Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#N.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[N:33]1C=CC=C[CH:34]=1>>[N:30]1[CH:31]=[CH:32][C:27]([N:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:17]=[CH:16][C:15]([C:14]#[N:13])=[CH:20][C:19]=3[CH2:34][NH:33][S:9]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:26][CH2:25]2)=[CH:28][CH:29]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: NCc1ccc(N2CCN(c3ccncc3)CC2)cc1
Product: N#Cc1ccc(N2CCN(c3ccncc3)CC2)c(CNS(=O)(=O)c2ccccc2)c1

Procedure:
4-Cyanophenylsulphonyl chloride (202 mg) was added to a solution of 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (268 mg) in pyridine (20 ml). The mixture was heated on a steam bath for three hours. The solvents were removed by evaporation and water (100 ml) added to give a precipitate which was extracted into ethyl acetate (2×100 ml). The ethyl acetate extracts were combined, washed with water, brine, dried (MgSO4)-10% methanol/methylene chloride as eluent to give a solid which was recrystallised from a mixture of tetrahydrofuran/methanol/isohexane to give 1-(4-pyridyl)-4-(4-cyanophenylsulphonamidomethyl-phenyl)piperazine (52 mg) as a solid m.p.229-230° C.; microanalysis found: C,62.8; H,5.6; N,15.7%; C23H23N5O2S.0.25H2O requires: C,62.4; H,5.4; N,15.8%; NMR: 3.15-3.3(m,4H), 3.4-3.55(m,4H), 3.85-4.0(d,2H), 6.8-6.9(dd,4H), 7.0-77.1(d,2H), 7.8-7.9(d,2H), 7.95-8.05(d,2H), 8.18-8.25(d,2H), 8.25-8.4(bt,1H); MS: m/z 434 (MH)+
Reaction SMILES: [OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][NH:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:47](=[O:71])[CH2:48][CH2:49][N:50]([CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=1)[C:51](=[O:60])[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[CH2:53]([O:52][C:51]([N:50]([CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=1)[CH2:49][CH2:48][C:47]([N:27]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:26][CH2:25][N:14]([CH2:13][CH2:12][C:5]1[C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[C:2]([OH:1])=[CH:3][CH:4]=1)[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:71])=[O:60])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(Cl)CCN(CCc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)N(CCNC1CCOCC1)CCc1ccc(O)c2[nH]c(=O)sc12
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N(CCC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCOCC1)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of benzyl 2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(2-(tetrahydro-2H-pyran-4-ylamino)ethyl)carbamate (2.5 g), as prepared as in Example 23 step i), in dichloromethane (40 mL) was added triethylamine (2.95 mL) followed by chlorotrimethylsilane (2.69 mL). The reaction was allowed to stir for 30 min before a solution of the acid chloride of step i) (2.198 g) in dichloromethane (20 mL) was added. The reaction was stirred for 2 h before the mixture was diluted with dichloromethane (200 mL), washed with water (150 mL) and saturated sodium hydrogen carbonate (150 mL), and the organic layer was dried over sodium sulphate, filtered and evaporated to afford crude product. This was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (3.10 g) as a off-white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C([N:14](CC)[CH:15]([CH3:17])[CH3:16])(C)C.[CH2:20](O)[CH3:21]>>[CH2:17]1[C:20]2[C:21](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH:15]1[NH:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(NC2Cc3ccccc3C2)nc1
Temperature: 0 °C
Yield: 88 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (4 g) and N,N-diisopropylethylamine (3 ml) was heated under reflux in dry ethanol (100 ml) for 2 h. The reaction mixture was cooled to 0° C., the solid which separated was filtered off washed with little cold ethanol, dried to give the product (6.25 g, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=1.B(O)(O)O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[C:18]1([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(Br)c2)cc1
Agent: O=C([O-])O
Agent: OB(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(-c3ccccc3)c2)cc1
Yield: 13.7 %

