Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[O:18])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=[CH:7]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[C:11](=[O:18])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=4[CH:8]=[CH:7]3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CN1CC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN1CC(=O)c2c(ccn2CCCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 83.7 %

Procedure:
A suspension of 233 mg (0.8 mmol) of Compound 17, 216 mg (1.2 mmol) of 1-(4-fluorophenyl)piperazine, 166 mg (1.2 mmol) of potassium carbonate and 240 mg (1.6 mmol) of sodium iodide in 20 ml of acetonitrile was refluxed for 23 hours. Post-treatment was conducted in a similar manner as in Example 18. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=1/49), whereby 291 mg of the title compound were obtained (yield: 84%).
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([C:40]([F:43])([F:42])[F:41])[C:36]([NH2:39])=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:19]1([S:16]([C:13]2[CH:14]=[CH:15][C:10]([C:7]3[S:6][C:5]4=[N:4][CH:3]=[C:2]([C:33]5[CH:34]=[C:35]([C:40]([F:43])([F:42])[F:41])[C:36]([NH2:39])=[N:37][CH:38]=5)[N:9]4[N:8]=3)=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(c1ccc(-c2nn3c(I)cnc3s2)cc1)N1CCOCC1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnc3sc(-c4ccc(S(=O)(=O)N5CCOCC5)cc4)nn23)cc1C(F)(F)F
Temperature: 90 °C
Yield: 33.7 %

Procedure:
A mixture of 5-Iodo-2-[4-(morpholine-4-sulfonyl)-phenyl]-imidazo[2,1-b][1,3,4]thiadiazole (85 mg, 0.18 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (60 mg, 0.27 mmol), PdCl2(PPh3)2 (26 mg, 0.037 mmol) and 2M aq Na2CO3 (0.5 mL) in dioxane (4 mL) was heated at 90° C. for 18 h. On cooling, the solvents were removed in vacuo and the residue was triturated from EtOAc and filtered off. The filtrate was evaporated and the residue was recrystallyzed from MeOH, filtered and washed with water. The solid was purified by column chromatography (DCM/MeOH) to afford the desired product (31 mg, 34%) as a yellow solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.12 min, [M+H]+ m/z 511.2; 1H NMR (300 MHz, DMSO) δ 8.89 (s, 1H), 8.36 (s, 1H), 8.26 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H), 7.84 (s, 1H), 6.77 (s, 2H), 3.65 (s, 4H), 2.95 (s, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[N:12]2[C:13](=[O:19])[NH:14][C:15]3=[CH:16][CH:17]=[CH:18][C:10](=[C:11]23)[O:9][CH2:8]1.C(O)(=O)C.[Br:24]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:24][C:18]1[C:10]2[O:9][CH2:8][CH:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)[N:12]3[C:13](=[O:19])[NH:14][C:15]([C:11]=23)=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2cccc3c2n1C(C1CCCCN1)CO3
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)c3c2n1C(C1CCCCN1)CO3
Reaction time: 2 h
Yield: 84.5 %

Procedure:
The 4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.20 g, 0.77 mmol) of Step 1 was dissolved in acetic acid (10.0 mL, 176 mmol) at room temperature and N-bromosuccinimide (0.14 g, 0.77 mmol) was slowly added. The reaction was stirred for 2 h and was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate, washed with brine, dried over magnesium sulfate, and concentrated to give 7-bromo-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a dark oil (0.22 g, 85%). LCMS calculated for C14H17BrN3O2 (M+H)+: m/z=338.0, 340.0. found: 338.0, 340.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:71][CH2:72][C:73]([NH:75][CH3:76])=[O:74]>CN(C=O)C.O>[CH3:32][N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29](=[O:30])[NH:71][CH2:72][C:73](=[O:74])[NH:75][CH3:76])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CNC(=O)CNC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Yield: 75 %

