Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[NH2:26][CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:26][CH2:27][C:28](=[O:29])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: NCC(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1=C(C(=O)NCC(=O)Nc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
179 mg (0.49 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 245mg (1.63 mmol) of 2-amino-N-phenylacetamide, 129 mg (0.67 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 11 mg (0.09 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the product was washed with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=100/1) to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[C:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[NH:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C.O>[C:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[NH:62][CH:63]1[CH2:68][CH2:67][N:66]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:65][CH2:64]1)([CH3:55])([CH3:53])[CH3:54]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: CC(C)(C)c1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccccc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.088 g, 0.00036 mol) in DMF (2 mL) was added DIPEA (0.211 g, 0.0016 mol), HOBt (0.048 g, 0.00036 mol) and EDCI.HCl (0.125 g, 0.000655 mol) at ambient temperature. After 2 minutes (2-tert-butyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00033 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.07 g (49%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-tert-butyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 460.26 (M+1)+, 89.75%, 1H NMR (DMSO-d6): δ 13.8 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.6-7.4 (m, 3H), 7.2-7.0 (m, 3H), 6.8 (d, 1H), 6.6 (t, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (m, 2H), 3.7 (s, 1H), 3.2 (t, 1H), 2.8 (t, 1H), 2.0 (t, 3H), 1.4 (s, 9H), 1.0 (bs, 1H).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:31]C1C2C(=CC(B3OC(C)(C)C(C)(C)C3)=CC=2)N=C(C2C=CC=CC=2)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([C:19]([CH3:31])=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: Cc1cc(-c2ccccc2)nc2cc(B3CC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2ccccc2)nc2cc(-c3nc(C4CCC4)n4ncnc(N)c34)ccc12

Procedure:
7-Cyclobutyl-5-(4-methyl-2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine was prepared using the same procedures described for 7-cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine, except 4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline was used in place of 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline and 2 equivalents of cesium carbonate was used in place of 3 equivalents of sodium carbonate; 1H NMR (CDCl3, 400 MHz) δ 2.06 (m, 1H), 2.17 (m, 1H); 2.47-2.52 (m, 2H); 2.67-2.72 (m, 2H); 2.82 (d, J=0.8 Hz, 3H); 4.14-4.25 (m, 1H); 5.78 (brs, 2H); 7.46-7.56 (m, 3H); 7.77 (d, J=0.8 Hz, 1H); 7.92 (s, 1H); 7.98 (dd, J=8.6, 1.8 Hz, 1H); 8.15-8.18 (m, 3H); 8.39 (d, J=1.6 Hz, 1H); MS (ES+): m/z 407.03 (100) [MH+], HPLC: tR=3.54 min (MicromassZQ, polar—5 min).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)[CH3:13].[CH2:25]([O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31])[CH3:26]>C(O)C>[CH2:25]([O:27][C:28]([C:29]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:1]=[N+:2]=[N-:3])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:32][C:30]=1[CH3:31])=[O:33])[CH3:26]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: [N-]=[N+]=Nc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2ccccc2N=[N+]=[N-])C(C(=O)OCC)=C(C)N1

Procedure:
A solution of 14.7 g of 2-azidobenzaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol is heated to the boil overnight and evaporated in vacuo. Yellow-brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1CCC1CCCN21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CCC1CCCN21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl 7-amino-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (Intermediate 33, 0.575 g) in pyridine (15 mL) and DCM (15 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give a pale yellow solid which was triturated with a mixture of ether and cyclohexane (1:1) to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (0.966 g)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.Cl.[CH2:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH:37]([C:45](O)=[O:46])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:28]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:45]([CH:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][NH:36]3)=[O:46])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH:29]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1ccnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c1
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccnc(CN(Cc2ccc(CNC(=O)C3Cc4ccccc4CN3)cc2CO)C2CCCc3cccnc32)c1
Yield: 27.1 %

