Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[C:34](OC(=O)C)(=[O:36])[CH3:35].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:32][C:30]1[CH:29]=[CH:28][C:27](=[O:33])[N:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:18]3[N:14]([CH2:13][C:11]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH:12]=4)[O:4][CH2:3][CH2:2][NH:1][C:34](=[O:36])[CH3:35])[CH:15]=[N:16][CH:17]=3)=[CH:25][N:24]=2)[CH:31]=1
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Reaction time: 2 h

Procedure:
2-(2-Amino-ethoxy)-4-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-benzonitrile (L-824,459, 50 mg, 0.11 mmol) was dissolved in CH2Cl2 (550 tl) and treated with acetic anhydride (208 μl, 0.22 mmol). DIEA was then added until pH=7-8. The reaction mixture was stirred at room temp. for 2 hours. Saturated NaHCO3 was added (10 mL) and the solution was extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to yield the final product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C1COCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:19][CH3:20])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=5[F:18])[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1F
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1F
Yield: 59.6 %

Procedure:
A solution of 2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (184.6 mg, 0.624 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (140 mg, 0.624 mmol) in THF (1095 μL) and acetic acid (1095 μL) was heated 80° C. in a capped vial overnight. The solvent was evaporated in vacuum and the residue was partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. the combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (179.6 mg, 0.372 mmol, 59.6% yield) as brown solid. LC-MS (M+H)+=483.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.97 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=1.5 Hz), 7.01-7.10 (2H, m), 7.00 (1H, d, J=1.5 Hz), 6.73-6.84 (3H, m), 4.44 (1H, s), 3.61 (3H, s), 3.11 (3H, d, J=4.9 Hz), 2.59-2.77 (2H, m), 1.95-2.05 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.N1C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9]1)[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1C1CCCN(C(=O)C(F)(F)F)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1C1CCCN(C(=O)C(F)(F)F)C1

Procedure:
2.2 g of 3-(2-aminophenyl)-1-(trifluoroacetyl)-piperidine in 100 ml of methylene chloride, 3 ml of pyridine and 1 ml of ethyl chloroformate were stirred for one hour, washed with 2N hydrochloric acid and then with water, dried, taken to dryness under reduced pressure to obtain 2.8 g of an oil which was used as is for the following step.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([OH:28])=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29].[CH2:30](O)[CH3:31].S(=O)(=O)(O)O.C(OCC)(=O)C>O>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([O:28][CH2:30][CH3:31])=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29]
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2N)C1c1ccc(Cl)cc1Cl

Procedure:
To 4.33 g of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 50 ml of ethanol and 2 ml of concentrated sulfuric acid, followed by heating under reflux overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.3 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a yellow foam.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16](=O)[CH2:17][N:18]2[C:22]([C:23]([O:25]CC)=O)=[CH:21][CH:20]=[N:19]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]>C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[NH:5][C:23](=[O:25])[C:22]3[N:18]([N:19]=[CH:20][CH:21]=3)[CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CCOC(=O)c1ccnn1CC(=O)c1ccc(OC)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2cn3nccc3c(=O)[nH]2)cc1OC
Temperature: 110 °C

Procedure:
Ammonium acetate (4.16 g, 54.0 mmol) was added to a solution of ethyl 1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-5-carboxylate 5.01 (195 mg, 0.61 mmol) in Acetic Acid (5.4 mL) at room temperature. Mixture was heated at 110° C. overnight. An additional 900 mg of ammonium acetate was added and mixture was heated at 110° C. for 3.5 hours, and then cooled to room temperature. Acetic acid was concentrated and residue was taken up in ethyl acetate and washed with 1:1 water/saturated NaHCO3 (aq). Layers were separated and aqueous was extracted with ethyl acetate. Combined organic layers were washed with 1:1 brine/saturated NaHCO3 (aq), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4(5H)-one 5.02, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH:10]([CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:15][CH2:14][N:13]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:12]2)[CH:10]([CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC1CN(C(=O)OC(C)(C)C)C12CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)C12CCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 104 %

