Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]#[N:26])=[CH:7]2.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(Cl)c23)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3cccc(Cl)c23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((8-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (450 mg, 1.21 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL). The resulting mixture was heated to reflux for 2 hours and the solvent was subsequently removed to give the title compound as a yellow solid, which was used without further purification (450 mg, 91%). ESI-MS m/z [M+H]+ 405.2.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
To a solution of 25 (2.864 g, 7.24 mmol) in DCM (30 mL) was added 2-methoxyethylamine (8) (0.756 mL, 8.69 mmol). After 45 min, sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the reaction mixture was stirred at r.t. for 18 h. More sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the mixture was stirred for an additional 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and the phases were separated. Organic phase was collected and the aqueous layer was extracted with DCM (3×100 mL). The combined organic solutions were concentrated and the residue was purified by flash column chromatography (eluent DCM/MeOH) to afford, intermediate 26 (1.742 g, 53% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.62 (d, J=5.6 Hz, 1H), 8.55 (d, J=1.2 Hz, 1H), 8.48 (dd, J=10.2, 2.6 Hz, 1H), 8.37 (s, 1H), 8.26-8.23 (m, 1H), 8.21 (ddd, J=8.8, 2.8, 1.2 Hz, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (dd, J=9.0, 8.2 Hz, 1H), 6.97 (dd, J=5.6, 0.4 Hz, 1H), 3.78 (s, 2H), 3.40 (t, J=5.6 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.6 Hz, 2H). MS (m/z): 455.2 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([CH:28]4[CH2:31][CH2:30][CH2:29]4)[N:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=34)[CH:13]=2)[CH:5]=1.[NH3:33]>CO>[NH2:27][C:23]1[C:22]2[N:21]([C:20]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[N:19][C:18]=2[C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:33])=[O:2])[CH:26]=[CH:25][N:24]=1
Reactant: N
Reactant: COC(=O)c1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Solvent: CO
Product: NC(=O)c1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Temperature: 60 °C

Procedure:
3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzoic acid methyl ester (150 mg, 0.35 mmol) was dissolved in a sealed tube with 2.0 ml of 7N NH3 in MeOH and heated to 60° C. overnight. LC/MS analysis indicated that the reaction was incomplete, therefore NH3 gas was bubbled into the solution and the reaction was run at 100° C. in a 100 mL Parr pressure vessel. The product was chromatographed on silica gel [Jones Flashmaster, 5 g cartridge, eluting with 2% NH3 in MeOH:CH2Cl2] to yield the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.99-2.08 (m, 1H), 2.13-2.25 (m, 1H), 2.46-2.55 (m, 2H), 2.55-2.65 (m, 2H), 3.78-3.87 (m, 1H), 5.21 (s, 2H), 6.95 (d, J=5.2 Hz, 1H), 7.08-7.11 (m, 1H), 7.13 (d, J=5.6 Hz, 1H), 7.22-7.24 (m, 2H), 7.42-7.51 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.80-7.83 (m, 1H), 7.94 s, 1H); MS (ES+): m/z 414.21 (100) [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[NH:14][C@@H:13]([CH2:25][CH3:26])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].[OH-].[K+]>ClCCl>[CH2:38]([O:37][C:35]([N:14]1[C:15]2[C:20](=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH2:12][C@@H:13]1[CH2:25][CH3:26])=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: CC[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (Example 7B) (37.0 g, 97.9 mmol) and pyridine (23.2 g, 293.7 mmol) in dichloromethane (1 L) was cooled in an ice/water bath as ethyl chloroformate (37.2 g, 342.6 mmol) was added slowly. After stirring at room temperature overnight, the mixture was cooled with an ice/water bath as a 1M potassium hydroxide solution was added to quench the reaction. The organic phase was washed twice with a 2M hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product which was purified by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent to afford 40 g of the title product. 1H NMR (CDCl3) δ 0.83 (t, 3H), 1.28 (t, 3H), 1.4-1.6 (m, 3H), 2.53 (m, 1H), 4.23 (m, 2H), 4.47 (m, 1H), 4.80 (m, 1H), 4.94 (m, 1H), 5.18 (s, 2H), 7.3-67.6 (m, 8H).
