Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49](O)=[O:50])=[C:46](C)[N:47]=3)[C:39]2=[O:52])=[CH:28]1.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][NH2:60])[CH:54]=1>>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[SH:44]([CH3:2])[C:45]([C:49]([NH:60][CH2:59][C:55]4[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=4)=[O:50])=[CH:46][N:47]=3)[C:39]2=[O:52])=[CH:28]1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)O
Product: C[SH]1C(C(=O)NCc2cccnc2)=CN=C1N1CCN(CCc2c[nH]c3ccccc23)C1=O
Yield: 36 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-(1H-indol-3-yl)ethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 36% yield: mp 198-201° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.60-8.52 (m, 2H), 8.27 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.31-7.06 (m, 5H), 6.26-6.23 (m, 1H), 4.56 (d, J=5.4 Hz, 2H), 3.99 (t, J=7.8 Hz, 2H), 3.67 (t, J=6.8 Hz, 2H), 3.48 (t, J=7.8 Hz, 2H), 3.05 (t, J=6.9 Hz, 2H), 2.60 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 162.7, 155.4, 153.7, 149.0, 148.9, 148.6, 136.3, 135.9, 127.2, 122.2, 121.9, 119.5, 118.4, 116.6, 112.3, 111.3, 44.2, 42.5, 42.1, 41.3, 23.5, 17.3: MS (ES+) m/z 341.2 (M+1): MS (ES+) m/z 461.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([NH:41][CH2:42][C:43](O)=[O:44])=O)(C)(C)C>>[CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([C:43](=[O:44])[CH2:42][NH2:41])[CH2:23][CH2:22]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(C(=O)CN)CC4)cn3)nc2n1C1CCCC1
Yield: 71.4 %

Procedure:
By repeating procedures outlined in Example 12, 7-cyclopentyl-2-(5-piperazin-1-ylmethyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyri-midine-6-carboxylic acid dimethylamide (0.108 g, 0.241 mmol) and tert-butoxycarbonylamino-acetic acid (42 mg, 0.241 mmol) gave 2-{5-[4-(2-amino-acetyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxy-lic acid dimethylamide as a white solid (87 mg, 69%). MS (ESI) m/z 506.3 (M+H)+ (method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:20])[NH2:19].[Cl:21][CH2:22][C:23]([CH2:25]Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:8]=[C:7]2[C:18]1[S:20][CH:25]=[C:23]([CH2:22][Cl:21])[N:19]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Solvent: Cc1ccccc1
Product: ClCc1csc(-c2cn(CC3CCOCC3)c3c(Cl)cccc23)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbothioic acid amide (920 mg, 3.0 mmol), 1,3-dichloroacetone (571 mg, 4.50 mmol) in toluene (30 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo, and the obtained crystals were washed with 10% dichloromethane (v/v) in n-heptane to give 7-chloro-3-[4-(chloromethyl)-[1,3]-thiazol-2-yl]-1-(tetrahydropyran-4-yl)methyl-1H-indole (590 mg, 1.5 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:15][CH2:14]3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.N.[H][H].C[OH:28]>[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][C:22]([NH2:23])=[O:28])[CH2:17][CH2:18]3)[O:9][CH2:10][CH2:11][O:12]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CO
Reactant: N#CCCCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Agent: [Ni]
Agent: N
Product: NC(=O)CCCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Yield: 95 %

Procedure:
A mixture of 28 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinebutanenitrile and 200 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 5 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated, yielding 25 parts (95%) of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinebutanamide as a residue (10).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[C:30](=[O:33])[CH2:31][CH3:32]>>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[C:10]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCC(=O)N(C)C