Procedure:
(5-Aminomethyl-2-{[(4-tert-butyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.047 g, 0.11 mmol), (±)-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid hydrochloride (0.027 g, 0.13 mmol), HOBT (0.017 g, 0.13 mmol), EDCI (0.024 g, 0.13 mmol) and DIPEA (40 μL, 0.26 mmol) in CH2Cl2 (8 mL) were reacted according to General Procedure G. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 94:5:1, v/v/v) afforded 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid 4-{[(4-tert-butyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamide as a white solid (0.018 g, 28%). 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.59 (m, 1H), 1.89-2.02 (m, 2H), 2.22 (m, 1H), 2.69 (m, 1H), 2.79 (m, 1H), 3.22 (dt, 1H, J=12.0, 3.0 Hz), 3.55-3.66 (m, 4H), 3.87 (m, 1H), 3.94 (d, 2H, J=4.5 Hz), 4.06 (d, 2H, J=12.0 Hz), 4.40 (m, 3H), 7.04-7.24 (m, 9H), 7.36 (d, 1H, J=7.5 Hz), 7.52 (br t, 1H), 7.89 (s, 1H), 8.36 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=3.0 Hz). HPLC: 89%. ES-MS m/z 604 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[N:33]([CH2:34][CH2:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[C:26]4[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=4[CH:24]=3)[C:12]2=[O:42])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH:36]1([CH2:35][CH2:34][N:33]2[C:26]3[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=3[CH:24]=[C:23]2[CH2:22][N:13]2[C:12](=[O:42])[C:11]3([CH2:43][CH2:44][NH:8][CH2:9][CH2:10]3)[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cc3cnc(C#N)nc3n1CCC1CCCCC1)CN2c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc2cc(CN3CN(c4ccccc4)C4(CCNCC4)C3=O)n(CCC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (340 mg, 0.56 mmol) in dichloromethane (5 ml), trifluoroacetic acid (5 ml) is added. After stirring for 1 h at room temperature, solvent is evaporated down to give 7-(2-cyclohexyl-ethyl)-6-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetic acid salt in quant yield.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C1C=NC2N(O)N=NC=2C=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:50]([N:52]([CH2:67][CH3:68])[CH2:53][CH2:54][O:55][C:56]1[CH:61]=[CH:60][C:59]([CH:62]([NH2:66])[CH2:63][CH2:64][CH3:65])=[CH:58][CH:57]=1)[CH3:51]>CN(C=O)C.C(OCC)(=O)C>[C:1]([CH2:3][C:4]([NH:66][CH:62]([C:59]1[CH:58]=[CH:57][C:56]([O:55][CH2:54][CH2:53][N:52]([CH2:67][CH3:68])[CH2:50][CH3:51])=[CH:61][CH:60]=1)[CH2:63][CH2:64][CH3:65])=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
To an ice cooled solution of cyanoacetic acid (37 mg, 0.43 mmol) in DMF (2 mL) was added 7-aza-1-hydroxybenzotriazole (HOAt; 59 mg, 0.43 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 165 mg, 0.43 mmol), diisopropylethylamine (DIPEA; 167 μL, 0.958 mmol) and 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-amine (25; 115 mg, 0.43 mmol). The resulting mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with sat. aqueous NaHCO3 (2×) and sat. brine, dried over sodium sulfate, and concentrated to a thick yellow oil. Purification by flash silica gel column chromatography, eluting with 5:95 methanol/dichloromethane, afforded 29 (116 mg, 80%) as a yellow oil: MS (ES+) m/z 332.2 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:48])[C@@H:20]([NH:28][C:29](=[O:47])[C@H:30]([C:40]([S:43]([CH3:46])(=[O:45])=[O:44])([CH3:42])[CH3:41])[NH:31][C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]1(=[O:55])[O:54][C:52](=[O:53])[CH2:51][CH2:50]1>O1CCCC1>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([O:48][C:49](=[O:55])[CH2:50][CH2:51][C:52]([OH:54])=[O:53])[C@@H:20]([NH:28][C:29](=[O:47])[C@H:30]([C:40]([S:43]([CH3:46])(=[O:45])=[O:44])([CH3:42])[CH3:41])[NH:31][C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccnc1)C(C)(C)S(C)(=O)=O
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](OC(=O)CCC(=O)O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccnc1)C(C)(C)S(C)(=O)=O
Yield: 67.6 %

