Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=S)[O:11][C:7]=2[CH:6]=1)=[O:4].Cl.Cl.[NH:18]1[CH2:22][CH2:21][C@@H:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19]1>C1(C)C(C)=CC=CC=1.ClCCl>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:19]3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: C1CCN([C@@H]2CCNC2)CC1
Reactant: CN(C)C(=O)c1ccc2[nH]c(=S)oc2c1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)oc2c1
Temperature: 150 °C

Procedure:
N,N-Dimethyl-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (Example 92C, 44 mg, 0.119 mmol) and (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 54 mg, 0.238 mmol) were combined in xylene (1 mL) and heated to 150° C. for 30 minutes. The mixture was diluted with dichloromethane, washed with water, and the organic layer was absorbed on silica gel. The crude mixture was purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (2-20%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43-1.53 (m, 2 H) 1.59-1.70 (m, 4 H) 1.91-2.07 (m, 1 H) 2.23-2.35 (m, 1 H) 2.40-2.62 (m, 4 H) 2.93-3.13 (m, 7 H) 3.41-3.51 (m, 1 H) 3.55-3.66 (m, 1 H) 3.80-3.90 (m, 1 H) 3.96 (dd, J=10.00, 7.29 Hz, 1 H) 7.22-7.28 (m, 1 H) 7.30-7.35 (m, 1 H) 7.37-7.40 (m, 1 H); MS (ESI+) m/z 343.0 (M+H)+.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]([C:7]1([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>C(O)C>[C:11]1([S:10][C:7]2([C:5]([CH:4]=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)=[O:6])[CH2:9][CH2:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C1(Sc2ccccc2)CC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
50 ml of water and 8 pellets of solid sodium hydroxide are added at room temperature to a mixture of 75 g (0.39 mol) of 1-phenylmercaptocyclopropyl methyl ketone, 56 g (0.39 mol) of 4-chlorobenzaldehyde and 200 ml of ethanol. The mixture is stirred at room temperature for 14 hours. The precipitated solid is then filtered off with suction. In this manner, 120.3 g (98% of theory) of 4-chlorophenyl-ethenyl 1-phenylmercapto-cyclopropyl ketone are obtained in the form of a solid substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:17][C@H:18]1[CH2:27][C:26]2[C:25]([NH2:28])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([NH:28][C:25]3[C:26]4[CH2:27][C@H:18]([OH:17])[CH2:19][CH2:20][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(c2cccc(Cl)c2)CC1
Reactant: Nc1cccc2c1C[C@H](O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c1C[C@H](O)CC2)C1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
120 mg (0.50 mmol) of 1-(3-chlorophenyl)-piperidine-4-carboxylic acid, 74 mg (0.46 mmol) of (7R)-7-hydroxy-5,6,7,8-tetrahydronaphthaleneamine, 74 mg (0.55 mmol) of 1-hydroxy-1H-benzotriazole and 113 mg (0.59 mmol) of (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were combined in 3 ml of N,N-dimethylformamide under an argon atmosphere and stirred at room temperature overnight. Ethyl acetate was added, the mixture washed with water and the aqueous phase re-extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by RP-BPLC in a water/acetonitrile gradient, yielding 57 mg (33% yield) of 1-[3-chlorophenyl]-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]piperidine-4-carboxamide.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:15]([O-])=O.C([O-])(O)=O.[Na+]>COCCOC.[Pd]>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:11])([F:10])([F:13])([F:14])[F:12])=[CH:5][C:4]=1[NH2:15]
Reactant: O=[N+]([O-])c1cc(S(F)(F)(F)(F)F)ccc1C(Cl)Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(F)(F)(F)(F)F)cc1N
Reaction time: 54 h
Yield: 78.3 %