Procedure:
For the preparation of the starting material compound 35.1, please see Example 35. A solution of 2-[(3R)-12-[(4-[[tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid (150 mg, 0.32 mmol, 1.00 equiv), HATU (183 mg, 0.48 mmol, 1.48 equiv), DIPEA (165 mg) and 2-amino-N-methylacetamide hydrochloride (intermediate 83.5, 120 mg, 0.96 mmol, 3.0 equiv) in 10 mL of anhydrous DMF was stirred for 24 h at room temperature under nitrogen. After completion of the reaction, the resulting solution was diluted with water and extracted with 3×40 mL of ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to afford tert-butyl N-methyl-N-(4-[[(3R)-3-([[(methylcarbamoyl)methyl]carbamoyl]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (130 mg, 75%) as a yellow oil. MS: m/z 532 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[N:24])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O:29]C(N1CCC(NC2N=CC(O)=CN=2)CC1)=O)(C)(C)C.BrCC(N)=O.C(=O)([O-])[O-].[K+].[K+].Cl.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>CN(C=O)C.O1CCOCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([NH2:24])=[O:29])=[CH:19][N:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OCC#N)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Agent: Cl
Agent: NC(=O)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC(=O)COc1cnc(NC2CCNCC2)nc1

Procedure:
The compound was prepared in analogy to the synthesis of 4-(5-cyanomethoxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C32/step 1) from 4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C31/step 2) by reaction with 2-bromo-acetamide and potassium carbonate in DMF at rt, followed by BOC cleavage with 4 M HCl in dioxane and DMF at 85° C. in analogy to the procedure described for 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (intermediate C26/step 3). MS (ISP): 252.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:23]4[C:24]5[C:14](=[CH:15][C:16]([C:25]6[NH:29][C:28]([C@@H:30]7[CH2:34][CH2:33][CH2:32][N:31]7C(OC(C)(C)C)=O)=[N:27][CH:26]=6)=[CH:17][C:18]=5[CH2:19][CH2:20][C:21]=4[CH:22]=2)[CH2:13][CH2:12]3)[O:3]1.Cl.[CH3:44][O:45][C:46]([NH:48][C@@H:49]([CH:53]([CH3:55])[CH3:54])[C:50]([OH:52])=O)=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:54][CH:53]([CH3:55])[C@H:49]([NH:48][C:46](=[O:47])[O:45][CH3:44])[C:50](=[O:52])[N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:28]1[NH:29][C:25]([C:16]2[CH:15]=[C:14]3[C:24]4[C:23]5[C:11]([CH2:12][CH2:13]3)=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:42])([CH3:1])[O:3]3)=[CH:22][C:21]=5[CH2:20][CH2:19][C:18]=4[CH:17]=2)=[CH:26][N:27]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(B5OC(C)(C)C(C)(C)O5)cc(c2-4)CC3)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(B5OC(C)(C)C(C)(C)O5)cc(c2-4)CC3)[nH]1)C(C)C
Reaction time: 1 h
Yield: 42 %

Procedure:
To (S)-tert-butyl 2-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.53 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 1 h, and the solvent was removed. The intermediate (247 mg, 0.53 mmol) was dissolved in DMF (5 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (93 mg, 0.53 mmol), HATU (200 mg, 0.53 mmol), and DIPEA (0.46 mL, 2.65 mmol) were added sequentially. The solution was stirred o/n. The mixture was diluted with EtOAc, and washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated, and the mixture was purified by silica gel chromatography to yield product (139 mg).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])(=[O:10])=[O:9].[CH3:21]C(C)=O>O.C(=O)([O-])[O-].[Na+].[Na+]>[F:20][C:14]1[CH:13]=[CH:12][C:11]([S:8]([CH3:21])(=[O:10])=[O:9])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
A solution of sodium sulphite (10.6 g) in water (20 mL) was warmed to 80° C. and slowly added with stirring to a solution of 5-chlorosulfonyl-2-fluorobenzoic acid (10 g) in acetone (10 mL), saturated aqueous sodium carbonate being added simultaneously for keeping the liquid in alkaline. The mixture was stirred at 60° C. for one and a half hours, and concentrated in vacuo. The residue was suspended in a mixture of ethanol (20 mL) and water (20 mL), then iodomethane (2.61 mL) was added to the mixture. The reaction mixture was stirred for 2 hours at 60° C. and for an hour at 100° C. After cooling to ambient temperature, ethanol was removed in vacuo. The resultant aqueous solution was acidified with concentrated hydrochloric acid. The aqueous solution was extracted with chloroform (3 times), and the combined organic layer was dried over magnesium sulfate. After evaporation of the solvent, the residual oil was crystallized from ethanol to give 2-fluoro-5-methanesulfonylbenzoic acid (563.6 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.Br[C:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=2[F:26])[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:17]=1[CH3:34].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:1][C:2]1[C:7]([NH:8][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[N:19]=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:17]=2[CH3:34])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: Nc1cc(N2CCOCC2)cnc1Cl
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-5-morpholinopyridin-3-amine (183.1 mg, 0.86 mmol), 4-bromo-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (160.1 mg, 0.48 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (37.7 mg, 0.079 mmol), tris(dibenzylideneacetone)dipalladium (0) (17.5 mg, 0.019 mmol), and sodium tert-butoxide (120.7 mg, 1.26 mmol) in dry toluene (3.0 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (5-20% EtOAc in hexanes) to afford a light yellow solid as N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.8, 1.3 Hz), 7.98 (2H, m), 7.73 (2H, m), 7.41 (1H, q, J=4.8 Hz), 7.21 (1H, d, J=9.8 Hz), 7.07 (1H, ddd, J=13.2, 8.6, 2.4 Hz), 6.42 (1H, d, J=2.7 Hz), 3.86 (4H, m), 3.71 (1H, s), 3.17 (4H, m), 2.21 (3H, s). Mass Spectrum (pos.) m/e: 468.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCCCCBr
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: CCCCCCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CC=CC[C@@H]2C1=O

