Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([CH:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:28])[CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[S:18][C:14]=3[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:2]1.[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:31]=1[CH:32]=O>C(Cl)Cl>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:31]=1[CH2:32][N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([CH:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:28])[CH2:21][CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[S:18][C:14]=3[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:2]1
Reactant: O=C(CC1CCCCC1)Nc1nc2c(s1)CCCC2C(=O)NCC1CCNC1
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1nc2c(s1)CCCC2C(=O)NCC1CCN(Cc2c(Cl)cccc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (1-pyrrolidin-3-yl)methylamide (1) (1.66 mmol) was dissolved in DCM (15 mL) under a blanket of nitrogen. 2,6-Dichlorobenzaldehyde (320 mg, 1.82 mmol) and sodium triacetoxyboron hydride (530 mg, 2.48 mmol) were added. The reaction mixture was stirred overnight at RT under a blanket of nitrogen. Following removal of the solvent in vacuo and purification by column chromatography (SiO2, DCM/MeOH 95:5), there were obtained 623 mg (1.11 mmol, 67% of theory) of the desired product 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid [1-(2,6-dichlorobenzyl)-pyrrolidin-3-yl]methylamide (K).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([NH2:33])([CH3:32])[CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)[NH:33][C:29]([CH3:32])([CH3:28])[CH2:30][CH3:31])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(C)(C)N
Reactant: COc1cc(NC(SC)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Product: CCC(C)(C)NC(Nc1cc(OC)cc(OC)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 26 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-methylsulfanyl-2-propenenitrile (0.30 g, 0.7 mmol) was stirred in 1,1-dimethylpropylamine (1 ml) for 17 h at 100° C. in a sealed flask under nitrogen. Work-up as described in Example 17, 2) without chromatography gave 84 mg (26%) of the title compound. Mp 189-190° C. 1H NMR (200 MHz, CDCl3): δ=0.95 (t, 3H), 1.35 (s, 6H), 1.65 (q, 2H), 3.62 (s, 6H), 6.20 (t, 1H) 6.45 (br s, 1H), 7.0 (br s, 1H), 7.50 (dt, 2H), 7.83 (dt, 2H); Analysis: calc. for C22H26ClN3O4S: C, 59.96%; H, 5.65%; N, 9.06%. Found: C, 56.82%; H, 5.64%; N, 8.90%.
Reaction SMILES: FC1C=CC([C:8]2[N:12](O)[C:11]3[CH:14]=[C:15](C(N4C=CN=C4)C4C=CC=CC=4)[CH:16]=[CH:17][C:10]=3[N:9]=2)=CC=1.[OH-].[Na+].CO>O>[NH:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[N:12]=[CH:8]1
Reactant: On1c(-c2ccc(F)cc2)nc2ccc(C(c3ccccc3)n3ccnc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.7 parts of 2-(4-fluorophenyl)-6-[(1H-imidazol-1-yl)-phenylmethyl]-1H-benzimidazol-1-ol, 7 parts of a sodium hydroxide solution in water 1N and 20 parts of methanol was stirred for 15 minutes at room temperature. After evaporation, the residue was taken up in methylbenzene and the solvent was evaporated (this proces was repeated twice). The residue was dissolved in 22.5 parts of N,N-dimethylformamide and a solution of 0.89 parts of (chloromethyl)benzene in a small amount of N,N-dimethylformamide was added dropwise. Upon complete addition, stirring was continued for 1 hour at room temperature. After standing overnight at room temperature, the solvent was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 17.5 parts of 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and 2-propanol and dried, yielding 2.1 parts (63.5%) of 2-(4-fluorophenyl)-6-[(1H-imidazol-1-yl)phenylmethyl]-1-phenylmethoxy)-1H-benzimidazole; mp. 177.6° C. (compound 241).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:22][NH:23]C>C(O)C>[CH3:22][NH:23][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNC
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Solvent: CCO
Product: CNCc1cccc(-c2nc3cccc(C(=O)OC)c3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 135 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and dimethylamine (50 mg, 1.6 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated under reduced pressure to obtain methyl 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (80 mg, yield 76%). LC-MS (ESI) m/z 297 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:25])[N:13]=[C:14]2[C:23]=1[C:22]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=1[N:16]=[C:15]2[NH2:24].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>ClCCl>[NH2:24][C:15]1[C:14]2=[N:13][N:12]([CH3:25])[C:11]([CH2:10][CH2:9][NH:8][C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:33])=[C:23]2[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=1
Reactant: Cn1nc2c(N)nc3c(c2c1CCN)CCCC3
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc2c(N)nc3c(c2c1CCNC(=O)N1CCOCC1)CCCC3
Temperature: 4 °C