Procedure:
An optically-active compound of 3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (6.9 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.3 g), potassium carbonate (7.7 g) and water (65 ml), and stirred for 4 hours with refluxing. The mixture was cooled to room temperature, and thereto was added water (60 ml). The mixture was extracted with chloroform/methanol (10/1, 120 ml). The organic layer was sequentially washed with water, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. To the mixture was added silica gel (4 g), and the mixture was stirred for 10 minutes, filtered through Celite and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/1, followed by chloroform/methanol=50/1 to 20/1) to give the titled compound (10.0 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1)(=[O:28])[CH3:27]
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 3 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (1 g, 2.4 mmol) in 24 mL of CH2Cl2 was added 4-dimethylamino pyridine (0.88 g, 7.2 mmol) and acetyl chloride (0.21 g, 2.6 mmol). The solution was stirred for 3 h and the solvent was removed under reduced pressure. The residue was treated with saturated NH4OH (20 mL) and the suspension was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (1×50 mL), dried over MgSo4, filtered and concentrated to leave a solid. The solid was triturated with ether and was filtered to leave the title compound: MS (M+H): 381 (base peak).
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:35][C@H:36]2[CH2:41][CH2:40][C@H:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([N:35]([C@H:36]2[CH2:37][CH2:38][C@H:39]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)[C@H]1CC[C@H](NC2CCCCCC2)CC1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Example 38) via cycloheptyl-(trans-4-isopropyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[CH2:13]2)[N:11]=1)[C:4]([NH2:6])=[NH:5].C(N(CC)CC)C.[N-:26]([C:29]#[N:30])[C:27]#[N:28].[Na+]>C(O)CCC>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:29]([NH2:30])=[N:26][C:27]#[N:28])[CH2:13]2)[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N#C[N-]C#N
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: N#CN=C(N)NC1CCCC(c2csc(NC(=N)N)n2)C1

Procedure:
A mixture of 2-guanidino-4-(3-aminocyclohexyl)thiazole dihydrochloride (0.62 g.), triethylamine (0.56 ml.) and sodium dicyanamide (0.23 g.) in n-butanol (10 ml.) was heated under reflux for four hours. The filtered reaction mixture was evaporated and the residue subjected to preparative thin layer chromatography on silica GF 254 (Merck) plates using chloroform/methanol/ammonia (s.g. 0.88) 8:2:03 v/v/v for development. Isolation of the appropriate region of the chromatogram and elution with hot ethanol/chloroform (50:50 v/v) gave 2-guanidino-4-[3-(2-cyanoguanidino)cyclohexyl] thiazole as a glass. The n.m.r. spectrum in d6 dimethylsulphoxide included resonances at 1.28(m); 1.8(m); 6.3(s); 6.55(br s); 6.67(d); 6.9(br s) and showed resonances attributable to solvation by ethanol (~0.5 mole) and water.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][NH:12][C:11](=[O:14])[CH2:10][CH:9]2[CH3:15])=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18]
Reactant: CC1CC(=O)NNC1c1ccc(N)cc1
Reactant: COC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 40.2 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-dihydro-5-methyl-3(2H)-pyridazinone and 3.3 g (34.9 millimoles) of methyl chloroformate in 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from dimethylformamide/water. 3.1 g (40% of theory) of 4,5-dihydro-6-(p-methoxycarbonylaminophenyl)-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 228°-229° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)CNCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a cold (0°-5° C.) solution of 3-(t-butyloxycarbonylamino)-1-propylamine (4.00 g, 23 mmol) and triethylamine (2.8 mL, 20 mmol) in anhydrous CH2Cl2 (15 mL) was added slowly a solution of p-methoxybenzyl bromoacetate (5.18 g, 20 mmol) in anhydrous CH2Cl2 (10 mL) over a period of 2.5 h. The mixture was stirred at 0°-5° C. for 2 h, at which time TLC indicated that the reaction was complete. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a dark residue. The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane) to afford 2.81 g (40% yield) of p-methoxybenzyl [3-(t-butyloxycarbonylamino)-1-propylamino]acetate as an amber oil. 1H NMR (300 MHz, CDCl3) δ1.41 (s, 9H), 1.61 (quint, J=7 Hz, 2H), 2.63 (t, J=7 Hz, 2H), 3.17 (q, J=6 Hz, 2H), 3.38 (s, 2H), 3.78 (s, 3H), 5.07 (s, 2H), 6.86 (m, 2H), and 7.26 (m, 2H); IR (film), 1736, 1708 cm-1 ; MS (isobutane-DCI) MH+ =353. Anal. Calcd. for C18H28N2O5 : C, 61.35; H, 8.01; N, 7.95. Found: C, 60.87; H, 8.30; N, 7.89.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([F:11])[CH:4]=1.[OH2:13]>CCO.[N+]([O-])([O-])=O.[Ag+]>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:13])=[CH:4][C:5]=1[F:11])#[N:10]
Reactant: O
Reactant: N#Cc1ccc(C(Br)Br)cc1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: N#Cc1ccc(C=O)cc1F
Reaction time: 18 h