Procedure:
5-bromo-3-(1-tosyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 51b (300 mg, 10.73 mmol), boric acid (107 mg, 10.88 mmol) and Pd(0) (26 mg) were mixed together in benzene (2 mrL), and the mixture was heated at reflux for 16 hours. NaHCO3 solution (2%, lmL) was added, and the mixture was extracted with CHCl3. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with EtOAc/hexane 1:1 to afford the title compound (300 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([Cl:31])[C:13]([C:16]2([CH2:19][NH:20][C:21](=[O:30])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:31][C:12]1[C:13]([C:16]2([CH2:19][NH:20][C:21](=[O:30])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[CH2:18][CH2:17]2)=[N:14][CH:15]=[C:10]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH:11]=1
Reactant: OB(O)c1ccoc1
Reactant: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCC1(c2ncc(-c3ccoc3)cc2Cl)CC1)c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a suspension of 3-furylboronic acid (80 μmol) in toluene (0.3 ml) was added successively a solution of N-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropylmethyl]-2,6-difluorobenzamide (40 μmol) (from step 4) in toluene (0.5 ml), aqueous sodium carbonate 2M (0.06 ml), water (0.4 ml) and a solution of tetrakis(triphenylphosphine)palladium (4 μmol) in toluene (0.2 ml). The reaction mixture was stirred at 90° C. for 16 hours under an atmosphere of Argon. The reaction mixture was evaporated. The crude mixture was extracted 3 times with ethyl acetate and water. The organic phases were combined and evaporated. The crude product was dissolved in N,N-dimethylformamide (1ml) and purified by HPLC to give 2.45 mg N-[1-(3-chloro-5-furan-3-yl-pyridin-2-yl)-cyclopropylmethyl]-2,6-difluoro-benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][CH2:42][CH:43]3[C:55]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:49]4[C:44]3=[CH:45][CH:46]=[CH:47][CH:48]=4)=[O:40])=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:23]=[CH:22][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][NH:18]4)=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[OH:56][C:57]([CH3:68])([CH3:67])[C@H:58]([NH:62][C:63]([O:65][CH3:66])=[O:64])[C:59](O)=[O:60]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32]([C@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][CH2:42][CH:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[C:50]4[C:55]3=[CH:54][CH:53]=[CH:52][CH:51]=4)=[O:40])=[O:33])=[CH:29][CH:30]=2)[CH2:9][C:10]2[CH:23]=[CH:22][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:59](=[O:60])[C@@H:58]([NH:62][C:63]([O:65][CH3:66])=[O:64])[C:57]([OH:56])([CH3:68])[CH3:67])=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)O
Reactant: O=C(Nc1ccc(CN(Cc2ccc3[nH]c([C@@H]4CCCN4)nc3c2)c2ccc(F)cc2)cc1)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4C(=O)OCC4c5ccccc5-c5ccccc54)cc3)c3ccc(F)cc3)ccc2[nH]1)C(C)(C)O
Yield: 101.3 %

Procedure:
The product from Example 99F (0.092 g, 0.125 mmol), (S)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.029 g, 0.15 mmol) was processed as in Example 99E to give 0.115 g (100%) of the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[C:7]([CH3:15])[C:5]=2[N:6]=1.C[O-:17].[K+]>CN1CCCC1=O>[CH3:15][C:7]1[C:5]2[NH:6][C:2](=[O:17])[S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[O-]
Reactant: COC(=O)c1ccc2sc(Cl)nc2c1C
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2sc(=O)[nH]c2c1C
Temperature: 100 °C
Yield: 54.8 %