Reaction SMILES: [CH:1]1([CH:7]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[C:29]([C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][NH:37][CH2:38]4)=[CH:33][CH:32]=3)[N:28]=[C:27]([NH2:41])[N:26]=2)[CH2:21][CH2:20]1>>[CH3:16][O:15][C:13](=[O:14])[NH:12][CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:8][C:9]([N:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][C:31]([C:29]3[CH:30]=[C:25]([N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)[N:26]=[C:27]([NH2:41])[N:28]=3)=[CH:32][CH:33]=2)[CH2:38]1)=[O:11]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: COC(=O)NC(CC(=O)O)C1CCCCC1
Agent: Cl
Product: COC(=O)NC(CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)C1CCCCC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 3-cyclohexyl-3-[(methoxycarbonyl)amino]propanoic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=536.2.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:55]1[CH:64]=[CH:63][C:62]([OH:65])=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59](=[O:66])[NH:60]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCNC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:67][O:68][C:69]1[CH:70]=[C:71]([NH:75][C:76]2[C:85]3[C:80](=[C:81]([CH3:110])[CH:82]=[C:83]([S:86]([C:89]4[CH:94]=[CH:93][CH:92]=[C:91]([C:95](=[O:109])[NH:96][C:97]5[CH:102]=[CH:101][C:100](C#CCCC=O)=[CH:99][CH:98]=5)[CH:90]=4)(=[O:88])=[O:87])[CH:84]=3)[N:79]=[CH:78][C:77]=2[C:111]([NH2:113])=[O:112])[CH:72]=[CH:73][CH:74]=1>>[Si:1]([O:8][C@H:9]([C:55]1[CH:64]=[CH:63][C:62]([OH:65])=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59](=[O:66])[NH:60]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:100]1[CH:101]=[CH:102][C:97]([NH:96][C:95]([C:91]2[CH:90]=[C:89]([S:86]([C:83]3[CH:84]=[C:85]4[C:80](=[C:81]([CH3:110])[CH:82]=3)[N:79]=[CH:78][C:77]([C:111]([NH2:113])=[O:112])=[C:76]4[NH:75][C:71]3[CH:72]=[CH:73][CH:74]=[C:69]([O:68][CH3:67])[CH:70]=3)(=[O:88])=[O:87])[CH:94]=[CH:93][CH:92]=2)=[O:109])=[CH:98][CH:99]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCC=O)cc5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 148, using Intermediate 115 in place of Intermediate 112. ES/MS calcd. for C53H57N6O8SSi+ 965.4. Found m/z=965.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:20][CH2:19][C:18]([F:22])([F:21])[F:17])=[O:8])[CH3:2]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)C(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 31.5 g (15.5 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 400 ml of tetrahydrofuran 16.9 g (17.1 mmol) of 2,2,2-trifluoroethylamine, 32.7 g (17.1 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 23.1 g (17.1 mmol) of 1-hydroxybenzotrizole hydrate and 58.1 ml (34.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The solvent was removed by distillation and the residue was extracted with water/ethylacetate. Chromatography on silicagel with heptane/ethylacetate 1:1 yielded 25.4 g (67%) 2-hydroxy-2-methyl-N-(2,2,2-trifluoroethyl)-malonamic acid ethyl ester, MS m/e (%): 242.1 (M−H, 100).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>C(Cl)Cl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[NH:5]1[CH2:6][CH2:7][O:8][CH:3]([CH2:2][OH:1])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCC1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1.1 g, 5.06 mmol) in DCM (15 mL) was treated with trifluoroacetic acid (2.5 mL, 10.1 mmol) and stirred at rt overnight. The reaction mixture was concentrated under reduced pressure to yield a thick oil (1.1 g, 94%): NMR (DMSO-d6) δ: 9.30 (1H, s), 4.95 (1H, s), 4.19-4.06 (1H, br s), 3.93 (1H, dd), 3.76-3.63 (2H, m), 3.47-3.32 (2H, m), 3.22-3.09 (3H, m), 3.92 (1H, td), 2.76 (1H, t).