Reactant: CCCN(CCC)C1CCc2c(ccc3[nH]ccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1CCc2c(ccc3[nH]cc(C(=O)CC)c23)C1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of dipropyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7-yl)amine (70 mg, 0.26 mmol) and phosphorous oxychloride (48 μL, 80 mg, 0.52 mmol) in N,N-dimethyl propionamide (250 μL) was heated at 80° C. for 6 hours. After cooling 5M sodium hydroxide was added and the mixture was heated again for 0.5 hour. After cooling, the mixture was extracted 3 times with ethyl acetate, dried (magnesium sulfate), filtered and evaporated to yield a residue to which 99% ethanol was added. This was then evaporated to dryness. A few repetions of the last procedure yielded a residue of 86 mg (100%) of the product.:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([O:18]CC2C=CC=CC=2)[C@H:16]([O:26]CC2C=CC=CC=2)[C:12]2([CH2:15][O:14][CH2:13]2)[O:11][C@H:10]1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH3:50])=[CH:44][CH:43]=2)[CH:35]=1)C1C=CC=CC=1.C(O)=O>C1COCC1.CCO.[Pd]>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:10]2[C@H:9]([OH:8])[C@@H:17]([OH:18])[C@H:16]([OH:26])[C:12]3([CH2:13][O:14][CH2:15]3)[O:11]2)=[CH:35][C:36]=1[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH3:50])=[CH:44][CH:43]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC4(COC4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC4(COC4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of (6S,7S,8R,9S)-7,8,9-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,5-dioxa-spiro[3.5]nonane (110 mg, 0.15 mmol) in THF:EtOH (1:1, 5 mL) was added 10% Pd/C (60 mg) followed by formic acid (0.46 mL, 12 mmol) and stirred under hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtered through cetlie bed, neutralized with saturated aqueous NaHCO3 solution, extracted with EtOAc, concentrated and purified by preparative HPLC to furnish 31 mg of (6S,7R,8R,9S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,5-dioxa-spiro[3.5]nonane-7,8,9-triol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([CH2:31][NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:26][C:27]([O:29]C)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.CC#N.[Li+].[OH-].C(O)(C(F)(F)F)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([CH2:31][NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC(CNS(=O)(=O)c1ccc(C)cc1)NC(=O)CNC(=O)c1cccc(NC=NN)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCC(CC(=O)O)NC(=O)CNC(=O)c2cccc(NC=NN)c2)cc1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A solution of the product of Example 64 (180 mg) in 1:1 CH3CN:H2O (4 ml) was treated with LiOH (100 mg). After 2 hours, the reaction was acidified with TFA and purified by HPLC (RP--CH3CN/H2O). The title compound (100 mg) was isolated as a white solid. MS, 1H-NMR and CHN analysis were consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/Br)=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4].[CH3:25][S-:26].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/[S:26][CH3:25])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/SC
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
6-Amino-5-((E)-2-bromovinyl)-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (0.915 g, 2.196 mmol) was dissolved in DMSO (10 mL) and sodium thiomethoxide (0.169 g, 2.416 mmol) was added. After 30 min at ambient temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was diluted with petroleum ether to decrease the solubility of residual DMSO, washed with water thrice, filtered and concentrated. The product was purified by flash chromatography (hexane/ethyl acetate gradient) to provide the title compound (0.510 g, 60.5% yield) as a yellow solid: 1H NMR (CDCl3) δ 7.63 (dd, 1H), 7.19 (dd, 1H), 6.74 (d, 1H), 6.32 (d, 1H), 5.34 (br s, 2H), 3.99 (d, 3H), 3.94 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][C:21]([NH:23][C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=2)=[O:22])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl.CN(C=O)C>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:52](=[O:53])[CH2:51][O:50][CH3:49])=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccncc3N)c3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cnccc1COc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(4-((3-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate C) (50 mg, 0.10 mmol) and DIPEA (33.5 μl, 0.19 mmol) in anhydrous DCM (1.0 mL) and anhydrous DMF (0.1 mL) was added methoxyacetyl chloride (10 μl, 0.11 mmol). The reaction mixture was stirred for 12 hr at RT. LC-MS indicated 50% conversion to the desired product. Methoxyacetyl chloride (10 μl, 0.11 mmol) was added and the reaction mixture was stirred at RT for a further 5 hr; LC-MS indicated the reaction was nearing completion. A further portion of methoxyacetyl chloride (8 μl, 0.09 mmol) was added, and after 2 hr, LC-MS indicated the reaction had reached completion. 