Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Cu][C:29]#[N:30]>N1C=CC=CC=1>[CH3:25][O:24][CH:23]([O:26][CH3:27])[C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:14][N:13]=[C:12]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([CH:3]=3)[C:29]#[N:30])[N:16]=2)=[CH:18][CH:19]=1
Reactant: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Br)c3)no2)cc1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(C#N)c3)no2)cc1
Temperature: 230 °C
Yield: 39.3 %

Procedure:
A 25 mL microwave vial equipped with a stirring bar was charged with 3-(3-bromo-4-isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.25 g, 0.577 mmol), copper(I) cyanide (0.133 g, 1.485 mmol) and pyridine (15 ml). The vessel was capped and the reaction heated to 230° C. for 30 min under microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled, the reaction mixture was concentrated, to the residue was added hydrated ferric chloride (0.8 g), concentrated hydrochloric acid (2 mL) and water (12 mL). The solution was heated at 65° C. for 20 min, the aqueous mixture was extracted by DCM (3×30 mL), the combined DCM layers were washed with FeCl3 solution (2×20 mL), then water (2×20 mL), dried (brine, MgSO4) and concentrated to yield yellow solid, which was purified via silica gel chromatography (40 g, 20% EtOAc:Heptane) to afford 5-(5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.086 g, 0.227 mmol, 39.3% yield) as pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[O-:14][CH2:15][CH3:16].[Na+].N1C=CC=CC=1C1C=CC=CN=1.C(OCC)(=O)C>CO>[CH2:15]([O:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:16]
Reactant: CC[O-]
Reactant: CCOC(=O)Nc1ccccc1Br
Agent: [Na+]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Nc1ccccc1OCC
Yield: 83.7 %

Procedure:
2.44 g of the 2-bromo-1-ethoxycarbonylaminobenzene was added to a solution containing 680 mg of sodium ethoxide, 170 mg of cupric chloride dihydrate, and 156 mg of 2,2'-bipyridine in 40 ml of methanol, and the mixture was heated under reflux for 1.5 hours. After the temperature was brought to room temperature, ethyl acetate was added thereto, and the resulting mixture was washed with water and dried over Glauber's salt. The solvent was distilled off, and the obtained crude crystals were recrystallized from a n-hexane/ethyl acetate solvent mixture, to obtain 1.75 g (yield: 84%) of the desired compound. The spectrum data of the compound was in agreement with the spectrum data of the separately synthesized reference compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1.I[CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][OH:27])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCI
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Product: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1ccn(CCO)c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=368.1, 370.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:44]([CH3:46])[CH3:45]>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH:44]([CH3:46])[CH3:45])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Potassium carbonate (430 mg, 3.11 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 325 mg, 0.62 mmol) in N,N-dimethylformamide (2 mL) at room temperature and stirred for 30 min and then 2-bromopropane (0.13 mL, 1.24 mmol) was added. The mixture was then heated to 60° C. and stirred for 3 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (310 mg, 100%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C30H32N2O5S2 [M+H]+ 565.73, observed 565.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>N1CCCCC1.C(O)C>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1C
Temperature: 90 °C
Yield: 68.1 %

Procedure:
A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90° C. for 2 hours. The reaction was cooled to room temperature; the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>O1CCCC1.CS(C)=O>[Br:33][C:34]1[CH:35]=[C:36](/[CH:37]=[CH:13]/[CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:39]=[CH:40][CH:41]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CC/C=C/c1cccc(Br)c1
Reaction time: 18 h

