Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][C:12]=1[Cl:18])[CH3:8].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)#[N:21]>CN(C)C=O>[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[N:13][C:12]=1[Cl:18])[CH3:8]
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Cl
Temperature: 5 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
96.7 mg (0.7 mmol) of potassium carbonate was added to a stirred solution of 2,6-dichloro nicotinic acid ethyl ester 0.15 g (0.7 mmol) in 10 ml of N,N-dimethyl-formamide (DMF) cooled to 5° C. This was followed by dropwise addition (over a period of 10 min) of 4-cyano phenol 80 mg (0.68 mmol) dissolved in 2 ml of DMF. The reaction mixture was allowed to stir at RT for 2 h, concentrated under reduced pressure and the residue was dissolved in 100 ml of ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane:ethylacetate (8:2) as eluants to afford 0.13 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 7.26 (1H, s), 7.38 (1H, s), 7.48 (2H, d), 7.96 (2H, d).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(CC(=O)c2ccoc2C)ccn1
Product: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Temperature: 100 °C
Yield: 99.9 %

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(2-methyl-4-pyridinyl)ethanone (0.430 g, 2.000 mmol) in N,N-dimethylformamide dimethyl acetal (0.266 ml, 2 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated to give the title compound (540 mg) which was used crude in the next step. LC/MS [M+H]+=271.
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:45])[C@@H:5]1[C@H:46]([OH:48])[CH3:47])C.[Cl:49]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:49][C@@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:45])[C@@H:5]1[C@H:46]([OH:48])[CH3:47]
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)Sc2ccccc2)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)Sc3ccccc3)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a stirred solution of 2.75 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-(1(R)-hydroxyethyl)-azetidin-2-on-1-yl]-3-[4-(phenylthio-(carbonyl))-phenoxy]-3-trimethylacetylthiopropenoate in 25 ml of dry chloroform at -40° C. was added a solution of 5.3 mmol of chlorine in 7 ml of carbon tetrachloride, and the solution was stirred for 30 minutes. The reaction mixture was allowed to reach room temperature and evaporated to dryness. Chromatography of the residue (silica gel, hexane/ethyl acetate mixtures as eluant) gave the title compound (1.98 g)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:33])=[O:32])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(O[N:42]1N=N[C:44]2C=CC=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(N)C.Cl>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:32])=[O:33])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:42][CH2:43][CH3:44])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCNC(=O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reaction time: 0.08 h

Procedure:
To a solution of {2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-phenyl}-acetic acid (40 mg, 0.86 mmol) in DMSO (0.7 mL) is added HATU (49 mg, 0.129 mmol) and diisopropylethylamine (0.045 mL, 0.256 mmol). The mixture is stirred for 5 min then ethylamine (0.086 mL, 2M in THF) is added dropwise. Upon completion of the reaction, the mixture is acidified with 1N HCl and extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[Cl:26][C:27]1[C:31]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:30][S:29][C:28]=1[C:38](Cl)=[O:39]>C1COCC1>[Cl:26][C:27]1[C:31]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])=[CH:30][S:29][C:28]=1[C:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:39]
Reactant: CC(C)S(=O)(=O)c1csc(C(=O)Cl)c1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3scc(S(=O)(=O)C(C)C)c3Cl)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-chloro-4-(isopropylsulfonyl)-2-thiophenecarbonyl chloride: ESMS m/e: 596.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].Cl>O1CCCC1>[CH2:17]([CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:18][CH3:19]
Reactant: CCCC(CCC)CCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCC(CCC)CCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a 250 mL flask containing potassium tert-butoxide (13.27 g, 108.7 mmol, 4.6 eq.) under nitrogen atmosphere was added anhydrous tetrahydrofuran (100 mL) and via cannula 1-bromo-6-propylnonane (5.87 g, 23.54 mmol) in solution with anhydrous tetrahydrofuran (20 mL) was transferred at 0° C. The mixture was then stirred at room temperature for 2 h. Hydrochloric acid (230 mL, 1M) was added slowly and the mixture was extracted with cyclohexane (300 mL+3×100 mL). The combined organic phase was washed with aqueous sodium bicarbonate (100 mL, 1M) and dried over magnesium sulfate. The solvent was carefully evaporated under moderate vacuum (at room temperature because of the high volatility of the alkene) to give 3.3 g (84%) of 6-propylnon-1-ene as a brown liquid. 1H NMR (CDCl3, 400 MHz) d?(ppm): 5.82 (ddt, J=6.8 Hz, J=10.2 Hz, J=16.9 Hz, H); 5.00 (broad d, J=16.9 Hz, H); 4.93 (broad d, J=10.2 Hz, H); 2.02 (dt, J=6.8 Hz, J=6.8 Hz, 2H); 1.41-1.30 (m, 2H); 1.32-1.15 (m, 11H); 0.88 (t, J=7.1 Hz, 6H′). 13C NMR (CDCl3, 129.9 MHz) d?(ppm): 139.3; 114.1; 36.8; 36.1 (2C); 34.3; 33.2; 26.0; 19.8 (2C); 14.5 (2C). MS (IE) m/z (%) 169.1 [M+] (25); 141.1 (30); 125.0 (57); 113.0 (40); 99.0 (44); 85.0 (67); 71.0 (73).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][C:12]([C@H:41]([N:43]3[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]3)[CH3:42])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:53][CH3:54].FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][C:12]([C@H:41]([N:43]3[CH2:44][CH2:45][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:47][CH2:48]3)[CH3:42])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:53][CH3:54]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(Cl)c(OC)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cnc1Cl
Temperature: 80 °C
Yield: 78 %