Reaction SMILES: [OH-].[NH4+:2].C[O:4][C:5](=O)[C:6]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:7]>O1CCCC1>[C:8]1([C:6](=[O:7])[C:5]([NH2:2])=[O:4])[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1
Reactant: [NH4+]
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reaction time: 3 h
Yield: 86 %

Procedure:
Add concentrated ammonium hydroxide (2 mL) to a solution of (5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (0.50 g, 2.06 mmol) in 10 mL of tetrahydrofuran at 0° C. Remove the cooling bath and stir the mixture for 3 hours. Dilute the reaction with 20 mL of water and filter the suspension. Wash the filter cake with 10 mL of water followed by 10 mL of diethyl ether, and dry under reduced pressure to provide the desired compound as a light yellow solid (0.403 g, 86%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:24]=[CH:23][C:22]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:25][C:26](=[O:34])[CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:19]=4)[C:14](=O)[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:37].P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl>[Cl:37][C:14]1[C:15]2[C:20]([N:21]=[C:22]3[C:13]=1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:24]=[CH:23]3)=[CH:19][C:18]([NH:25][C:26](=[O:34])[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(CCN1CCCC1)Nc1ccc2c(=O)c3cc(NC(=O)CCN4CCCC4)ccc3[nH]c2c1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CCN1CCCC1)Nc1ccc2c(Cl)c3cc(NC(=O)CCN4CCCC4)ccc3nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A suspension of 2,6-bis(3-pyrrolidinopropionamido)acridone AR-ACO-10 (2.0 g, 4.2 mmol) in CHCl3 (40 mL) was treated with phosphorus pentachloride (0.9 g, 4.2 mmol), followed by cautious addition of phosphorus oxychloride (50 mL). This suspension was stirred at room temp. for 30 min and brought to a gentle reflux over 1 hr. Gentle reflux was maintained for 26 hr. The reaction mixture was cooled to rt then slowly dropped onto ice (˜600 mL) over 10 min. The aqueous mixture was made basic to pH 7/8 with ammonia whilst maintaining a temp. <25° C. The aqueous layer was extracted with CHCl3 (5×200 mL). The organic extracts were combined, washed with brine (200 mL), dried (Na2SO4) and concentrated. The resulting solid was tritrated with diethyl ether (30 mL) to give the desired product (1.3 g, 62%) as a light brown solid.
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl.NCCC(OC)=[O:19]>>[O:19]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCN
Reactant: COC(=O)CCNCc1cccs1
Agent: Cl
Product: COC(=O)CCNCc1ccco1

Procedure:
Methyl 3-[(2-furanylmethyl)amino]propanoate (22) was prepared in the manner methyl 3-[(2-thienylmethyl)amino]propanoate (15) was prepared, as described above in Example 15, on a 6.5 mmol scale from methyl β-alaninate hydrochloride and furrural to yield 0.28 g (28%) of product.
Reaction SMILES: [C:1]1([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[Br:30]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[Br:30][C:20]1[CH:21]=[CH:22][C:23]2[N:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-n3c4ccccc4c4ccccc43)cccc2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2ccccc12
Yield: 99.4 %

Procedure:
5.9 g (20 mmol) of 9-(1-naphthyl)carbazole was put into a 500 mL Meyer flask, and 50 mL of ethyl acetate and 50 mL of toluene were added thereto, and the reaction mixture was stirred. Then, 3.6 g (20 mmol) of N-bromosuccinimide was slowly added to the solution, and the solution was stirred for about 170 hours (one week) at room temperature. After this solution was washed with water, the organic layer was dried with magnesium sulfate. Filtration and concentration of the reaction mixture gave 7.4 g of 3-bromo-9-(1-naphthyl)carbazole as white powder (99% yield). The Rf values (SiO2, eluent; hexane:ethyl acetate=2:1) of 3-bromo-9-(1-naphthyl)carbazole and 9-(1-naphthyl)carbazole were 0.43 and 0.35, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]2=[O:19])[C:3]=1[CH2:20]OC1CCCCO1.O=S(Cl)[Cl:30].O>C(Cl)Cl>[Cl:30][CH2:20][C:3]1[C:4]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]2=[O:19])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1COC1CCCCO1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (100 mg. 0.26 mmol) was dissolved in DCM (5 mL). SOCl2 (97 μL. 1.31 mmol) and water (25 μL) were added and the reaction mixture was stirred for 1 h at RT. After removal of the solvents in vacuo the resulting title compound was used for the next reaction without purification. MS (m/z): 317.0 [M+H+].
