Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43]1>C(#N)C>[S:42]1[CH:46]=[CH:45][C:44]([S:47]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:49])=[O:48])=[CH:43]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccsc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 63.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0951 g, 0.206 mmol) was dissolved in acetonitrile (4.0 mL), and the solution was treated with triethylamine (0.0860 mL, 0.618 mmol) and 3-thiophenesulfonyl chloride (0.0754 g, 0.412 mmol) to obtain 4-(3-thiophenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0796 g, yield 64%).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>COCCOC.O.CCO>[C:37]1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9](=[O:14])[CH:8]=[C:7]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(-c3ccccc3)ccc2o1
Temperature: 160 °C
Yield: 29.2 %

Procedure:
Into a dry microwave vial under N2 was added 6-bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(PPh3)Cl2 (about 1 mol %), and Cs2CO3 (17.8 mg, 0.0547 mmol) in DME/H2O/EtOH (7/3/2, 0.5 mL). Phenyl boronic acid (5.6 mg, 0.046 mmol) was added and the solution was heated in the microwave for 5 minutes at 160° C., filtered, and was purified by Prep HPLC to give 5.86 mg (23%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 435 (M−H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.83-1.91 (m, 2H), 2.24 (br d, 2H), 3.15-3.23 (m, 2H), 3.61 (br d, 2H), 3.82-3.97 (m, 3H), 5.45 (s, 1H), 6.36-6.42 (m, 1H), 6.90 (d, 1H), 7.34-7.56 (m. 10H), 7.74 (d, 2H), 7.89 (dd, 1H), 8.40 (d, 1H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=1.C(N(C(C)C)CC)(C)C.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][C@@H:39]([O:42][C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([NH2:50])[CH:44]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:44]=[C:45]([NH:50][C:2]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[O:4])[CH:46]=[C:47]([F:49])[CH:48]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cc(N)cc(F)c2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cc(F)cc(OC3CCN(C(=O)OC(C)(C)C)C3)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A round bottom flask was charged with triphosgene (3 g, 10 mmol, 1 eq) and THF (33 mL) and chilled to 0° C. A solution of 5-amino-2-methyl pyridine (3.3 g, 10 mmol, 3 eq), diisopropylethylamine (10.3 mL, 60 mmol, 6 eq) and THF (33 mL) was added dropwise to the triphosgene solution. The mixture was allowed to warm to room temperature and stirred for 30 minutes. A solution of (R)-tert-butyl-3-(3-amino-5-fluorophenoxy)-pyrrolidine-1-carboxylate (3.0 g, 10 mmol, 1 eq) in THF (33 mL) was added dropwise. The resultant reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated sodium bicarbonate solution and the THF was removed in vacuo. The mixture was extracted with dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate and brine. The organic layers were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica column chromatography with 500 mL of ethyl acetate, 500 mL of 2.5% methanol in ethyl acetate, 500 mL of 5% methanol in ethyl acetate, 500 mL 7.5% methanol in ethyl acetate, and 10% methanol in ethyl acetate as the gradient elute to yield 3.4 g of 3-{3-fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=1)C.Cl>[OH-].[Na+]>[CH3:14][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[C:8]=1[O:12][CH3:13])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)c1cc(C)c(OC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)cc(C(=O)O)cc1C