Procedure:
Triethylamine (2.84 mL, 20.4 mmol) was added to a suspension of 1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 50) (1.0 g, 4.08 mmol) in dichloromethane (50 mL) and cooled to 4° C. 4-Morpholinecarbonyl chloride (0.61 g, 4.08 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed sequentially with water (50 mL), 4% sodium bicarbonate (2×50 mL), water (50 mL), and brine (50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with mixtures of chloroform and CMA). The material was crystallized from acetonitrile to provide N-[2-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]morpholine-4-carboxamide as orange needles, mp 187-188° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)(C)C.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])=[CH:36][C:35]=1[CH3:45]>C(Cl)Cl>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([C:41]#[N:42])([CH3:43])[CH3:44])=[CH:36][C:35]=3[CH3:45])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: Cc1cc(C(C)(C)C#N)ccc1CN
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(C)(C)C#N)ccc1CNC(=O)Cn1cnc2cccc(C#N)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
(7-cyano-1H-benzimidazol-1-yl)acetic acid (86 mg, 0.43 mmol) prepared according to scheme 3 is dissolved in DCM (3 mL). DIPEA (0.1 mL) is added, followed by pivaloyl chloride (53 μL, 0.43 mmol). After 1 hour, 2-[4-(aminomethyl)-3-methylphenyl]-2-methylpropanenitrile (80 mg, 0.43 mmol) prepared according to scheme 19 is added. The mixture is stirred overnight at room temperature, concentrated under vacuo and purified on HPLCMS: Waters prep LCMS, 27 ml/min, X-Bridge Prep C18 OBD, 30×50 mm, 5 μm particle size, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, Gradient used 30% to 50% B in A, in 10 min. The fractions are combined and freeze dried to give the desired product (47 mg, 0.13 mmol, 30%). MS (ESI) (M+1) 372.3. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.65 (s, 6H) 2.31 (s, 3H) 4.29 (d, J=5.08 Hz, 2H) 5.26 (s, 2H) 7.25-7.29 (m, 1H) 7.30-7.40 (m, 3H) 7.73 (dd, J=7.62, 0.98 Hz, 1H) 8.03 (dd, J=8.20, 0.78 Hz, 1H) 8.38 (s, 1H) 8.74 (t, J=5.27 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:19](=[O:21])[CH3:20])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(C)=O)cc1
Yield: 58.5 %

Procedure:
To 4-butyl aniline (20 g; 134 mmol) dissolved in toluene (160 mL) with stirring was added 4-dimethylaminopyridine (0.82 g; 6.70 mmol) and triethylamine (26.0 mL; 188 mmol). The mixture was then treated with acetic anhydride (15.2 mL; 161 mmol) dropwise via an addition funnel over 30 minutes. After addition, the ice bath was removed and the reaction mixture was stirred for 12 hours at room temperature. The mixture was poured into aqueous hydrochloric acid (240 mL; 2M) and stirred 20 minutes. The layers were separated and the organic layer was washed with water. The organic layer was separated and crystals formed while standing. The resulting precipitate was isolated by filtration and dried under vacuum to give the title product as white crystals (15.0 g).
Reaction SMILES: [N+](C1C=C(S([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=2)(=O)=O)C=CC=1)([O-])=O.O[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:35]([C:34]1[CH:37]=[CH:38][C:31]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:20][CH:21]=2)=[CH:32][CH:33]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
26.7 g (63 mmole) 4-(tert-butoxycarbonylamino)phenethyl 3-nitro-benzenesulfonate, 8.5 g (69 mmole) p-hydroxybenzaldehyde, 9.54 g (69 mmole) potassium carbonate and acetonitrile was refluxed for 3 hours and thereafter stirred over night at room temperature. The precipitate was filtered off and the solvent was evaporated. Dichloromethane was added and the organic phase was washed with saturated sodium carbonate and thereafter with sodium hydroxide (0.1 M), dried (sodium sulfate), filtered and the solvent was evaporated to give 17 g (yield 79%) of tert-butyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:54]Br)=[N:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:54][CH:19]2[C:18]3[N:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:16][N:17]=3)[C:13]3[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]=3[N:11]([CH2:10][C:9](=[O:34])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:35]([CH3:37])[CH3:36])[C:20]2=[O:21])=[N:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 34.2 %