Procedure:
A solution of (R)-4-(2-(6-chloro-5-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (130 mg, 0.168 mmol) in 3 mL of TFA was treated with 0.1 mL of trifluoromethanesulfonic acid. It was heated in an oil bath at 80° C. for 3 h. The dark solution was concentrated and the residue was treated with ice cube followed by 0.5 N NaOH until the pH was about 8. The mixture was extracted with 2×30 mL of EtOAc followed by 2×15 mL of DCM. The combined organic solution was dried and concentrated. The residue was loaded on a silica gel column and eluted with 1 to 10% MeOH in DCM to give (R)-4-(2-(6-chloro-5-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (70 mg, 78% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.22 (s, 1H), 8.74 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.36 (dd, J=10.4, 2.2 Hz, 2H), 7.95 (br., 1H), 7.83 (br., 1H), 3.94 (s, 3H), 3.60 (m, 1H), 3.09 (m, 4H), 2.86 (s, 3H), 2.46 (s, 3H), 2.44 (m, 4H), 1.36 (d, J=6.7 Hz, 3H). m/z (ESI, positive ion) 534.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([O:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH2:40])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C1COCC1.CC#N.[Cl-].[Na+].O>[NH2:40][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:34]=1[CH2:33][CH2:32][O:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([NH:20][C:11]([NH:10][C:8]2[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)=[O:12])=[CH:22][CH:23]=1
Reactant: Nc1cnccc1CCOc1ccc(N)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccncc3N)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole (19) (530 mg, 2.076 mmol) in THF (2.0 mL) was added to a solution of 4-(2-(4-aminonaphthalen-1-yloxy)ethyl)pyridin-3-amine (18) (580 mg, 2.076 mmol) and DIPEA (1085 μl, 6.23 mmol) in THF (10 mL) and MeCN (1.0 mL) the reaction mixture stirred at RT overnight. The mixture was poured into brine (25 mL) and extracted with EtOAc (2×25 mL), dried, filtered and the solvent removed in vacuo. The product was pre-adsorbed onto hyflo (10 g), and purified by reverse phase column chromatography (40 g, C18 (from Silicycle), acetonitrile/water, 0 to 100%) and the product fractions concentrated in vacuo to give 1-(4-(2-(3-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl) urea (Intermediate E) as an off white solid (410 mg, 36%). m/z 535 (M+H)+ (ES+).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O.C1CN([P+](O[N:34]2N=[N:41][C:36]3C=CC=C[C:35]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([NH:41][CH2:36][C:35]#[N:34])=[O:8]
Reactant: CC(C)CC(Cc1ccccc1Br)C(=O)O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(Cc1ccccc1Br)C(=O)NCC#N
Reaction time: 2.5 h

Procedure:
To 2-(2-bromobenzyl)-4-methylpentanoic acid (1.248 g, 4.38 mmol), PyBOP (3.12 g, 6.0 mmol), aminoacetonitrile hydrochloride (1.11 g, 12.0 mmol) in dry DMF (30 mL) under dry nitrogen was added triethylamine (1.9 mL, 18.53 mmol) dropwise and the reaction was stirred for 2.5 hours. Aqueous Sat. NaHCO3 was added and the product, extracted with Et2O (2×), dried on Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford 2-(2-bromobenzyl)-N-(cyanomethyl)-4-methylpentanamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]1[CH2:14][N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=2[NH:10][C:9]1=[O:29])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]1[C:9](=[O:29])[N:10]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=2[N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Yield: 86 %

Procedure:
In an analogous manner to that described in Example 2a), the alkylation of the [(S)-1-(2-benzyloxy-ethyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with 2,2,2-trifluoroethyl trifluoromethanesulphonate using lithium bis(trimethylsilyl)amide (1M solution in tetrahydrofurane) as the base yielded title compound as a white foam (yield 86% of theory); MS (m/e): 494 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][NH:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].P(OCC)(OCC)(O[CH2:30][CH3:31])=O>O>[CH2:30]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=2[O:13][CH3:14])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]1)[CH3:31]
Reactant: CCOC(=O)c1c[nH]c2c(OC)c(OC)ccc2c1=O
Reactant: CCOP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC)c2c(OC)c(OC)ccc2c1=O
Temperature: 120 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
A mixture of ethyl 7,8-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (40 g, 144 mmol) and potassium carbonate (29.9 g, 216 mmol) in triethyl phosphate (123 ml, 721 mmol) was stirred at 120° C. for 24 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to rt and diluted with water, extracted with DCM, dried over sodium sulfate and evaporated in vacuo. The crude material was recrystallized in EtOH, the precipitate was collected by filtration, washed by cold EtOH and dried in air to afford ethyl 1-ethyl-7,8-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (26 g, 85 mmol, 59.0% yield) as a yellow solid. LCMS: (M+H)+: 306.2.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:4]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[CH:19]1([NH:25][C:3]2[CH:4]=[C:5]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=3)[N:6]=[CH:7][N:8]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(Nc2cc(NC3CCCCC3)ncn2)c1
Temperature: 200 °C
Yield: 94 %

