Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:12]([N:6]1[CH2:7][CH2:8][CH:3]([CH3:2])[CH2:4][CH:5]1[C:9]([OH:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: CC1CCNC(C(=O)O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CC1CCN(Cc2ccccc2)C(C(=O)O)C1
Yield: 22 %

Procedure:
A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25.6 g (0.134 mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-n-hexane and recrystallized to give 10 g (22%) of benzyl 4-methyl-2-piperidinecarboxylic p-toluenesulfonate, M.P. 160°-163° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O.ClCCCl>[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([N:27]2[CH2:28][CH2:29][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25][CH2:26]2)[CH2:33][CH2:32]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 2) (199 mg, 0.515 mmol), 1-methyl-4-piperidone(70 ul, 0.566 mmol), sodium triacetoxyborohydride (163 mg, 0.772 mmol) and glacial acetic acid(34 mg, 0.566 mmol) were mixed with 3 ml of 1,2-dichloroethane. After stirring at room temperature overnight, 2 ml of water was added followed by solid sodium bicarbonate until the pH reached about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography to give 92 mg of 1-[1-(1-methyl-4-piperidinyl)-4-piperidinyl](4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO) 1.47 (m, 2H), 1.72 (d, J=1 1.75 Hz, 2H), 1.88 (m, 4H), 2.14 (s, 3H), 2.35 (m, 5H), 2.81(d, J=11.32 Hz, 2H), 3.01(d, J=11.26 Hz, 2H), 4.62 (m, 1H), 7.16 (m, 5H), 7.44 (m, 2H), 7.67 (d, J=8.69 Hz, 2H), 8.23 (s, 1H); LC/MS (MH+32 484).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)[CH:18]=O>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: O=CC(Cl)Cc1ccc2ncccc2c1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CC(C)O
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Temperature: 110 °C

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (800 mg, 2.97 mmol) and 2-chloro-3-quinolin-6-ylpropanal (784 mg, 3.57 mmol) in isopropyl alcohol (10.0 mL) in a sealed tube was heated at 110° C. for 48 h. After the reaction mixture was cooled to ambient temperature, the product was precipitated and collected by filtration. The mother liquor was concentrated and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, water, brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column with methanol in dichloromethane (0-6%) to give the desired product. (65%) LCMS: (M+H)=434.0/436.0.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7](I)[CH2:8][CH2:9][CH3:10].O[C:13]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].CI>CN(C)C=O>[CH2:7]([O:21][C:19]1[CH:20]=[CH:13][C:14]([CH:15]=[O:16])=[C:17]([O:4][CH3:1])[CH:18]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCI
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Potassium carbonate (1.50 g, 10.9 mmol) and butyl iodide (666 mg, 3.6 mmol) were added to a solution of 2,4-dihydroxybenzaldehyde (500 mg, 3.6 mmol) in dimethylformamide (5 ml), and they were stirred at room temperature for 2 hours. Then methyl iodide (2.57 ml) was added to the reaction mixture, and they were stirred at room temperature for 12 hours. After the extraction with ethyl acetate followed by the silica gel chromatography, 4-butoxy-2-methoxybenzaldehyde (yield: 233 mg, 31%) was obtained in the form of a colorless oil.
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:27]C)C=C4)N(CC2)C1.[F:64][C:65]([F:77])([F:76])[CH2:66][O:67][C:68]1[CH:73]=[CH:72]C(C=C)=[CH:70][N:69]=1>O>[F:64][C:65]([F:77])([F:76])[CH2:66][O:67][C:68]1[N:69]=[CH:70][C:2]([CH:1]([OH:5])[CH2:3][OH:27])=[CH:72][CH:73]=1
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc(OCC(F)(F)F)nc1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Product: OCC(O)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A 200 mL flask is charged with tert-butanol (30 mL), water (30 mL) and AD-mix-beta (10 g, 4.92 mmol). Stirring room temperature producted two clear phased. The lower aquerous phase bright yellow. The mixture is cooled to 0° C. Whereupon some of the dissolved salts precipitate. 2-(2,2,2-trifluoroethoxy)-5-vinylpyridine (1.00 g, 4.92 mmol, Step-2) is added at once, and the heterogeneous slurry is stirred vigorously at 0° C. for 15 hours. White precipitate is filtrated and filtrate is removed under reduced pressure. The residue is extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (1:3) to give 1.01 g (86% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)s1
Yield: 26.6 %

Procedure:
In the same manner as in Example 18-4 and using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (107 mg, 0.678 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (27.0 mg, 27%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1

