Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[NH:6])#[N:3].C([OH:18])(C)C>>[ClH:1].[ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[NH:6])(=[O:18])[NH2:3]
Reactant: CC(C)O
Reactant: N#CNC(=N)NCc1ccccn1
Agent: Cl
Product: N=C(NCc1ccccn1)NC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated HCl (15.4 ml) is added to a stirred solution of 1-cyano-3-(2-pyridylmethyl)guanidine (4.50 g) in 310 ml of isopropanol. The reaction mixture is stirred at room temperature overnight. The solvent is concentrated in vacuo and the residue treated with 1.8 liters of boiling ethanol. The resulting suspension is stirred and heated while adding small portions of water until most of the solid has dissolved. The solution is filtered through Celite, diluted to 2 liters with absolute ethanol and concentrated on a hot plate and cooled. The first crop of crystals, MP 214°-215° C. w/dec, and the second crop of crystals, MP 215°-216° C. w/dec, obtained by concentration of the filtrate, were combined to give 2.60 g of the carbamoyl guanidine as a grey-green solid. The grey-green solid is dissolved in boiling ethanol, treated with Darco G-60 and filtered. The filtrate is boiled down on a hotplate and the white crystalline precipitate is collected, washed with absolute ethanol and dried in air yielding 1.77 g of the desired product MP 214°-216° C. w/dec.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[C:10]2[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:10]1[C:9]2[C:14](=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH:6]=[CH:7][CH:8]=2)[N:13]=[C:12]([CH3:15])[CH:11]=1
Reactant: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCN)c2n1
Reactant: CS(=O)(=O)Cl
Product: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCNS(C)(=O)=O)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(2,4-dichlorobenzyl)-amine (example 36) and methanesulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:10]([O-])([O-])OC.[C]=O>>[CH3:10][O:1]/[C:2](/[CH2:8][CH3:9])=[CH:3]/[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: COC([O-])[O-]
Agent: [C]=O
Product: CC/C(=C\C(=O)OC)OC

Procedure:
A 250-ml 2-necked round-bottomed flask was equipped with a magnetic stirring bar, a thermometer and an argon inlet. To a mixture of 30.00 g of methyl 3-oxovalerate (0.225 mol) and 125 ml of methyl orthoformate (121.1 g, 1.12 mol) was added under stirring 7.5 g of amberlist 15. The reaction was slightly exothermal at beginning and the temperature reached 31° C. A check with Drager test tube indicated the development of carbon monoxide. The suspension was stirred at rt for 3 h and then filtered into a 500-ml 4-necked pear-shaped flask equipped with an oil bath, a thermometer, an argon inlet, a 20-cm Vigreux column with a distillation head, a vacuum pump with vacuum controller and a cold trap. The volatile components of the reaction mixture were removed by distillation at a still temperature between 37 and 48° C. and a pressure between 250 and 40 mbar. The head temperature reached max 30° C. The residue, 31.3 g Methyl (E)-3-methoxy-2-pentenoate as a yellow oil was used without purification in the next step (theor. amount 32.5 g calculated as enol ether).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1CCCCC1.C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[OH:21][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCCC(=O)OCC
Reactant: O=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)CCC(C(=O)OCC)C(O)c1ccccc1
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
2.0 g of diethyl glutarate and 1.1 g of benzaldehyde were dissolved in 30 ml of tetrahydrofuran, and 8.5 ml of a 1.5M lithium diisopropylamide cyclohexane solution was dropwise added thereto at -78° C. under a nitrogen atmosphere, followed by stirring at the same temperature for 1.5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (Lobar column™, size C, Lichroprep™Si60, manufactured by Merck Co.; hexane/ethyl acetate=3/1) to obtain 1.56 g of the above-identified compound as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][C:11]1[NH:15][CH2:14][CH2:13][N:12]=1
Reactant: NCCN
Reactant: COc1cccc(Cl)c1CC#N
Product: COc1cccc(Cl)c1CC1=NCCN1

Procedure:
2-(2-Chloro-6-methoxy-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-chloro-6-methoxyphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): light brown powder; MS (ISP): 224.9 ((M+H)+.).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[N:59]=[C:60]([C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)[O:61][C:62]=4[CH3:63])=[O:57])=[CH:51][N:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[N:59]=[C:60]([C:64]5[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=5)[O:61][C:62]=4[CH3:63])=[O:57])=[CH:51][N:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(-c2ccc3c(c2)C(=O)N([C@H](C(=O)O)C(C)C)C3)nc1
Yield: 92 %

Procedure:
The compound of example 655 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 654.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[C:12]([CH3:17])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1>ClCCl.[O-2].[Mn+4].[O-2]>[CH3:1][O:2][CH2:3][C:4]1[C:5]([N:10]2[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([CH3:17])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCc1cccnc1-n1cc(CO)c(C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCc1cccnc1-n1cc(C=O)c(C)n1
Yield: 82.8 %