Procedure:
Following the procedure described in Example 3(A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (200 mg, 0.399 mmol) was alkylated with 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (136 mg, 0.439 mmol). The reaction was diluted with a pH 6.8 buffer solution and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine (4×), dried (Na2SO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 30% MeOH in CH2Cl2) provided 100 mg of 3-{6-[(benzyl-isopropyl-carbamoyl)-methyl]-8,9-difluoro-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester. MS 732.5 (M+1), 730.4 (M−1).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([C:15]1([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19]2[CH2:20][NH:21][CH2:22][CH2:23][C:18]=2[C:17](=[O:24])[O:16]1)[CH:12]([CH3:14])[CH3:13]>ClCCl>[CH2:1]([NH:8][C:9]([N:21]1[CH2:22][CH2:23][C:18]2[C:17](=[O:24])[O:16][C:15]([CH2:25][CH:26]([CH3:28])[CH3:27])([CH2:11][CH:12]([CH3:14])[CH3:13])[C:19]=2[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC1(CC(C)C)OC(=O)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC(C)CC1(CC(C)C)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Benzyl isocyanate (0.04 g, 0.3 mmol) was added to a solution of 3,3-diisobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.075 g, 0.30 mmol prepared in a manner analogous to compound 2) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.042 g, 36%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.75-0.93 (m, 12H), 1.39-1.60 (m, 4H), 1.77-1.92 (m, 2H), 2.28-2.45 (m, 2H), 3.36-3.55 (m, 2H), 4.03-4.18 (m, 2H), 4.34-4.48 (m, 2H), 4.85-5.03 (m, 1H), 7.17-7.39 (m, 5H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[N:13]1[CH:14]=[C:15]2[N:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=13)[S:18][C:17]([C:25]([OH:27])=O)=[CH:16]2.ON1C(=O)CCC1=O.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][C:41]1=[O:53].C(N(CC)CC)C>C(#N)C>[C:49]([O:48][C:46]([N:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][CH2:37][NH:36][C:25]([C:17]2[S:18][C:19]3[N:24]4[C:15](=[CH:14][N:13]=[C:23]4[CH:22]=[CH:21][CH:20]=3)[CH:16]=2)=[O:27])[C:41](=[O:53])[CH2:42]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)C(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCNC(=O)C2=Cc3cnc4cccc(n34)S2)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.4 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.22 g, 22.0 mmol) was added to a stirred suspension of 5-thia-1,8b-diazaacenaphtylene-4-carboxylic acid (2.40 g, 11.0 mmol) and N-hydroxysuccinimide (2.53 g, 22.0 mmol) in acetonotrile (30 ml) at room temperature and the mixture was stirred at room temperature for 1.5 hours. A solution of 1-(3-aminopropan-1-yl)-4-tert-butoxycarbonyl-2-oxopiperazine (3.67 g, 14.3 mmol) and triethylamine (4.45 g, 44.0 mmol) in acetonitrile (15 ml) was added to the mixture. After stirring at room temperature for 19 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with Ethyl acetate-Methanol (10:1) to give N-[3-(4-tert-butoxycarbonyl-2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powder(1.53 g, 30%).
Reaction SMILES: C([O-])=O.C([NH+](CC)CC)C.C(O)=O.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:26][C:25](=[O:33])[CH:24]=1>O>[CH2:23]([C:24]1[C:25](=[O:26])[O:33][C:20]2[C:15]([C:14]=1[OH:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:32]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: O
Solvent: O=CO
Product: O=c1oc2ccccc2c(O)c1Cc1ccccc1
Temperature: 135 °C

Procedure:
Triethylammonium formate (TEAF) was prepared by adding TEA (20.0 mL) to formic acid (16.5 mL) with ice cooling. To TEAF was added benzaldehyde (3.78 mL) and 4-hydroxy-chromen-2-one (6.0 g) and the resulting mixture was heated to 130-140° C. for 3 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and conc. in vacuo to give a light yellow solid. The crude solid was recrystallized from EtOH to give 3-Benzyl-4-hydroxy-chromen-2-one as a white solid (1.95 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br-]>O.CN(C)C(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccccn1
Reactant: Nc1nc2cc(Br)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc2ccc(Br)cc2n1-c1ccccn1
Temperature: 150 °C
Yield: 26 %

