13](=[O:30])[C:12]2[C:17](=[CH:18][C:19]([C:20]([F:22])([F:21])[F:23])=[C:10]([N:8]3[CH:9]=[C:5]([C:3]([NH2:33])=[O:2])[N:6]=[CH:7]3)[CH:11]=2)[NH:16][C:15]1=[O:24])(=[O:27])=[O:28]
Reactant: COC(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cnc(C(N)=O)c3)cc2c1=O
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methyl ester (50 mg, 0.112 mmol) and formamide (0.15 ml, 0.374 mmol) in 5 ml of dimethylformamide is heated to 120° C. and sodium methylate (6 mg, 0.112 mmol) is added under stirring. After two hours at 120° C. the solution is cooled to room temperature, evaporated in vacuo and the residue chromatographed to give 30 mg (0.069 mmol, 62%) of amorphous 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H -imidazole-4-carboxylic acid amide, ES-MS: m/z 433 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1.[C:25](Cl)(=[O:27])[CH3:26].[OH-].[Na+]>C1COCC1>[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH:1][C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]1)(=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 33.2 %

Procedure:
A solution of 5-nitro-2-(piperazin-1-yl)benzenamine (2.4 g, 10.7 mmol), benzoyl chloride (1.2 ml, 12.8 mmol) and triethylamine (6.0 ml, 42.7 mmol) in 40 ml DCM was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. (4-(2-Amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (3.0 g, 86%) was obtained by flash column chromatograph (40% ethyl acetate in hexanes). A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.3 g, 0.9 mmol), acetyl chloride (0.065 ml, 0.9 mmol) and sodium hydroxide (0.037 g, 0.9 mmol) in 20 ml THF was stirred at 0° C. for 2 hours. The mixture was concentrated. N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)acetamide (0.11 g, 32%) was obtained by flash column chromatograph (65% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.29 (s, 3H), 3.00 (s, br, 4H), 3.84 (s, br, 4H), 7.23 (d, J=8.8 Hz, 1H), 7.47-7.51 (m, 5H), 8.00 (dd, J=8.6, 2.6 Hz, 1H), 8.16 (s, br, 1H), 9.24 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 25.3, 52.3, 116.0, 119.9, 120.8, 127.6, 129.2, 130.7, 135.6, 171.2.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:21]([N:23]([CH2:32][CH3:33])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1)[CH3:22].N1CCCCC1.CCOCC>C(O)C>[OH2:29].[Br-:1].[CH2:32]([N:23]([CH2:21][CH3:22])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N+:14]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:26][CH:25]=1)[CH3:33].[CH2:21]([N:23]([C:24]1[CH:25]=[CH:26][C:27]([CH:28]=[CH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N+:14]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:30][CH:31]=1)[CH2:32][CH3:33])[CH3:22].[Br-:1]
Reactant: CCCCCCCCCCCC[n+]1ccccc1C
Reactant: CCN(CC)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCCCCCCC[n+]1ccccc1C=Cc1ccc(N(CC)CC)cc1
Product: O
Yield: 41.2 %

Procedure:
1-Dodecyl-2-methylpyridinium bromide (3.42 g), 0.01 mole) and 4-diethylaminobenzaldehyde (1.9 g), 0.011 mole) were refluxed in ethanol (15 ml) in the presence of piperidine (0.2 ml) under nitrogen for two hours. The solution was cooled and ether was added when an orange solid crystallised which was collected giving 2-[4-(diethylamino)styryl]-1-dodecylpyridinium bromide hemihydrate, (2.1 g), melting point 199°-200° C.
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[O:9][CH2:10][C:11]#[CH:12].[C-]#N.Br[CH2:19][C:20]#[C:21][CH2:22][C:23]#[CH:24]>CCOCC.O1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[O:9][CH2:10][C:11]#[C:12][CH2:19][C:20]#[C:21][CH2:22][C:23]#[CH:24]
Reactant: C#CCOc1cccc(Cl)c1
Reactant: C#CCC#CCBr
Agent: CC[Mg]Br
Agent: [C-]#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC#CCC#CCOc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
21.76 ml (9.8 g, 0.735 mmol) of a 3.38N solution of ethylmagnesium bromide in ether was added dropwise, under argon to a cold (0°-5° C.) solution of 11.66 g (0.7 mol) of 3-(m-chlorophenoxy)-1-propyne [I. Iway, et al., Chem. Pharm. Bull., 11, 1042 (1963)] in 80 ml of anhydrous tetrahydrofuran. The rate was monitoredto maintain a temperature of 0° C. Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 31.35 mg ofcuprous cyanide were added and the mixtured stirred 20 minutes more. Then asolution of 5.5 g (0.035 mol) of 1-bromo-2,5-hexadiyne in 20 ml of anhydrous tetrahydrofuran was added dropwise to the mixture as the temperature was maintained at between 0°-5° C. Then the reaction was stirred at room temperature for 3 additional hours and quenched with 200 ml of 1N sulfuric acid and ice. After extraction with ether (3×200 ml), the combined organic extracts were concentrated invacuo to a small volume, and washed several times with EDTA and water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on 350 g of silica gel, using hexane as eluant, and the product crystallized from methylene chloride-hexane, to yield 9-(m-chlorophenoxy)-1,4,7-nonatriyne, as an oil. The product was stored in dry ice.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH:13]=[CH2:14])[CH:7]=[CH:8][N:9]=2)[N:4]=1.Cl.[CH3:16][NH2:17].CC(O)=O>CO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][NH:17][CH3:16]
Reactant: C=Cc1ccnc2ccc(OC)nc12
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CNCCc1ccnc2ccc(OC)nc12
Yield: 18.6 %

Procedure:
A solution of 2-methoxy-8-vinyl-[1,5]naphthyridine (prepared as in WO 02/08224; 0.28 g, 1.5 mmol) in MeOH (6 mL) was treated with methyl amine hydrochloride (0.1 g, 1 eq.) and heated in a sealed flask at reflux for 5 h. AcOH (0.9 mL) was added and the mixture heated at reflux overnight. The mixture was concentrated in vacuo, taken up in aq. ammonia and extracted with DCM/MeOH (9:1). The combined org. extracts were dried over MgSO4 and concentrated. The residue was purified by FC (DCM/MeOH 9:1+1% NH4OH) to give the title amine as a brown oil (0.06 g, 19% yield).