Procedure:
Prepared from compound 3 and 1-bromohexane as described for compound 8. Purified by chromatography; crystallized from petroleum ether (60-80° C.) at -20° C. M.p. 74-75° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:7][C:6]=2[CH:22]=1.C([Li])CCC.[B:28](OC)([O:31]C)[O:29]C.Cl>CCCCCC.C1COCC1>[C:16]1([C:8]2[O:7][C:6]3[CH:22]=[C:2]([B:28]([OH:31])[OH:29])[CH:3]=[CH:4][C:5]=3[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Temperature: -40 °C
Yield: 60 %

Procedure:
Under an argon atmosphere, 400 mL of anhydrous THF were added to 40.2 g of 6-bromo-2,3-diphenylbenzo[b]furan, and the mixture was stirred at −40° C. During the stirring, 72 mL of a 1.6-M solution of n-butyllithium in hexane were added to the mixture. The reaction solution was stirred for 1 hour while being heated to 0° C. The reaction solution was cooled to −78° C. again, and a solution of 54.0 g (250 mmol) of trimethyl borate in 50 mL of dry THF was dropped to the solution. The reaction solution was stirred at room temperature for 5 hours. 200 mL of 1N hydrochloric acid were added to the reaction solution, and the mixture was stirred for 1 hour. After that, the water layer was removed. The organic layer was dried with magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resultant solid was washed with toluene, whereby 21.7 g of 2,3-diphenylbenzo[b]furan-6-boronic acid were obtained (60% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][NH:18][CH2:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:10])=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-bromo-2-hydroxybenzaldehyde (10 g g 50 mmol), tert-butylcarbazate (6.7 g, 52 mmol) and acetic acid (3 mL, 52 mmol) in CH2Cl2 (200 mL) was stirred under N2 atmosphere for 60 min at RT. Then sodium triacetoxyborohydride (34 g, 159 mmol) was added portion wise and the resulting mixture was stirred at RT overnight. The reaction was quenched with 2 M HCl (100 mL) and stirred at RT for 1 h. The reaction mixture was partitioned between water (100 mL) and CH2Cl2 (250 mL). The organic layer was washed with sat. NaHCO3 and brine (100 mL each), dried (MgSO4) and evaporated to dryness to give hydrazine 1 as a white solid, 13 g (82%).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.B(O[O-])=[O:18].[Na+]>Cl>[ClH:3].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:18])=[CH:8][CH:9]=1
Reactant: Clc1ccc(SC2CCNCC2)cc1
Reactant: O=BO[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(c1ccc(Cl)cc1)C1CCNCC1