Procedure:
A mixture of A mixture of [1-[3-(methoxymethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methanol (2.2 g, 9.4 mmol) and manganese (IV) oxide (19 g, 188.8 mmol) is stirred in dichloromethane (20 mL) at room temperature overnight. The reaction mixture is filtered over celite and the solvent evaporated under reduced pressure to yield 1.8 g of the title compound that is used without further purification. MS (m/z): 232 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:19][CH3:20])([CH3:18])[C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1.O.[NH2:23][NH2:24]>C(O)C>[CH2:19]([C:4]1([CH3:18])[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:8][CH:7]=2)=[N:24][NH:23][C:3]1=[O:2])[CH3:20]
Reactant: NN
Reactant: CCC(C)(C(=O)OC)C(=O)c1ccc(-n2ccnc2)cc1
Solvent: CCO
Solvent: O
Product: CCC1(C)C(=O)NN=C1c1ccc(-n2ccnc2)cc1

Procedure:
A solution of 3.8 g of α-ethyl-4-(1H-imidazol-1-yl)-α-methyl-β-oxobenzenepropanoic acid methyl ester, 2.0 g of hydrazine hydrate and 25 ml of ethanol was refluxed for 20 hours. The ethanol is removed and the residue is treated with ether and water. Filtration of the solid gives after recrystallization from ethyl acetate, 2.7 g of a crystalline solid, mp 86°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]([CH3:37])([CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:35])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:38])[C:4]([CH3:36])([CH3:37])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:35])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:34])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid methyl ester (2.05 g, 0.00398 mol) was dissolved in 100 mL of acetone and chilled in an ice-bath. To the solution was added Jones reagent (Prepared via the method of Feiser and Feiser) dropwise until a red color persisted. The reaction was allowed to warm to room temperature and then stirred for 18 hours at ambient temperature. The mixture was concentrated under vacuum to give a green solid. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was separated, washed with water (3×100 mL), brine (1×100 mL) and treated with MgSO4, filtered and concentrated in vacuo to give alight green solid. Purification via column chromatography yielded 1.25 g (61% yield) of the title compound as a white solid. MH+ 514.6.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29].O>ClCCl>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[C:11]([NH:28][NH2:29])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)nc(Cl)c(=O)n2OCc1ccccc1
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc2c(cc1C(F)(F)F)nc(NN)c(=O)n2OCc1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 5.2 g (13.7 mmol) of 1-benzyloxy-3-chloro-7-cyano-6-trifluoromethylquinoxalin-2(1H)-one in 150 ml of dichloromethane was added 2.7 ml of hydrazine monohydrate (~55.7 mmol) at 0° C. Stirring was continued at 0° C. for 1 h. The evaporated reaction mixture was stirred with water to give the title compound (5.0 g; 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)[CH3:2].[NH3:16].C(O)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[C:8]([NH2:16])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)CSc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1cnc(Cl)nc1N
Temperature: 25 °C

Procedure:
A solution of ethyl[(2,4-dichloro-5-pyrimidinyl)thio]acetate (2.0 g, 7.49 mmol) in DMF (75 ml) was treated with ammonia in isopropanol (7.49 ml, 14.97 mmol) in a pressure tube. The tube was capped, and the reaction was stirred at ambient temperature. Upon completion, the solution was concentrated under reduced pressure and pumped on to remove any residual DMF. The crude material was chromatographed using a gradient of 0-10% acetone/chloroform. The product contained a small amount of cyclized material (which is the product of the next step). The product was isolated as a light yellow solid.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.O[CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:28]=[C:22]3[C:21]2=[O:37])[CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:10][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:28]=[C:22]3[C:21]2=[O:37])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(CO)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(CCl)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
Toluene-4-sulfonyl chloride (73 mg, 0.38 mmol) was added to a solution of 5-(6-hydroxymethyl-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (67 mg, 0.19 mmol) and TEA (0.06 mL, 0.478 mmol) in DCM (1 mL) at 0° C. The reaction was stirred for 10 minutes at 100° C. under microwave irradiation. The mixture was basified with a saturated solution of NaHCO3, the organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash column chromatography (silica, AcOEt in DCM 0/100 to 10/90). Desired fractions were collected and the solvent evaporated in vacuo. The residue was triturated with DIPE to yield 5-(6-chloromethyl-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (19 mg, 27% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.47-4.56 (m, 2H), 4.62 (s, 2H), 4.62-4.67 (m, 2H), 5.13 (s, 2H), 6.94-7.00 (m, 1H), 7.00-7.05 (m, 2H), 7.08 (s, 1H), 7.27-7.35 (m, 3H), 7.77 (dd, J=8.3, 7.6 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.Cl.CN(C)CCCN=C=NCC.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:32]([NH:39][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 40 °C
Yield: 57.3 %

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (50 mg, 0.22 mmol) (from example 11), p-hydroxybenzotriazole hydrate (HOBt) (74 mg, 2.5 eq.), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDAC HCl) (105 mg, 2.5 eq.), benzylamine (94 mg, 4 eq.) and triethylamine (TEA) (0.5 mL) in DMF (1 mL) was heated at 40° C. for overnight. The reaction was concentrated and the residue was purified on a silica gel column to give 40 mg of the titled compound as a white solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)=[O:19]
Reactant: CON(C)C(=O)C=Cc1ccc(Cl)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(4-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (13 g) as an oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:16]=[C:15]([NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][N:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>>[CH2:18]([NH:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1ccnc(N2CCc3ccccc3C2)c1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: c1ccc(CNc2ccnc(N3CCc4ccccc4C3)c2)cc1