1% NH3 In MeOH (10 mL) was added and the reaction mixture was stirred for 20 min at RT. The solvents were removed in vacuo to afford a purple oily solid. This was dissolved in MeOH (2.0 mL) and 3 drops of AcOH were added. The solution was subjected to SCX capture and release, eluting the product with 1% NH3 in MeOH. The solvent was removed in vacuo and the residue was triturated with diethyl ether (10 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-3-yl)-2-methoxyacetamide (Example 16) as a light purple solid (24 mg, 41%) m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.39 (3 H, s), 3.31 (3 H, s (obscured by DHO peak)), 4.06 (2H, s), 5.34 (2H, s), 6.35 (1H, s), 6.96 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.64-7.54 (4H, m), 7.93 (1H, d), 8.29 (1H, dd), 8.45 (1H, d), 8.58 (1H, s), 8.70 (1H, s), 8.79 (1H, s), 9.76 (1H, s).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22](=[O:35])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:32]([C:28]1[S:27][C:26]([N:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][C:22]2=[O:35])=[N:30][C:29]=1[CH3:31])=[O:33]
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1nc2ccccc2s1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1nc2ccccc2s1
Yield: 69 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use benzo[d]thiazol-2-ylmethanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 69% yield: 1H NMR (300 MHz, DMSO-d6) δ 9.23 (t, J=5.8 Hz, 1H), 8.63 (d, J=8.1 Hz, 1H), 8.04-8.02 (m, 1H), 7.93-7.91 (m, 1H), 7.49-7.31 (m, 7H), 6.40 (dd, J=8.1, 2.7 Hz, 1H), 6.24 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 4.78 (d, J=5.8 Hz, 2H), 2.58 (s, 3H); MS (ES+) m/z 489.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].[C:8](#N)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14].[H][H]>[Ni]>[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][NH:1]1)#[N:14]
Reactant: CCC(N)CCN
Reactant: N#CCCCCC#N
Reactant: [H][H]
Agent: [Ni]
Product: CCC1CCNC(CCCCC#N)N1
Temperature: 90 °C
Yield: 59 %

Procedure:
Fifty grams of 1,3-diaminopentane (99%, 0.485 mole), 116 g (1.07 moles) adiponitrile and 2.3 g Raney® nickel were charged to a 300 cc autoclave reactor. The mixture was stirred and heated at 90° C. and 650 psig hydrogen pressure for 10 hours. The mixture was cooled and filtered under nitrogen. Capillary GC analysis of the filtered product indicated a 56% conversion of 1,3-diaminopentane and 59% yield of 2-(4-cyanobutyl)-4-ethylhexahydropyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].CN1C(=O)CCC1.CO>ClCCl>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1OC
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc1OC
Temperature: 140 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A pressure tube was charged with 6-chloro-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (310 mg, 1.00 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (429 mg, 2.00 mmol) and NMP (4 mL). The reaction mixture was stirred at 140° C. for 18 h, then the NMP was distilled using a Kugelrohr under high vacuum and at 120° C. to afford a brown viscous oil. The crude oil was dissolved in dichloromethane and methanol then adsorbed onto silica and purified by chromatography (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH, 40 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate as a brown viscous oil (291.3 mg). This was dissolved in dichloromethane (2 mL) and TFA (740 mg, 500 μL, 6.49 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The TFA and the dichloromethane were removed in vacuo and the residue obtained was purified by chromatography (Spherical silica 20-45 μm, 50 g, Versaflash from Supelco, eluting with 0.1:1.9:98 NH4OH:methanol:dichloromethane to 0.6:11.4:88 NH4OH:methanol:dichloromethane, 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (81 mg, 21%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (br. s., 1H), 8.34 (br. s., 1H), 7.59 (br. s., 1H), 7.46 (s, 1H), 7.35 (d, J=8.08 Hz, 1H), 6.70 (d, J=7.83 Hz, 1H), 6.57 (d, J=8.34 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.10 (br. s., 1H), 2.03 (br. s., 2H), 1.18-1.78 (m, 8H), 0.98-1.12 (m, 1H); LC-MS 388 [M+H]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1([C:17]2[CH:31]=[CH:30][C:20]3[NH:21][C:22]([CH2:24][C:25]([O:27]CC)=O)=[N:23][C:19]=3[CH:18]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]#[N:40]>C1COCC1>[NH2:40][C:39]1[C:34]2[C:33](=[CH:38][CH:37]=[N:36][CH:35]=2)[NH:32][C:25](=[O:27])[C:24]=1[C:22]1[NH:21][C:20]2[CH:30]=[CH:31][C:17]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:18][C:19]=2[N:23]=1