Procedure:
A solution of 5.78 g (0.020 mole) of 4-[(p-chlorophenyl)thio]piperidine hydrochloride hydrate and 4.61 g (0.030 mole) of sodium perborate in 200 ml of dilute hydrochloride acid was stirred at room temperature overnight. The reaction mixture was quenched in dilute sodium hydroxide and the resulting basic solution was extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and the solvent was removed in vacuo to give a white solid, the free base of the title compound. The free base was reacted with ethereal hydrogen chloride and the salt was recrystallized from methanol-diethyl ether to give the product as a white crystalline solid, m.p. 220°-221° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]3[S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][CH:17]3[CH2:16]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([N:35]([CH:45]2[CH2:47][CH2:46]2)CC2C=CC(OC)=CC=2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]3[S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][CH:17]3[CH2:16]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([NH:35][CH:45]2[CH2:46][CH2:47]2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN5C(CCS5(=O)=O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN3C(CCS3(=O)=O)C2)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
TFA (0.107 mL, 1.390 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13 mg, 0.020 mmol) and anisole (8.80 μl, 0.081 mmol) in DCE (0.3 mL) and the reaction mixture was heated at 60° C. for 1 hours. The solvent was removed in vacuo and the material azeotroped with toluene 3× to remove the excess TFA. 2 ml of 2N NH3 in MeOH was added, and the solution was stirred for 20 min. The solvent was removed in vacuo and the material was purified by prep-HPLC to give 2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (5.1 mg)
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[I:20]I>C1COCC1>[I:20][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: II
Reactant: C#CCCCCCC#CC#CCCCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC#CC#CCCCCCC#CI
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Nonadeca-1,8,10-triyne (0.802 g, 3.133 mmol) and anhydrous THF (96 mL) was cooled to −78° C. in a dry flask under nitrogen. LiN[Si(CH3)]2 (LHMDS) in THF (3.76 mmol) was added to the reaction mix slowly via dry syringe. In a separate flask I2 (9.55 g, 3.76 mmol) was dissolved in dry THF (20 mL). The iodine solution was added dropwise to the nonadeca-1,8,10-triyne solution until reaction completion (notably becoming orange-red). The reaction was stirred for 30 min, and slowly warmed to room temperature. The reaction was extracted with diethyl ether and 1M K2S2O3. The organic phase was dried over anhydrous MgSO4, and concentrated by evaporation to yield 1-iodo-nonadeca-1,8,10-triyne (0.93 g, 2.45 mmol). GC/MS showed no starting material remaining. 79% yield; 1H NMR (CDCl3) δ 2.15-2.33 (m, 6H, CH2—C≡C), 1.48 (m, 6H, CH2—C—C≡C), 1.33-1.39 (m, 2H, CH2—CH2—CH3), 1.28 (m, 10H, C—CH2—C), 0.85 (t, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)\[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]>P(=O)(O)(O)O>[CH3:1][C:2]([CH3:22])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)/[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(CCC/C=C(/c1cccnc1)c1cccs1)C(=O)O
Agent: O=P(O)(O)O
Product: CC(C)(CCC/C=C(\c1cccnc1)c1cccs1)C(=O)O
Yield: 48 %

Procedure:
(Z)-2,2-dimethyl-7-(3-pyridyl)-7-(2-thienyl)-6-heptenoic acid (1.0 g) was heated in 50% aqueous phosphoric acid (20 ml) at 100° C. for 20 hours, and the product was separated and extracted in the conventional manner. High performance liquid chromatography of this crude product revealed that its E isomer/Z isomer ratio was E/Z=56:23. The crude product was separated in the same manner as Example 2 to give (E)-2,2-dimethyl-7-(3-pyridyl)-7-(2-thienyl)-6-heptenoic acid (0.48 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52](Cl)=[O:53])=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:52](=[O:53])[CH2:51][C:48]4[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=4)=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Reaction time: 0.5 h

Procedure:
Prepared using General Procedure 7: To a stirring solution of 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (70 mg, 0.12 mmol) in DCM (2 mL) was added TEA (0.042 mL, 0.31 mmol) and 2-(4-methoxyphenyl)acetyl chloride (0.85 mL, 0.171 mmol). Additional TEA (0.042 mL, 0.31 mmol) and 2-(4-methoxyphenyl)acetyl chloride (0.85 mL, 0.171 mmol) were added and the reaction stirred for 30 min to yield 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-5. The crude reaction mixture was concentrated to 1.0 mL volume and carried onto the next step without further purification. LCMS-ESI (m/z) calculated for C43H50N2O8: 722; no m/z observed, tR=3.24 min (Method 3).