Procedure:
A 1M solution of potassium tert-butoxide in tetrahydrofuran (80 mL) was added dropwise to (3-carboxypropyl)triphenylphosphonium bromide (17 g, 40 mol) in anhydrous DMSO (20 mL) under nitrogen at 24° C., and the solution was stirred 30 min. before addition of 3-bromobenzaldehyde (4.7 mL, 40 mmol). After several minutes a precipitate was observed and an additional 20 mL of DMSO was added to aid solvation, and the reaction was stirred 18 h. The solution was poured onto water (120 mL) and washed with chloroform. The aqueous layer was acidified with conc. HCl and extracted with chloroform (3×250 mL). The organic phase was concentrated and applied to a 65i Biotage silica gel column, gradient elution from 15-65% B (A=Hexanes; B=ethyl acetate) over 2 L to give J.1, (E)-5-(3-bromophenyl)pent-4-enoic acid, 8.2 g (82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (t, J=1.5 Hz, 1H), 7.30 (dt, J=7.7, 1.5 Hz, 1H), 7.2-7.16 (m, 1H), 7.12 (t, J=7.7 Hz, 1H), 6.40-6.32 (m, 1H), 6.23-6.14 (m, 1H), 2.52 (s, 4H). LC (Cond.-J1): RT=2.0 min; LRMS: Anal. Calcd. for [M−H]− C11H11BrO2: 252.97; found: 252.98.
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](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[F:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[F:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.227 mmol) to afford the crude product (64 mg) as an off-white solid: ESI MS m/z 540 [C30H35F2N3O4+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].[C:11](OC)(OC)(OC)[CH2:12][CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[CH3:7][C:4]1[C:3]2[C:8](=[O:9])[NH:10][C:11]([CH2:12][CH2:13][CH3:14])=[N:1][C:2]=2[S:6][N:5]=1
Reactant: Cc1nsc(N)c1C(N)=O
Reactant: CCCC(OC)(OC)OC
Solvent: CC(=O)OC(C)=O
Product: CCCc1nc2snc(C)c2c(=O)[nH]1
Temperature: 130 °C
Yield: 40 %

Procedure:
A mixture of 29 (3.0 g, 19.1 mmol), trimethyl orthobutyrate (7.0 mL) in acetic anhydride (7.0 mL) was heated at 130° C. in an open flask for 3 h, then cooled to room temperature and poured into ice water. The mixture was extracted with EtOAc for 3 times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give 30 (1.6 g, 40%) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 12.15 (brs, 1H), 2.81 (s, 3H), 2.78 (t, J=7.68 Hz, 2H), 1.90 (m, 2H), 1.07 (t, J=7.37 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[N:21]3)=[C:11]([O:25][CH3:26])[CH:10]=2)[N:3]=1.[Cl:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O>[Cl:27][C:28]1[N:32]([C:6]2[N:7]=[CH:2][N:3]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([O:25][CH3:26])[C:12]([O:17][CH2:18][CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)=[C:13]([O:15][CH3:16])[CH:14]=3)[N:5]=2)[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[N:29]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OCCn1ccnn1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)cc(OC)c1OCCn1ccnn1
Temperature: 70 °C

Procedure:
(4-Chloro-[1,3,5]triazin-2-yl)-[3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenyl]amine (407 mg, 1.076 mmol) is combined with 2-chlorobenzimidazole (164 mg, 1.076 mmol) and K2CO3(179 mg, 1.292 mmol) in AcCN (10 ml) and heated at 65 to 75° C. for 4 to 20 hours. The mix is concentrated down under reduced pressure and treated with water. A white precipitate forms which is filtered and dried under vacuum, giving [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenyl]-amine.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:32][C:33]([OH:35])=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:47][CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:47][CH2:46][CH2:45][N:44]2[C:33](=[O:35])[CH2:32][N:15]2[CH2:16][CH2:17][CH2:18][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]2=[O:13])=[CH:41][CH:42]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCC1c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 68E, 0.050 g, 0.169 mmol) and 2-(4-fluorophenyl)pyrrolidine (0.028 g, 0.169 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF10-4 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.42-6.83 (m, 14H), 5.14 (m, 1H), 4.64-4.10 (m, 1H), 3.97-3.73 (m, 2H), 3.73-3.47 (m, 2H), 3.25-2.91 (m, 1H), 2.78-2.15 (m, 3H), 1.85 (m, 5H)); MS (DCI+) m/z 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29]C)[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: COc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1cccc(O)c1)c1cc2ccccc2o1
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide (315 mg, 0.69 mmol) in CH2Cl2 (5 ml) at room temperature was added BBr3 (1M solution in CH2Cl2, 2.1 ml, 2.1 mmol) and the reaction was stirred for 2 h, diluted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (25% ethyl acetate in hexane) to give the title compound (196 mg, 64%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccoc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of phenylboronic acid (15 g, 123.02 mmol) in dioxane (150.0 mL) and water (3.0 mL) was added 3-bromofuran (16.3 g, 110.91 mmol), K3PO4 (43 g, 202.57 mmol) and Pd(PPh3)4 (6.0 g, 5.19 mmol) with stirring for 2 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 3-phenylfuran as a white solid (15 g, 85%).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1