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][N:8]=1.[CH2:14]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:14]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][N:8]=2)=[O:30])=[CH:32][CH:33]=1)/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: CC(C)CSc1nnc(N)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCC(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-isobutylthio-1,3,4-thiadiazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.6 g) and carbonyldiimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.9 g of the aimed compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[N:20]=[CH:21][N:22]=[C:23]2[C:30]=1[C:29]1[C@H:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26][C:25]=1[S:24]2>O1CCCC1>[C:11]([O:10][C:9]([NH:8][CH:5]1[CH2:6][CH2:7][CH:2]([O:1][C:19]2[N:20]=[CH:21][N:22]=[C:23]3[C:30]=2[C:29]2[C@H:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26][C:25]=2[S:24]3)[CH2:3][CH2:4]1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CCOC(=O)C[C@@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (412 mg, 1.91 mmol, 1.10 equiv) in freshly distilled tetrahydrofuran (10 mL) was treated with sodium hydride (60% dispersion in mineral oil, 280 mg, 4.00 equiv) for 1 h at room temperature under nitrogen. To this mixture was then added a solution of 16.3 (510 mg, 1.72 mmol, 1.00 equiv) in dry tetrahydrofuran (5 mL) via syringe. After stirring overnight at room temperature, the reaction was then quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2) and purified to afford ethyl 2-[(3S)-12-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetate (16.4, 400 mg, 49%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:24]=[N:25][C:26]([NH:29][C:30]([NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])=[CH:27][CH:28]=3)[CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:31])=[N:25][CH:24]=3)[CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.6 %

Procedure:
A mixture of tert-butyl methyl(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)carbamate (0.1 g, 0.192 mmol) and TFA (0.148 mL, 1.921 mmol) in DCM (4 mL) was stirred at RT for 7 h, then concentrated to dryness. The residue was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with 30% EtOAc/Hex, sonicated and the resulting solid collected via filtration to afford N-((5-((6′-(methylamino)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (61 mg, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 10.42 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.44 (d, J=5.7 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.02 (dd, J=8.8, 2.5 Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 6.83 (q, J=5.0 Hz, 1H), 6.73 (dd, J=5.7, 2.4 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 2.80 (d, J=4.7 Hz, 3H), 1.21 (s, 9H); MS (ESI) m/z: 421.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([N:34]2[CH2:35][CH2:36][CH:31]([N:28]3[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]3)[CH2:32][CH2:33]2)[N:7]=1
Reactant: CC1CCN(C2CCNCC2)CC1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(C2CCN(c3nc(Cl)c4ccc(=O)n(-c5c(F)cccc5F)c4n3)CC2)CC1
Temperature: -20 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.39 g, 3.9 mmol) in dichloromethane (80 mL) were added 4-methyl-1,4′-bipiperidine (0.75 g, 5.85 mol) and triethylamine (1.03 mL, 11.7 mmol). The mixture was stirred at about −20° C. overnight. Filtration followed by concentration, the crude was purified with flash chromatography to afford the title compound (0.904 g, 51%). LC-MS m/z 474 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:16][CH:15]3[S:17](=[O:19])(=[O:18])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:20][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:11][CH:12]3[S:17](=[O:19])(=[O:18])[CH:15]([CH2:14][CH2:13]3)[CH2:16]2)([OH:9])[CH3:20])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (4-bromo-phenyl)-(8,8-dioxo-8-thia-bicyclo[3.2.1]oct-3-yl)-methanone (885 mg, 2.58 mmol) in THF (7 ml) at −10° C. to −8° C. was added methylmagnesium bromide 1.4M in toluene/THF 3/1 (3.68 ml, 5.16 mmol). The reaction mixture was stirred for 30 min. The solution was cooled with an ice bath and quenched with a solution of aqueous saturated NH4Cl and water 1/1 (7.5 ml), diluted and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The crude product (940 mg, 2.54 mmol, 97%) was used in the next step without further purification.