Procedure:
To a stirred solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (91 mg, 0.21 mmol) in CH2Cl2 (3 mL) at rt was added TFA (0.5 mL). The mixture was stirred until complete removal of the Boc group had occurred. The solvent was removed under vacuum to give methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate as its TFA salt. MS: 327 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3]C1.[F:28]C1C=C(C2C(C(C3C=C(C(=O)C(Cl)(Cl)Cl)NC=3)=O)=C(C)ON=2)C=CC=1F.C(N)C#C>>[CH2:4]([NH:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])=[O:14])[CH:12]=1)=[O:7])[C:1]#[CH:3]
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Agent: C#CCN
Product: C#CCNC(=O)c1cc(C(=O)c2c(-c3ccc(F)c(F)c3)noc2C)c[nH]1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 19) and prop-2-ynylamine (commercially available) in 28.1 yield. (m/e): 370.0 (MH+; 100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]#[N:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][C:17]([NH2:18])=[S:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: S
Reactant: CC(C)(C)c1cc(CC#N)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(CC(N)=S)cc(C(C)(C)C)c1O

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenylacetonitrile (20.0 g) and 11.4 ml of triethylamine were dissolved in 40 ml of pyridine, and hydrogen sulfide was blown into the solution at room temperature over 13 hours. The reaction mixture was concentrated, and the crude product thus obtained was purified by silica gel column chromatography (diethyl ether-hexane =3:7) to give 4.9 g of the desired compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([OH:18])=O)[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.CN(C)C=O.S(Cl)(Cl)=O.[NH2:30][CH:31]([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:18])[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)N
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Reaction time: 65 h

Procedure:
To a solution at room temperature of 6.0 g (20.6 mmoles) of cis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid and ca. 1 ml of anhydrous DMF (dimethylformamide) in 300 ml of anhydrous CH2Cl2 was added dropwise a solution of 8.95 ml (123.6 mmoles) of thionyl chloride in 50 ml of anhydrous CH2Cl2. After addition, the solution was stirred and refluxed for 2.5 hours. The solvent and excess SOCl2 were then removed under reduced pressure and the residue was flashed down twice with anhydrous benzene to remove traces of SOCl2. The residue was redissolved in ca. 200 ml of CH2Cl2 and a solution of 7.7 g (130 mmoles) of 2-aminopropane in ca. 50 ml of CH2Cl2 was added. Heat was evolved. The solution was mixed well and allowed to stand in a stoppered flask at room temperature for 65 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([NH:20][C@H:21]([C:23]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27](=[O:35])[C:26]4=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]4[N:24]=3)[CH3:22])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+].Cl>C(O)C.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C@H:21]([C:23]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27](=[O:35])[C:26]4=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]4[N:24]=3)[CH3:22])[N:12]=[CH:11][N:10]=2)=[CH:40][CH:41]=1
Reactant: CCOC(=O)c1c(NCc2ccc(OC)cc2)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2C(=O)O)cc1
Temperature: 50 °C
Yield: 111.9 %

Procedure:
(S)-Ethyl 4-((4-methoxybenzyl)amino)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxylate (281 mg, 0.51 mmol) was dissolved in 2 mL ethanol and 3 mL tetrahydrofuran. Lithium hydroxide (213 mg, 50.8 mmol) in 3 mL water was added and the mixture was heated at 50° C. overnight. Further lithium hydroxide (213 mg, 50.8 mmol) in 3 mL water was added and the reaction mixture heated at 50° C. for 4 h more. The reaction mixture was diluted with water and acidified to pH 5 with hydrochloric acid 5N. The aqueous phase was extracted with ethyl acetate and the organics were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to give 300 mg (99% yield) of the title compound as a white solid. Purity 90%.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[CH2:5]1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[CH2:5]3)[C:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][C:24]=3[C:15]=2[CH:14]=1
Reactant: CC1(C)CCN(CCBr)C1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCN2CCC(C)(C)C2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-3,3-dimethylpyrrolidine, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4].[NH:26]1[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[N:27]1>CN(C1C=CN=CC=1)C.CC#N>[CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:26]3[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[N:27]3)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: O=Cc1cn[nH]c1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Yield: 23.8 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (2.12 g, 5.5 mmol), 1H-pyrazole-4-carbaldehyde (0.48 g, 5.0 mmol) and DMAP (0.73 g, 6.0 mmol) in MeCN (20 mL). The crude product was purified by MPLC using CH2Cl2/EtOAc (1:1) on silica gel to give 0.53 g (24%) of a white solid as the title compound. MS (ESI) (M+H)+=444.92.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18](OC3C=CC=CC=3)=[CH:17][CH:16]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C([N:35]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36]1)(OC(C)(C)C)=O.[ClH:41].[O:42]1[CH2:47][CH2:46]OCC1>>[ClH:41].[O:42]([N:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5]1[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:3]([NH:40][C@H:37]2[CH2:38][CH2:39][NH:35][CH2:36]2)[N:4]=1)[C:47]1[CH:46]=[CH:9][CH:7]=[CH:6][CH:5]=1
Reactant: CSc1nc(Nc2ccc(Oc3ccccc3)cc2)c2c(=O)[nH]ccc2n1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: Cl
Product: O=c1[nH]ccc2nc(N[C@H]3CCNC3)nc(N(Oc3ccccc3)c3ccccc3)c12
Yield: 52 %