Procedure:
Same procedure as above with Z-Trp-OH (2 g, 5.9 mmol), benzylamine (645 μL, 5.9 mmol), DCC (1.58 g, 7.65 mmol) and THF (88 mL). A white solid was obtained after precipitation in methanol/pentane (777 mg, 31%). 1H NMR (300 MHz, CDCl3) δ 3.18 (dd, J=14.3 Hz, J=8.1 Hz, 1H, CH2), 3.39 (dd, J=14.3 Hz, J=4.9 Hz, 1H, CH2), 4.3 (m (AB), 2H, CH2 (Bn)), 4.53 (m, 1H, CHα), 5.11 (s, 2H, CH2 (Z)), 5.52 (m, 1H, NH), 5.90 (m, 1H, NH), 6.91-7.70 (m, 15 aromatic H), 8.01 (s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 28.7 (CH2 Trp), 43.4 (CH2), 56.1 (CHα), 67 (CH2 (Z)), 111.2, 118.7, 119.7, 122.2, 123.2, 123.4, 127.2, 127.3, 127.6, 128, 128.2, 128.5, 136.1, 136.2, 137.5, 137.6 (20 aromatic C), 156 (CO carbamate), 171.2 (CO amide). Anal. Calcd. for C26H25N3O3, 0.75H2O: C, 70.81; H, 6.06; N, 9.53. Found: C, 70.84; H, 6.80; N, 9.21.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:42])=[O:41]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCN(S(C)(=O)=O)CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.073 g, 0.158 mmol) was suspended in DCM (1 mL) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) was added. Methanesulfonyl chloride (0.015 mL, 0.19 mmol) was added and the resulting solution stirred at RT overnight. The solvent was evaporated. The remaining semi-solid was purified by SiO2 chromatography (12 g SiO2, DCM/MeOH 0-4% MeOH). Obtained 0.065 g of 1-(1-methanesulfonyl-piperidin-4-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (88% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].S(Cl)([Cl:15])=O>>[Cl:15][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1cccc(CO)c1
Product: CS(=O)(=O)c1cccc(CCl)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of (3-methanesulfonyl)phenyl methanol (0.21 g, 1.1 mmol) in thionyl chloride (3 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to provide 1-chloromethyl-3-methanesulfonylbenzene as a yellow oil (0.23 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.59 (t, J=8 Hz, 1H), 4.65 (s, 2H), 3.08 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH3:20][CH2:21][O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:28]3[CH2:27][CH2:26][N:25]([C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:30][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 7.88 g (0.025 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml toluene was heated under nitrogen until a solution resulted. Then there was added 39.6 g (0.250 mole) of ethyl N-piperazinocarboxylate followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was taken up in 25 ml of hot methanol from which 8.5 g (75%) of product crystallized. Recrystallization from ethyl acetate gave the analytical sample, mp 128°-131° C.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[Br:28][Si](CC)(CC)CC.C(=O)([O-])O.[Na+]>ClCCl.[Bi](Br)(Br)Br>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: CC[Si](Br)(CC)CC
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Br[Bi](Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
β-D-Galactose pentaacetate (5.00 g, 12.8 mmol) and bismuth(III) bromide (287 mg, 640 μmol) were dissolved in dichloromethane (25 mL), the solution was added with bromotriethylsilane (6.76 mL, 51.2 mmol), and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. The reaction mixture was poured into aqueous saturated sodium hydrogencarbonate cooled on ice, then the mixture was extracted with dichloromethane, and the organic layer was washed with brine. The organic layer was dried over sodium sulfate, and the solvent was removed to obtain 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (5.30 g, quantitative).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:25][C:24]1[CH:19]=[CH:20][C:21]([CH3:26])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(COc3ccc(C)cc3)c(C)o2)cc1
Yield: 93.7 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (3.1 g, 11.70 mmol, 1.00 equiv), p-cresol (2.0 g, 18.52 mmol, 1.58 equiv), Cs2CO3 (4.5 g, 13.80 mmol, 1.18 equiv) in N,N-dimethylformamide (60 mL) was stirred under nitrogen overnight at 50° C. The resulting solution was diluted with 100 mL of water and extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.7 g (94%) of methyl 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 379 [M+CH3CN+H]+, 338 [M+H]+, 271, 230, 203, 146, 91.