Procedure:
A solution of 22.5 g (93 mmol) of methyl 2-chloro-4-methyl-benzothiazole-5-carboxylate in 360 ml of N-methylpyrrolidone was admixed with 13.6 g (186 mmol) of potassium methoxide and heated at 100° C. for 5 hours. After cooling, the resulting precipitate was filtered off with suction and the filtrate was admixed with water. The pH of the reaction solution was then adjusted to pH 1, the aqueous solution was extracted three times with ethyl acetate and the combined organic phases were washed and dried. The solvent was removed under reduced pressure and the residue was purified by trituration with methylene chloride/n-hexane. This gave, in a yield of 55%, 11.38 g (51 mmol) of methyl 4-methylbenzothiazol-2-one-5-carboxylate of m.p. 262° C.-266° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[CH3:13][S:14]([O:12][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(O)CCCCC
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC(CCCCC)OS(C)(=O)=O
Reaction time: 8 h
Yield: 105 %

Procedure:
After dissolving 29.95 g (0.17 mol) of 6-undecanol to 60 mL of pyridine, 29.98 g (0.26 mol) of methanesulfonyl chloride was added dropwise under cooling with ice and the mixture was stirred overnight. Thereafter, 35 mL of 0.5 N aqueous hydrochloric acid was added and the mixture was extracted twice with 200 mL of ethyl acetate. The organic layer was washed with 100 mL of water and a saturated aqueous solution of sodium chloride in that order and thereafter dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off to give 44.7 g of 6-methanesulfonyloxy-undecane.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:20]([O-:22])=[O:21])[CH2:4][C:5](=O)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7].[CH2:23]([O:30][C:31]([NH:33][C@H:34]1[CH2:38][O:37][NH:36][C:35]1=[O:39])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:23]([O:30][C:31]([NH:33][C@H:34]1[CH2:38][O:37][N:36]([C:5]2([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)=[O:7])[CH2:4][CH:3]([O:2][CH3:1])[C:20](=[O:21])[O:22]2)[C:35]1=[O:39])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(CC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC1CC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In 10 ml of dichloromethane was dissolved 896 mg of Compound (93). To the solution were added 680 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 593 mg of DCC, and the mixture was stirred at room temperature for one hour. Then, precipitating crystals were filtered off, and the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane--ethyl acetate (3:2) to give 723 mg of the subject Compound (94) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][C:15]=1[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:14]=1[Cl:13])[CH2:20][NH:21][C:22]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2)=[O:23]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc2cn1
Temperature: 25 °C

Procedure:
5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 194A (0.36 mL, 2.45 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.27 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.74 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.61 (m, 2H), 7.50 (t, 1H, J=8.0 Hz), 7.35 (dd, 1H, J=8.3 Hz, 2.2 Hz), 7.12 (t, 1H, 5.9 Hz), 4.37 (d, 2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[CH2:44][CH:43]([NH2:59])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1.O>[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([CH:53]3[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]3)[CH2:44][CH:43]([NH:59][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reaction time: 0.05 h
Yield: 202.7 %

Procedure:
Ethyl 3-aminobenzoate (100 mg) was dissolved in tetrahydrofuran (5 ml), the solution was cooled on ice, triphosgene (65 mg) was added thereto at internal temperature 5° C., triethylamine (220 mg) was added thereto at 3 minutes intervals, the mixture was allowed to come to room temperature and stirred for 10 minutes. A solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (820 mg) in tetrahydrofuran (5 ml) was added, additionally stirred for one hour. Water was added to the reaction mixture, extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1), to thereby obtain 265 mg of the titled compound (Yield 81%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[OH-].[Na+]>CCOCC.O>[O:12]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butylamine (9.05 g, 0.1225 mole) was dissolved in Et2O (30 ml). Succinic anhydride (5 g, finely powdered) was added portionwise. After addition was complete, the heterogeneous mixture was stirred 1 hour at room temperature. The reaction mixture was then poured into 10% NaOH in H2O (10 ml) and Et2O (30 ml). The layers were separated and the ether layer was extracted with additional 10% NaOH (10 ml). The combined aqueous layers were washed with ether (30 ml) and acidified with concentrated HCl to give a layer of oil above the water layer. This was extracted with Et2O (50 ml×2). The ether extracts were washed with saturated NaCl solution (3×30 ml) and dried (MgSO4). The solvent was removed in vacuo to give a white solid (7.5 g) which was recrystallized from benzene to give title acid as needle shaped crystals (4.83 g, 56%), m.p. 93.5°-94.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([S:10]([N:13]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO.[CH3:28][NH2:29].[BH4-].[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:9]=[C:8]([S:10]([N:13]2[CH:17]=[C:16]([CH2:18][NH:29][CH3:28])[CH:15]=[C:14]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1Cl
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C#N)c(Cl)c2)c1
Product: Cl
Yield: 24 %