Procedure:
To a solution of α,α-dibromo-4-cyano-3-fluorotoluene, as described above in Step A, (5.60 g, 19.1 mmol) in EtOH (255 mL) and water (45 mL) was added AgNO3. The mixture was heated to reflux for 3 hours, then stood at ambient temperature for 18 hours, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to a volume of approximately 20 mL. Water (30 mL) was added, and the mixture was concentrated to dryness in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dried for several days at ca. 0.5 mm Hg to yield the desired aldehyde as a pale solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[C:24]([Cl:29])=[N:25][CH:26]=[CH:27][CH:28]=1>>[Cl:29][C:24]1[C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Clc1ncccc1Br
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cccnc2Cl)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 3-bromo-2-chloro-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([C:38]2[S:39][CH:40]=[C:41]([CH2:43][NH2:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:44][CH2:43][C:41]4[N:42]=[C:38]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[S:39][CH:40]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1csc(-c2ccccc2)n1
Product: O=C(NCc1csc(-c2ccccc2)n1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in General Procedure 10 to give the title compound. LCMS: m/z=619.90 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:14]([F:15])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19]([OH:21])=[O:20])=[CH:11][N:12]2[CH:16]2[CH2:18][CH2:17]2)=[CH:7][C:6]=1[F:23])(=[O:3])N.S(=O)(=O)(O)[OH:25].N([O-])=O.[Na+]>>[CH:16]1([N:12]2[C:13]3[C:8](=[CH:7][C:6]([F:23])=[C:5]([CH2:4][C:1]([OH:25])=[O:3])[C:14]=3[F:15])[C:9](=[O:22])[C:10]([C:19]([OH:21])=[O:20])=[CH:11]2)[CH2:18][CH2:17]1
Reactant: NC(=O)Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Reaction time: 1 h

Procedure:
3.0 g of the compound from Example 10 are warmed to 90°-100° C. in 17 ml of 30% strength sulphuric acid. At this temperature, 6 ml of 2.5 molar sodium nitrite solution are added dropwise. The mixture is stirred for one hour more at 100° and then cooled. The precipitated solid is isolated, washed and dried.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:4][CH2:5][S:6]([NH2:9])(=[O:8])=[O:7].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH:19]=[N:9][S:6]([CH2:5][CH2:4][C:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:2][OH:1])(=[O:7])=[O:8])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: CCC(CC)(CO)CCS(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCC(CC)(CO)CCS(=O)(=O)N=CN(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 2.0 g of the 4-hydroxy-3,3-diethyl-1-butanesulfonamide obtained in Reference Example 33 in 30 ml of toluene was added 1.2 g of N,N-dimethylformamide dimethyl acetal and the mixture was stirred at 90° C. for 1 hour. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel (70 g) column chromatograhy and elution was carried out with ethyl acetate-chloroform-methanol (20:20:1) to provide 2.43 g of the title compound as oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][OH:33])=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:35]1[N:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][N:36]=1>O1CCCC1.CC(N(C)C)=O.[H-].[Na+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][O:33][C:35]4[N:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][N:36]=4)=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1nc(OCCOc2ncc(S(C)(=O)=O)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.4 %

Procedure:
To a solution of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 17) (300 mg, 0.63 mmol) in anhydrous tetrahydrofuran (12 ml) and dimethyl acetamide, sodium hydride 60% dispersion in oil (55 mg, 1.39 mmol) was added under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 20 minutes. 2-chloro-5-(methylsulfonyl)pyrimidine (0.69 mmol) was added, in one portion, to the reaction mixture which was then stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue poured onto water (150 ml). The aqueous was extracted with ethyl acetate (4×50 ml). The organic fractions were washed with brine (4×100 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield the title compound (65 mg) as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:27]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:27])[C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C[C@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 60 °C
Yield: 59 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester (3.0 g, 8.2 mmol) was dissolved in acetonitrile (40 mL). Mixture was warmed to 60° C. N-Chlorosuccinimide (1.29 g, 9.7 mmol) was added to the warm solution. Reaction mixture was heated at reflux for 10 minutes. Mixture was cooled to room temperature then diluted with ethyl acetate (20 mL). Mixture was washed successively with saturated aqueous sodium bicarbonate (40 mL), and brine (20 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 59% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=6.98 (s, 1H), 5.15 (d, J=3.3, 2H), 4.09 (m, 4H), 2.99 (m, 2H), 2.69 (m, 2H), 2.39 (dd, J1=4.8, J2=16.5, 1H), 2.17 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e (M−C2H4O2+H)+=340.0.