Procedure:
Compound No. 125 was prepared as described in Example 1g by starting from 2-(methylthio)-4-(4-phenoxy phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (87 mg, 0.23 mmol) and (S)-(−)-1-boc-3-amino pyrrolidine (129 mg, 0.69 mmol) and treating with 4 N HCl in dioxane continuing until the reaction yielded the title compound (54 mg, 52%). MS m/z: 415 (M+1)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[N:12]([C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=3)[N:13]=[C:14]([CH2:25][OH:26])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[N:8][CH:9]=1.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C>[N:32]1([C:38]([O:26][CH2:25][C:14]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=3)[C:11]3[N:12]([C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=3)[N:13]=2)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(COC(=O)N2CCOCC2)nn2c(CC)ccc2c1-c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a suspension of 60% NaH (69.5 mg) in DMF (3 mL) was added ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (200 mg) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this was added 4-morpholinecarbonyl chloride (659 mg) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-1:1) to give [4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 4-morpholinecarboxylate as yellow oil (75 mg).
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O-:12][C:13]#[N:14].[K+].C(O)(=O)C.O>CC(O)C>[CH3:11][C:2]1[O:1][C:13](=[O:12])[NH:14][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: CC(O)C(=O)c1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: Cc1oc(=O)[nH]c1-c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
To a solution of 2-hydroxy-1-phenylpropan-1-one (1.00 g, 6.66 mmol) and potassium cyanate (1.08 g, 13.3 mmol) in 2-propanol (15 mL) was added dropwise acetic acid (960 mg, 16.0 mmol) at 50° C. over 1 hr. The mixture was stirred at 50° C. for 5 hr, and the reaction mixture was poured into water. The resulting precipitate was collected by filtration and recrystallized from isopropyl ether-hexane to give the title compound (430 mg, yield 37%) as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].S(Cl)([Cl:14])(=O)=O>ClCCl>[CH3:9][O:8][C:6](=[O:7])[CH:5]([Cl:14])[C:4](=[O:10])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)CC(=O)OC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
46.0 g Methyl 4-methoxyacetoacetate were dissolved in 500 ml dichloromethane. 28.1 ml Sulfuryl chloride were added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml ethyl acetate and washed with 100 ml water and 100 ml brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=5:1=>2:1 to obtain 45.0 g 2-chloro-4-methoxy-3-oxo-butyric acid methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:26][CH2:27]CCCSC(C)(C)C(OCC)=O.COC1C=CC(S(N)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]([CH3:24])([CH3:23])[C:20]([O:22][CH2:26][CH3:27])=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)SCCCCCBr
Reactant: COc1ccc(S(=O)(=O)NCCCCCSC(C)(C)C(=O)O)cc1
Agent: COc1ccc(S(N)(=O)=O)cc1
Product: CCOC(=O)C(C)(C)SCCCCCNS(=O)(=O)c1ccc(OC)cc1
Yield: 69 %

Procedure:
In an analogous way, there are obtained: 2. 8-(4-Methoxybenzenesulphonamido)-2,2-dimethyl-3-thiaoctanoic acid by reaction of ethyl 8-bromo-2,2-dimethyl-3-thiaoctanoate with 4-methoxybenzenesulphonamide to give (a) ethyl 8-(4-methoxybenzenesulphonamido)-2,2-dimethyl-3-thiaoctanoate; after chromatography on silica gel/cyclohexane+diethyl ether (2:1 v/v), the yield is 69% of theory; colourless oil; nD20 =1.5280 and subsequent saponification of this ester to give (b) the desired acid; yield 90% of theory; m.p. 57°-59° C. 3. 8-(3-Trifluoromethylbenzenesulphonamido)-2,2-dimethyl-3-thiaoctanoic acid by reaction of ethyl 8-bromo-2,2-dimethyl-3-thiaoctanoate with 3-trifluoromethylbenzenesulphonamide to give