Procedure:
Using 2-chloro-4-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile (248 mg), 40% methylamine methanol solution (1.4 mL) and sodium borohydride (28.9 mg), a procedure as in Example 9 was performed to give the title compound as white crystals (yield 67.8 mg, 24%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:23])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1.CCCCCCC>ClCCl>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:23])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Cl:3])=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CO)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5.66 ml (78.12 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 10 g (39.06 mmol) of 4-(3-(2-methylphenyl)ureido)benzyl alcohol in 150 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 1.5 hours and poured onto 200 ml of n-heptane. The heptane was decanted off from the deposited oil and the oil was stirred with diisopropyl ether. The solid obtained was filtered off and washed with diisopropyl ether. Yield: 8.32 g (78%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:25])[C:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:29]>C(Cl)(Cl)Cl>[ClH:29].[ClH:1].[ClH:29].[NH2:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][C:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)([N:3]([CH3:25])[CH3:2])[CH2:5][CH2:6]1
Reactant: ClC(Cl)Cl
Reactant: CN(C)C1(c2cccs2)CCN(CCNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2cccs2)CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
HCl gas was passed through a solution of 9 g (1 eq) tert-butyl 2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethylcarbamate in chloroform at 0° C. for ˜30 min. The reaction mixture was then stirred at room temperature for one hour. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and 9 g (97%) of product were obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:25][CH3:26])[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 3.0 g, 9.9 mmol) in 100 mL of DMF was added to a suspension of sodium hydride (0.47 g, 11.8 mmol) in 40 mL of DMF and stirred for 30 minutes. Ethyl iodide (7.9 mL, 99 mmol) was added, and the mixture was warmed to 50° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 3.2 g of the title compound as a solid, mp 133-135° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1.O>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Br)ccc2OCC2CCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)nn1Cc1cc(Br)ccc1OCC1CCC1
Temperature: 100 °C

Procedure:
To a solution of -(5-bromo-2-cyclobutylmethoxy-benzyl)-5-methyl-1h-pyrazole-3-carboxylic acid ethyl ester, 24 (0.12 g, 0.29 mmol) in a mixture of MeOH (2 mL) and THF (4 ml) was added a solution of NaOH (0.061 g, 1.45 mmol) in 2 ml of H2O. The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 20 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles were removed in vacuum to yield 1-(5-bromo-2-cyclobutylmethoxy-benzyl)-5-methyl-1h-pyrazole-3-carboxylic acid, 25
Reaction SMILES: [O:1]=[C:2]1[N:7]([Na])[C:6](=[O:9])[CH:5]=[N:4][NH:3]1.[CH2:10](Br)[C:11]#[CH:12]>C(O)CO>[O:1]=[C:2]1[N:7]([CH2:12][C:11]#[CH:10])[C:6](=[O:9])[CH:5]=[N:4][NH:3]1
Reactant: C#CCBr
Reactant: O=c1cn[nH]c(=O)n1[Na]
Solvent: OCCO
Product: C#CCn1c(=O)cn[nH]c1=O
Temperature: 80 °C

Procedure:
A mixture of 4.59 g 3,5-dioxo-4-sodio-2,3,4,5-tetrahydro-1,2,4-triazine, 4.64 g propargyl bromide and 40 ml ethylene glycol was heated to 80° C. for 3 hours.