Procedure:
To two 10-20 mL microwave vials was added 5-bromo-1H-benzo[d]imidazol-2-amine (3.00 g, 14.1 mmol, Carbocore, The Woodlands, Tex.), N,N-dimethylacetamide (20 mL), 2-fluoropyridine (1.46 mL, 17.0 mmol, Aldrich, St. Louis, Mo.) and cesium carbonate (7.84 g, 24.1 mmol). (One-half of the material in each vial, ie 1.5 g of the bromide in each vial.) The mixture was heated at 150° C. for 140 min in the microwave. After cooling to rt, the combined reaction mixtures were poured into water (400 mL) and then extracted with EtOAc/hexane (80:20) (3×150 mL). The combined extracts were washed with water (3×100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0.5 to 3.8% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound (1.06 g, 26%). MS (ESI, positive ion) m/z: 289 (M(79Br)+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][N:8]=[C:7]([S:12][CH3:13])[N:6]=1)=[O:4].[Na+].[C:15]1([S:21]([O-:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[CH:9][N:8]=[C:7]([S:12][CH3:13])[N:6]=1)=[O:4]
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)c1nc(SC)ncc1Br
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1nc(SC)ncc1S(=O)(=O)c1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
A mixture of 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (2.3 g), benzenesulfinic acid sodium salt (1.9 g) and dimethyl sulfoxide (35 mL) was treated with bis[copper(I)triflate]benzene complex (3.3 g), and the resulting mixture was stirred at 65° C. for 1.5 hours. The mixture was cooled to 40° C. and filtered through Celite. The filtrate was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 4:1 by volume) to afford the title compound as a pale yellow solid (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](O)=[O:28]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccco1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccco2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-furamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 2-furoic acid using method D. NMR; δH [2H6]—DMSO 10.18,(1H, s), 8.62,(1H, t), 7.93-7.91,(3H, m), 7.69,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.31,(1H, d), 7.27,(1H, d), 6.69,(1H, m), 3.16,(2H, m), 2.19,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.25 min, MH+375.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[N:11]#[C:12][NH2:13]>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]([NH2:13])=[NH:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: N#CN
Reactant: COc1cc(Br)ccc1N
Agent: Cl
Solvent: O
Product: COc1cc(Br)ccc1NC(=N)N
Temperature: 60 °C
Reaction time: 6 h
Yield: 99.2 %

Procedure:
To a solution of 4-bromo-2-methoxyaniline 7.1 g (35.1 mmol) in HCl 25% m/v 20 mL, cyanamide 20.6 g (494.3 mmol) was added in portion (1.6 g every half hour). The reaction was stirred at 60° C. for 6 hours, then cooled down to room temperature, diluted with H2O (20 mL), extracted with AcOEt (10 mL). NaOH 35% (30 mL) was added to pH>>14. The aqueous phase was extracted with AcOEt (3×50 mL), dried over Na2SO4 and concentrated to afford 8.5 g (quantitative yield) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Reaction time: 18 h
Yield: 67 %

Procedure:
Triethylamine (6.8 mL, 48.6 mmol) was added to a stirred solution of 4-chloro-2-aminopyridine, 11, (Townsend, L. B. et al Synthetic Commun. 1997 27, 861-870) (5 g, 38.9 mmol) in dichloromethane (75 mL). After cooling to 0° C. a solution of trimethylacetyl chloride (5.3 mL, 42.8 mmol) in dichloromethane (10 mL) was added dropwise over 15 min. The mixture was allowed to warm to 23° and stirred for 18 h then washed with saturated sodium bicarbonate. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an off-white solid. This was recrystallised from isopropyl ether to afford the title compound as white crystals (5.5 g, 67%). MS(EI) m/e 213, 215 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[S:9][N:8]=1
Reactant: Cc1cccc2c(=O)[nH]sc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc2c(Cl)nsc12
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 82.6 g (0.5 mol) of 7-methyl-1,2-benzisothiazol-3-one, 80.4 g (1.1 mol) of N,N-dimethylformamide and 200.0 g of toluene. While stirring, 83.3 g (0.7 mol) of thionyl chloride was added dropwise thereto at 70° to 80° C. over 1 hour, and the mixture was reacted at the same temperature for 3 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was distillated under reduced pressure of 0.40 kPa at 110° C. to give 81.7 g (0.45 mol) of 3-chloro-7-methyl-1,2-benzisothiazole. The yield based on 7-methyl-1,2-benzisothiazol-3-one was 89%.