Procedure:
A mixture of 3,5-dimethyl-4-methoxybenzoic acid ethyl ester (PREPARATION 2, 10.5 g) and aqueous sodium hydroxide (20%, 100 ml) is refluxed for 18 hours. The solution is cooled and acidified with hydrochloric acid (12N, pH 2). The acidified solution is extracted with chloroform (3 X). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure to give a solid which is recrystallized from ether/pet ether mixture to give the title compound, mp 189°-191°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].FC(F)(F)C(O)=O.[NH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].C(N(CC)CC)C>C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:25]2[C:24]3[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:16][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])=[C:22]([O:40][CH3:41])[CH:23]=3)[N:28]=[CH:27][N:26]=2)=[C:33]([F:39])[CH:34]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCNC(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Isobutyl chloroformate (88 mg, 5.9 mmol) was added to a stirred solution of 7-(3-aminopropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline trifluoroacetate (151 mg, 0.4 mmol) and triethylamine (0.2 ml, 1.4 mmol) in THF (15 ml). The reaction mixture was stirred at ambient temperature for 30 minutes and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride, the solution was washed with aqueous sodium hydrogen carbonate solution and then brine, dried (MgSO4) and the solvent was removed by evaporation. The residue was recrystallised from acetonitrile to give 4-(4-chloro-2-fluoroanilino)-7-(3-[N-isobutoxycarbonylamino]propoxy)-6-methoxyquinazoline (41.2 mg, 20%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:32][S:33]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:13][CH:12]1[C:28]([O:30][CH3:31])=[O:29])=O)(C)(C)C.C([SiH](CC)CC)C.[Cl:60]CCl>>[ClH:60].[NH2:8][C@@H:9]([CH2:32][SH:33])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:13][CH:12]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: ClCCl
Reactant: COC(=O)C1CN(Cc2cccc3ccccc23)CCN1C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Product: COC(=O)C1CN(Cc2cccc3ccccc23)CCN1C[C@@H](N)CS
Product: Cl

Procedure:
The title compound was obtained according to the procedure described in Example 1, Step E except using methyl 1-(2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropyl)-4-(1-naphthylmethyl)-piperazine-2-carboxylate (0.274 g, 0.383 mmol), triethylsilane (0.24 mL, 1.53 mmol) trifluoroacetic acid (5 mL) in dichloromethane (10 mL). The crude product was purified by HPLC by gradient elution (100% Solvent A to 50% Solvent A/50Solvent B over 60 min. After ion exchange, the title compound was obtained as a white solid. FAB ms m/e 374 (m+1).
Reaction SMILES: Cl[NH:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NCl)ccc3N2)=C(O)c2ccccc21
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 42F (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]1([CH2:19][O:20][C:21]([NH:23][C:24]2([C:30]([OH:32])=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[NH2:43][C@H:44]([CH2:48][OH:49])[CH:45]([CH3:47])[CH3:46]>C(Cl)Cl>[C:13]1([CH2:19][O:20][C:21]([NH:23][C:24]2([C:30]([NH:43][C@H:44]([CH2:48][OH:49])[CH:45]([CH3:47])[CH3:46])=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
After 422 mg (2.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 555 mg (2 mmol) of 1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid, 322 mg (2.1 mmol) of 1-hydroxybenzotriazole and 206 mg (2 mmol) of L-valinol in 20 ml of methylene chloride under ice-cooling, the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 662 mg (91%) of the title compound.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][C:9]1([CH3:40])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:18]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:28]=4[CH3:29])[C:19]3=[O:30])[CH:16]=2)[N:11]([CH2:31][O:32]CC[Si](C)(C)C)[C:10]1=[O:39].CO.C(=O)(O)[O-]>C(Cl)(Cl)Cl>[OH:32][CH2:31][N:11]1[C:12]2[C:17](=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:28]=4[CH3:29])[C:19]3=[O:30])=[CH:14][CH:13]=2)[C:9]([CH3:8])([CH3:40])[C:10]1=[O:39]
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)C(C)(C)C(=O)N3COCC[Si](C)(C)C)C1=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)C(C)(C)C(=O)N3CO)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Dioxane HCl (4 mL) was added to 3,3-dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (I-147a: 50 mg) and the resulting mixture was stirred room temperature for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was basified with bicarbonate solution and extracted with DCM. The organic layer was concentrated; the concentrate was recrystallized with DCM and hexane and dried to afford 37 mg of the product (94.87% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.N1C=CC=CC=1C([OH:28])C.[CH2:29]1[CH2:39][CH2:38][N:37]2C(=N[CH2:34][CH2:35][CH2:36]2)C[CH2:30]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([O:28][CH2:34][CH2:35][C:36]2[CH:30]=[CH:29][CH:39]=[CH:38][N:37]=2)[N:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(O)c1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(F)cc2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccc(F)cc1