Procedure:
A solution of 68 mg (0.1 mmol) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide (example 7) in 10 ml of tetrahydrofuran was treated with 10 mg (1 mmol) of succinic anhydride (Aldrich 23,960-0) and heated at reflux overnight. The volatiles were evaporated under reduced pressure and the residue chromatographed on silica eluting with dichloromethane/methanol (19:1) to give 53 mg of N-tert-butyl-2-[2(R)-(3-carboxypropionyloxy)-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valyl]amino]-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8a(S)decahydro-3(S)-isoquinolinecarboxamide as a foam, [M+H]+ 784.5.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[O-:24][C:25]#[N:26].[K+]>O>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][C:25]([NH2:26])=[O:24])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 60 °C
Yield: 79.8 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) and potassium cyanate (0.137 g, 1.69 mmol) added to 30 mL stirring water, and the mixture was heated to 60° C. for five minutes. The reaction mixture was then cooled to room temperature, and the resulting white precipitate was collected by filtration, washed with cold water, and dried under vacuum to give 0.408 g of (R)-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea, M+H=363.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27](O)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH:63]([C:65]([S:67][CH3:68])=[S:66])[NH2:64]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([NH:64][NH:63][C:65]([S:67][CH3:68])=[S:66])=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:30])[CH3:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C1(C)C
Reactant: CSC(=S)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSC(=S)NNC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a solution of 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (500 mg, 1.122 mmol, from Step 3 of Example 346). HOBT (206 mg, 1.347 mmol) and DIEA (0.490 mL, 2.81 mmol) in DMF (4 mL) were added EDCI (280 mg, 1.459 mmol) and methyl hydrazinecarbodithioate (144 mg, 1.178 mmol) at 23° C. The reaction mixture was stirred for 1.5 hrs followed by the addition of 25 mL of water. The solids were removed. The water phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with 10% LiCl solution (2×20 mL), 20 mL of brine and dried over Na2SO4. Filtration and concentration gave methyl 2-(4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carbonyl)hydrazinecarbodithioate (466.5 mg, 76% yield). MS (ES+) m/z: 550.08 (M+H); HPLC retention time: 3.168 min (analytical HPLC Method F).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 61.4 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.4%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].CN(C)C=O.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([Cl:20])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Yield: 103.4 %

Procedure:
3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropane carboxylic acid (32.0 grams) was stirred in 400 ml of methylene chloride under nitrogen. To this was added N,N-dimethylformamide (12 ml) and thionyl chloride (22.6 grams). The resulting solution was heated at reflux temperature for about 1.5 hours. The solvent was then removed in vacuo leaving about 36 grams of the desired 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxoyl chloride, which was confirmed by IR and NMR spectroscopy.
Reaction SMILES: CS[C:3]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=O)=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].C(O)(=O)C.C(Cl)Cl>[Zn].S([O-])([O-])(=O)=O.[Cu+2].O>[O:24]=[C:22]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][N:14]1[C:11]1[CH:12]=[CH:13][C:8]([CH:3]([CH3:7])[C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: CSC(C)(C(=O)O)c1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 84.5 %

Procedure:
α-Methylthio-α-[p-(o-carboxybenzoylamino)phenyl]propionic acid (130 mg), 300 mg of zinc powder and 20 mg of of anhydrous copper sulfate were added to 1.5 ml of acetic acid and the resulting mixture was heated under reflux for 5 hours with stirring. After cooling, 30 ml of methylene chloride and 20 ml of water were added. The insoluble precipitate was separated by filtration. The filtrate was acidified to a pH of 1 with conc. hydrochloric acid, and extracted three times with 20 ml of methylene chloride. The organic layer was washed with 20 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 86 mg of α-[p-(1-oxo-2-isoindolinyl)phenyl]propionic acid in a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].[N:10]1([C:16]2[N:17]=[C:18]([CH2:23][C:24]([O-])=O)[NH:19][C:20](=[O:22])[CH:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Na+].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(OCC)(=O)C>CO>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:24]([CH2:23][C:18]3[NH:19][C:20](=[O:22])[CH:21]=[C:16]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:17]=3)=[N:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)ccc3[nH]2)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.5 %

Procedure:
151 mg of 1,2-diamino-4-fluorobenzene are added to a solution of 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 8 ml of methanol. The resulting mixture is stirred at ambient temperature for 5 minutes and then 354 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride hydrate are added. The resulting mixture is thus stirred for 30 minutes at ambient temperature. The reaction mixture is then concentrated to dryness under reduced pressure, and the residue is then taken up in 30 ml of acetic acid. The reaction mixture is brought to reflux for 1 hour, and then concentrated under reduced pressure. 30 ml of water are then added and a saturated aqueous solution of sodium bicarbonate is added until a pH in the region of 7 is obtained. 20 ml of ethyl acetate are then added and the resulting mixture is stirred for 1 hour. The precipitate formed is filtered off and subsequently purified by silica gel column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 80/20 in dichloromethane of 0% to 100% in 25 minutes. 140 mg of 2-[(5-fluoro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1cccc(Oc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2cccc(CCC(=O)O)c2)ccn1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a solution of methyl 3-[3-({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}oxy)phenyl]propanoate (427 mg, 1.15 mmol) in MeOH (10 mL) and THF (5 mL), was added 1M NaOH solution (4.59 mL, 4.49 mmol). The reaction was stirred for 18 h. The solvents were evaporated and the residue was dissolved in water. The solution was acidified to pH=3 by addition of 1N HCl. The precipitate was filtered off and washed with water and then hexane, then dried under vacuum to yield the title compound as a white solid (333 mg, 81%). LCMS: (FA) ES+ 359.1 (M+1), ES− 357.0 (M−1).