Procedure:
60 mg of 6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride, 32 mg cyclohexylamine and 69 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was precipitated from n-BuOH. Purification was carried out by filtering and washing with cold n-BuOH. Pure N4-cyclohexyl-N6-(3-nitrophenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][N:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 36.3 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyrimidin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (35 mg, 36% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.34 (s, 1H), 8.47 (s, 2H), 8.26 (m, 2H), 8.04 (d, J=8.8 Hz, 1H), 7.41 (s, 2H), 4.07 (m, 2H), 3.91 (m, 1H), 3.81 (m, 2H), 2.81 (s, 1H), 2.52 (m, 1H), 2.23 (tt, J=13.0, 5.7 Hz, 1H), 1.20 (s, 4H); ESI MS m/z 535 [C27H24Cl2N6O2+H]+; HPLC 100.0% (AUC), tR=10.30 min.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.[C:43]([Zn])#[N:44]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:43]([C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1)#[N:44]
Reactant: N#C[Zn]
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C#N)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 120 °C

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (75 mg, 0. 113 mmol), tetrakis(triphenylphosphine) palladium(0) (13.1 mg, 0.011 mmol) and cyanozinc (20.7 mg, 0.226 mmol) were combined in dry N,N-dimethylformamide (2 mL) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate and washed with water and brine, concentrated and purified by flash chromatography on silica gel (20% EtOAc/Hex) to afford 21 mg (30.5%) as an oil. LC/MS (HPLC method 2): tR=3.265 min, 609.18(MH)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])=[CH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:41][C:42]1[CH:49]=[C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=2[C:59]([F:62])([F:61])[F:60])[CH:47]=[CH:46][C:43]=1[CH2:44][NH2:45]>O1CCCC1.CN(C=O)C.C(N(CC)CC)C>[F:41][C:42]1[CH:49]=[C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=2[C:59]([F:60])([F:61])[F:62])[CH:47]=[CH:46][C:43]=1[CH2:44][NH:45][C:16]([C@:11]1([NH:10][C:8]([C:4]2[CH:5]=[N:6][NH:7][C:2](=[O:1])[CH:3]=2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12]1)=[O:18]
Reactant: COc1ccc(Nc2ccc(CN)c(F)c2)c(C(F)(F)F)c1
Reactant: O=C(N[C@@]1(C(=O)O)CCOC1)c1cn[nH]c(=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cn[nH]c(=O)c4)CCOC3)c(F)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
(S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (0.55 mmol) was dissolved in a mixture of 30 mL tetrahydrofuran, 4 mL DMF and 0.15 mL triethylamine, then TBTU (0.19 g, 0.58 mmol) was added and the mixture was stirred for 30 minutes at ambient temperature. Then 2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzylamine (0.17 g, 0.55 mMol, from 1b) was added and the mixture was stirred for a further two hours. As there was still some unreacted amine present, another 10 mg of the acid and 20 mg TBTU were added and the mixture was stirred further overnight. Then the solvents were evaporated off and the residue was chromatographed on silica gel (eluant: dichloromethane/methanol/ammonia: 95/5/0.5). In this way the product was obtained in a yield of 19% of theory.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][C:3]1=2.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][C:17]1[C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)O)cc(Cl)c21
Yield: 56.1 %

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (2.0 g) was dissolved in chloroform (50 ml), and the solution was refluxed for 2 hours with the addition of N-chlorosuccinimide (1.4 g). The reaction mixture was treated in the same manner as described in Example 8 to obtain 5,6-dihydro-4-chloro-5-methyl-11-oxodibenz[b,e]azepine-2-acetic acid (1.2 g) having a melting point of 168.0°-170° C. (prismatic crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[O:17]=[C:18]([C:27]1[CH:32]=[CH:31][N:30]=[N:29][CH:28]=1)[CH2:19][C:20](OC(C)(C)C)=[O:21]>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:18](=[O:17])[C:27]2[CH:32]=[CH:31][N:30]=[N:29][CH:28]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnnc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1NC(=O)CC(=O)c1ccnnc1

Procedure:
The title compound was prepared from the reaction of tert-butyl 2-amino-4-bromophenylcarbamate (Example B1; 1 mmol) and tert-butyl 3-oxo-3-(pyridazin-4-yl)propanoate (Example C1; 1 mmol) according to the general procedure D. Obtained as a yellow solid (89%), MS (EI) 435 [(M+1)+].