Procedure:
From 2-amino-4-(4-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, (2-pyridyl)ethanol and DBU in DME. ES-MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[NH:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:44][N:45]([CH3:51])[CH2:46][CH2:47][CH2:48][CH2:49][NH2:50]>CN(C=O)C>[CH:16]([O-:18])=[O:17].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:22])[NH:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:50][CH2:49][CH2:48][CH2:47][CH2:46][N:45]([CH3:51])[CH3:44])=[O:18])=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)CCCCN
Reactant: N#Cc1ccc(NC(=O)NCc2cccc(C(=O)O)c2)cc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)CCCCNC(=O)c1cccc(CNC(=O)Nc2ccc(C#N)cc2)c1
Product: O=C[O-]
Reaction time: 0.5 h
Yield: 1599.4 %

Procedure:
3-[3-(4-Cyano-phenyl)-ureidomethyl]-benzoic acid (30 mg, 0.1 mmol), prepared as described in Example 1, EDC (28.8 mg, 0.15 mmol), and HOBt (17.6 mg, 0.13 mmol) were combined in a reaction vial and DMF (1 mL) then N-methylmorpholine (0.017 mL, 0.15 mmol) were added. The reaction mixture was agitated for 30 minutes, then N1,N1-dimethyl-butane-1,4-diamine (14 mg, 0.12 mmol) was added. Shaking was continued overnight. The reaction mixture was purified by preparative HPLC using an acetonitrile/water/formic acid gradient. The title compound was collected as a formate salt (36 mg, 90% yield) following evaporation of the solvent; MS analysis electrospray, 394 (M+H).
Reaction SMILES: [Br:1][C:2]([CH2:4]Br)=[CH2:3].[C:6]1([CH2:12][CH:13]=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>[Zn].C1(C)C=CC=CC=1>[Br:1][C:2]([CH2:4][CH:13]([OH:14])[CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:3]
Reactant: C=C(Br)CBr
Reactant: O=CCc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Product: C=C(Br)CC(O)Cc1ccccc1

Procedure:
49.93 Grams of 2,3-dibromo-1-propene were added dropwise to a mixture of 20.00 g of phenylacetaldehyde, 40 g of toluene, 60 g of 0.01% hydrochloric acid and 16.33 g of zinc powder at 30° C., and the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was separated. The organic phase was washed with a 7% sodium carbonate aqueous solution, and the toluene was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 24.01 g of 2-bromo-5-phenyl-1-penten-4-ol; nD25 =1.536, FI-MS m/e 240(M+), 242(M+2+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)=[O:7]
Reactant: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(=O)N2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
2-Methoxy-3-nitro-benzoic acid (1.20 g, 6.09 mmol), 1-Methylpiperazine (1.01 mL, 9.13 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1750 mg, 9.13 mmol, 1-hydroxybenzotriazole hydrate (1.45 g, 9.13 mmole) and N,N-Dimethylformamide (40.4 mL) were combined into a vial and stirred at room temperature for 1 hour. LCMS showed complete conversion to product. Diluted reaction mixture with saturated NaHCO3 and filtered off resulting ppt. The solid was filtered and washed with water. The solid was dried under vacuum overnight to give (2-Methoxy-3-nitro-phenyl)-(4-methyl-piperazin-1-yl)-methanone as a white solid (0.70 g, 44%)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:19](B1OC(C)(C)C(C)(C)O1)=[CH2:20].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:17][CH:16]([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[N:6]=[N:7][C:2]([CH:19]=[CH2:20])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: FC(F)Oc1ccc(Nc2ccc(Cl)nn2)cc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc(Nc2ccc(OC(F)F)cc2)nn1
Temperature: 80 °C
Yield: 61.9 %

Procedure:
To a solution of 6-chloro-N-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (0.2 g, 0.736 mmol) in dioxane and water mixture were added vinylboronic acid pinacol ester (0.146 mL, 1.104 mmol), and K2CO3 (0.305 g, 2.209 mmol). The mixture was flushed for 15 min with nitrogen. PdCl2 (dppf)-CH2Cl2 adduct (0.060 g, 0.074 mmol) was then added and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate and purified by flash chromatography on silica gel using ethyl acetate in hexane to give N-(4-(difluoromethoxy)phenyl)-6-vinylpyridazin-3-amine as a white solid (0.12 g, 59%). 1HNMR 400 MHz, DMSO-d6: δ ppm 5.47 (d, J=1.20 Hz, 1H), 6.06 (dd, J=0.80, 23.80 Hz, 1H), 6.84-7.38 (m, 5H), 7.75-7.82 (m, 3H), 9.42 (s, 1H).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[O:11])[CH:8]=[CH:9][C:2]=12.[H-].[Na+].[CH3:21]I>CN(C)C=O.O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][CH3:21])[CH2:14][CH2:13]3)=[O:11])[CH:8]=[CH:9][C:2]=12
Reactant: CI
Reactant: O=C(c1ccc2nonc2c1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2ccc3nonc3c2)CC1
Reaction time: 3 h
Yield: 30.3 %