Procedure:
Following the general method described in example 9, N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl]-benzamide (example 17a) was reacted with lithium aluminum hydride. After workup and chromatography the free base of the title compound was treated with hydrogen chloride and triturated with Et2O/pentane. The title compound was obtained as white amorphous material. MS: m/e=315 (M+).
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC.CCCCCC>[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[C@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CSC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of CuBr.SMe2 (2.74 g, 2.2 eq, 13.33 mmol) in ether (100 mL) under an argon atmosphere at −70° C., was added methyl lithium (1.6 M in ether, 15.13 mL, 4.0 eq, 24.21 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (2 g, 1 eq, 6.05 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h and then at −55° C. for 4 h, when TLC (hexane:Et2O; 80:20) indicated that the reaction had gone to completion. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:Et2O (80:20) to afford the title compound as a light yellow oil. Yield: 1.37 g (66%). (80% de 2R,3S: 20% de 2S,3S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.0.47 & 0.55 (2×t, J=7.50 & 7.26 Hz —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5H, —NHCH(CH2CH3)CH(CH3OH), 2.01 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 3.22-3.43 (m, 1H, —NHCH(CH2CH3) CH(CH3)OH), 4.41 (d, 1H, J=3.31 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.14-7.56 (m, 15H, 3×Ph).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:37][C@@H:38]1[CH2:42][CH2:41][C@@H:40]([CH3:43])[NH:39]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[CH3:37][C@@H:38]1[CH2:42][CH2:41][C@@H:40]([CH3:43])[N:39]1[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: C[C@@H]1CC[C@@H](C)N1CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 36.7 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (100 mg, 0.313 mmol) and (2R,5R)-2,5-dimethylpyrrolidine (449 mg, 1.56 mmol) were allowed to react in the presence of K2CO3 (886 mg, 0.63 mmol) and NaI (251 mg, 1.56 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (60 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=1.[CH3:24][O-].[Na+].CI.CO>O.C(OCC)(=O)C.O1CCCC1>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[N:6]2[C:11]1[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH3:24])[CH:16]=1
Reactant: Nc1ncnc2c1nc(-c1ccccn1)n2-c1ccc(O)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-n2c(-c3ccccn3)nc3c(N)ncnc32)ccc1=O
Reaction time: 0.75 h
Yield: 57.4 %

Procedure:
A solution of 150 mg of 5-[6-amino-8-(2-pyridyl)-9H-9-purinyl ]-2-pyridinol, 133 mg of sodium methoxide and 306 μL methyl iodide in 20 mL mixture of methanol and tetrahydrofuran in a ratio of 1/1 was stirred at room temperature for 2 hours and 35 minutes and then at 60° C. for 45 minutes. Ethyl acetate and water were added to the reaction mixture, and this mixture was extracted once with ethyl acetate. The organic layer was washed with brine, and the whole aqueous layer was extracted twice with ethyl acetate. The whole organic layer was dried over magnesium sulfate and filtered, and from the resulting residues, the solvent was evaporated, to give 90 mg of the title compound as brown crystals (58% y.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[H-].[Na+].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH2:20]([N:8]1[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][C:13]2[C:3]([O:2][CH3:1])=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]1=2)[CH3:21]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCCc2c1ccc([N+](=O)[O-])c2OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of 6-methoxy-7-nitro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (4.5 g, 19.0 mmol) in dimethylformamide (30 mL) at 0° C. was added sodium hydride (60% on mineral oil, 1.15 g, 28.5 mmol) in small portions within 30 minutes. The mixture was stirred for 30 minutes at this temperature followed by adding ethyl iodide (1.84 mL, 22.9 mmol) dropwise. The mixture was warmed to room temperature and stirred for another 2 hours. Upon completion, the mixture was poured into ice-water and filtered to afford the product 1-ethyl-6-methoxy-7-nitro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one as a off-white solid (3.77 g, yield 78.5%). 1H NMR (400 MHz, CDCl3) δ ppm 7.81-7.84 (dd, 1H, J=1.6 Hz, 8.8 Hz), 7.08-7.10 (dd, 1H, J=1.2 Hz, 8.8 Hz), 3.76-3.94 (s+m, 5H), 2.89-2.96 (m, 2H), 2.22-2.32 (m, 4H), 1.16-1.26 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([Cl:21])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCCC2
Product: Clc1ccc(-c2nc(Cl)c3c(n2)CCCC3)cc1
Reaction time: 3 h

Procedure:
8.0 g of 2-(4-chlorophenyl)-4-hydroxy-5,6,7,8-tetrahydroquinazoline were heated to 100° C. in 10 ml of phosphorus oxychloride. After 3 hours, the cooled solution was carefully poured onto ice water. The crystalline product was filtered off with suction, washed well with water and dried in vacuo at room temperature. Yield: 6.2 g; m.p.: 121° C.