Reactant: N#Cc1cnccc1N
Reactant: CCOC(=O)Cc1nc2cc(N3CCOCC3)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3cc(N4CCOCC4)ccc3[nH]2)c(=O)[nH]c2ccncc12
Reaction time: 8 h

Procedure:
LiHMDS (3.3 eq) was added to ethyl (5-morpholin4-yl-1H-benzimidazol-2-yl)acetate (1.0 eq) and 4-aminopyridine-3-carbonitrile (see J. Chem. Soc. 1967, p 1558-1564; 1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was washed successively with CH2Cl2 and MeOH, and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 363.2 (MH+), Rt 1.55 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=[O:7].CCN=C=NCCC[N:21]([CH3:23])C.Cl.C(N(CC)CC)C.N[O:33][CH3:34].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([N:21]([O:33][CH3:34])[CH3:23])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CON
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
A mixture of 2-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g), DMAP (12.2 g), triethylamine (28 mL), and NH2OMe.HCl (12 g) in CH2Cl2 (300 mL) was stirred at room temperature for 16 h. The reaction was quenched with water, and the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrated was evaporated in vacuo, and the crude product was purified by silica gel flash chromatography eluting with 33% hexanes in ethyl acetate gave the title compound (22 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1([CH3:29])C=CC=C[CH:24]=1.ClC(Cl)([O:33][C:34](=O)[O:35]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC(O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34](=[O:33])[O:35][CH:23]([CH3:29])[CH3:24])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)C)cc3)c2cc1OC
Yield: 59 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-propanol (16 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (42 mg, yield 59%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([C:11]#[N:12])=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N+]([CH3:17])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1([C:11]#[N:12])[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:17]1)=[O:13]
Reactant: COC(=O)C(C#N)=C1CCCCC1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: COC(=O)C1(C#N)CC12CCCCC2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 85.9 %

Procedure:
To a solution of cyano-cyclohexylidene-acetic acid methyl ester (20.0 g, 112 mmol) in acetonitrile (400 mL) was added nitromethane (30 mL, 558 mmol) followed by dropwise addition of DBU (16.9 mL, 113 mmol) over five minutes. The solution went from clear to orange and was stirred at room temperature for 5.5 hours. The solution was diluted with ether (1 L), washed with 1N HCl (2×250 mL) and then brine (2×250 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a wet-packed silica gel column (6.5×40 cm) eluting with 95:5 hexanes/ethyl acetate. The appropriate fractions were combined and evaporated to give 18.6 g (86%) of 1-cyano-spiro[2.5]octane-1-carboxylic acid methyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 1.35 (m, 1H), 1.49 (d, J=5.0 Hz, 1H), 1.5–1.75 (m, 9H), 1.82 (d, J=5.0 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([C:24]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:9]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:33])=[O:32].C(Cl)Cl>CO>[CH3:30][C:24]([C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([C:10]3[CH:9]=[C:8]([C:3]4[C:2]([C:37]5[CH:38]=[CH:39][C:34]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=5)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccccc3Br)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(c1cc(-c2cccc(-c3ccccc3-c3ccc(C(=O)O)cc3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared according to the general procedure Coupling—1 using Arylbromide from step 1 and 4-carboxybenzeneboronic acid as starting materials. Flash chromatography (CH2Cl2:MeOH, 9:1) afforded the title compound.