Procedure:
1-(Benzofurazan-5-ylcarbonyl)-4-hydroxypiperidine (840 mg, 3.40 mmol) was dissolved in dimethylformamide (12 mL) and treated with 60% sodium hydride (150 mg, 3.75 mmol) for 30 minutes. Methyl iodide (650 mg, 4.54 mmol) was added, and, after 3 hours at room temperature, the reaction mixture was further treated with the same quantities of sodium hydride and methyl iodide as above and allowed to stand for 16 hr. The reaction solution was diluted with water and product was extracted into ethyl acetate. The organic solution was washed with water and saturated sodium chloride and dried over MgSO4. The crude product was purified by decolorization with charcoal in ethanol, twice chromatographed on silica gel by elution with hexane/ethyl acetate (2:1), and finally by kugelrohr distillation at 125-140° C. to yield 1-(benzofurazan-5-ylcarbonyl)-4-methoxypiperidine (269 mg, 30%) as a pale yellow oil. IR: 1639, 1440, 1274, 1101, and 1089 cm−1. 1H NMR (500 MHz): δ 7.91 (1H, dm, J=9.2 Hz), 7.85 (1H, t, J=1.1 Hz), 7.43 (1H, dd, J=9.2 and 1.2 Hz), 3.90-4.05 (1H, m), 3.55-3.72 (2H, m), 3.53 (1H, sept, J=3.5 Hz), 3.38 (3H, s), 3.20-3.35 (1H, m), 1.90-2.02 (1H, m), 1.65-1.85 (2H, m), and −1.65 ppm (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25](=[O:30])C(Cl)(Cl)Cl)=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CS(C)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:30])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2)C(Cl)(Cl)Cl
Reactant: NCc1cccnc1
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2
Yield: 90.9 %

Procedure:
To a solution of 1-{10-[(4-bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-2,2,2-trichloroethanone of Step B (1.80 g, 3.297 mmol) and dimethyl sulfoxide (1.17 mL, 16.487 mmol) in dry acetonitrile (30 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.67 mL, 6.595 mmol) and the reaction mixture heated to reflux for 20 hours. The cooled reaction mixture was concentrated in vacuo, the oily residue dissolved in ethyl acetate (100 mL), washed with 1M sodium hydroxide (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 0 to 3% methanol in dichloromethane gave the title compound (1.61 g, 91%) as a yellow foam.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([O-:18])=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:19]=[CH:20][S:21][C:5]1=2>C(O)C.O>[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([OH:18])=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:19]=[CH:20][S:21][C:5]1=2
Reactant: O=C([O-])c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Yield: 88.2 %

Procedure:
13.9 ml (0.0556 mol) of 4N sodium hydroxide solution were added dropwise to a suspension of 13.5 g (0.0445 mol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylate in 10 ml of ethanol and 16 ml of water and the mixture was heated at reflux for 1/2 hr. Subsequently, the ethanol was distilled off. The aqueous phase was washed twice with dichloromethane and adjusted to pH=3 with 4N hydrochloric acid. The resulting precipitate was filtered off, washed with water, ethanol and subsequently with diethyl ether. There were obtained 10.8 g (88%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid as a colourless powder; m.p. 260° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.O.[CH2:12](O)[CH3:13]>C(C=O)=O>[Cl:1][C:2]1[C:7]2[C:6](=[N:9][CH:12]=[CH:13][N:8]=2)[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1N
Reactant: CCO
Agent: O=CC=O
Solvent: O
Product: Clc1cc2nccnc2c(Cl)n1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of the solution of 2,6-dichloropyridine-3,4-diamine (7.85 g, 0.044 mol) in ethanol and 40% glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83% yield).