Procedure:
2.0 g of 1-dichloromethyl-2-nitro-4-pentafluorosulfanylbenzene were dissolved in 25 ml of DME and, after addition of 200 mg of Pd/C (5%) and 100 ml of a saturated aqueous NaHCO3 solution, hydrogenated under 5 bar of H2 for 54 hours. The catalyst was then removed by filtration and the reaction solution was extracted 3 times with 50 ml of MTB each time. Drying over MgSO4 was followed by removal of the solvent in vacuo. 1.1 g of a colorless oil were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24]C)=O)[CH2:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:12](=O)[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.O.C(O)C>[CH3:13][C@H:12]1[N:33]([CH2:32][C:31]([F:35])([F:34])[F:30])[C:22](=[O:24])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: NCC(F)(F)F
Reactant: COC(=O)[C@H](CC(C(C)=O)c1ccccc1C)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(F)(F)F)[C@@H]1C
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-4-(2-methylphenyl)-5-oxonorleucinate (1.60 g, 4.58 mmol) in dichloroethane (23 mL) were added glacial acetic acid (0.524 mL, 9.16 mmol), 2,2,2-trifluoroethylamine (1.83 mL, 22.9 mmol) and 4 {acute over (Å)} molecular sieves (500 mg). The mixture was stirred at 23° C. for 20 min and then sodium triacetoxyborohydride (4.85 g, 22.89 mmol) was added. The mixture was stirred at 23° C. for 18 h. The mixture was diluted with water and extracted with ethyl acetate (3×). Molecular sieves were removed by filtration and the combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. A solution of the residue in ethanol (45 mL) was stirred in the presence of solid potassium carbonate (1.86 g, 13.49 mmol) at 60° C. for 2 h. The bulk of the ethanol was removed under reduced pressure and the remaining slurry was then partitioned between water (25 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (5% ethyl acetate→50% ethyl acetate/hexane) was followed by separation of the enantiomers using normal-phase HPLC using a ChiralPak® AD column, eluting with 20% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second enantiomer to elute. MS: m/z=423.2 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][O-].[Na+].CI.Cl>CO>[CH3:17][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C[O-]
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 120 °C

Procedure:
150 mg (0.57 mmol) of the compound of Example 24A were dissolved in 1.5 ml of methanol, 0.25 ml (1.14 mmol) of a 25% strength solution of sodium methoxide in methanol and 0.04 ml (0.62 mmol) of methyl iodide were added and the mixture was heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 120° C. for 30 min. After cooling, the reaction was acidified with 1 M hydrochloric acid and concentrated slightly on a rotary evaporator. The precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 96 mg (94% pure, 57% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[CH2:14])[C:7]=12.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[CH2:14])[C:7]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccccc1
Product: C=Cn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 59.7 %

Procedure:
The title compound was prepared as a white powder in 59.7% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-vinylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[C:8]=2[C:7]1=[O:37].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[C:8]2[C:7](=[O:37])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1

Procedure:
A solution of cis-tert-butyl 2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (109 mg, 0.183 mmol) in TFA (5 mL) was heated at 60° C. for 2 h. After removal of the solvent, the residue was diluted in MeOH (2 mL) and was purified by preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to give the title compound as a TFA salt. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.47 (br s, 2 H), 1.57-1.75 (m, 3 H), 1.84 (br s, 2 H), 3.12-3.23 (m, 2 H), 3.87-3.94 (m, 3 H), 4.35-4.50 (m, 3 H), 6.73 (br s, 1 H), 7.71 (br s, 2 H), 8.28-8.44 (m, 2 H), 8.84 (d, J=3.91 Hz, 1 H). [M+H] calc'd for C17H21FN6O, 345; found, 345.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)#[CH:9]>>[CH3:7][C:5]1[NH:4][CH:3]=[C:2]([C:9]#[C:8][C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[N:6]=1
Reactant: C#Cc1cccc(C)c1
Reactant: Cc1ncc(I)[nH]1
Product: Cc1cccc(C#Cc2c[nH]c(C)n2)c1

Procedure:
The title compound, orange solid, MS: m/e=197.2 (M+H+) was prepared in accordance with the general method of example 1c from 5-iodo-2-methyl-1H-imidazole and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C@H:3]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)[C:4]([O:6]C)=[O:5].[O:20]1CCC[CH2:21]1>>[CH3:1][CH:2]([CH3:19])[C@H:3]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)[C:21]1=[O:20])[C:4]([OH:6])=[O:5]
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H](NCCNCc1csc(C)n1)C(C)C
Product: Cc1nc(CN2CCN([C@H](C(=O)O)C(C)C)C2=O)cs1

Procedure:
A solution of the product of Example 143C (5.4 g) in tetrahydrofuran (80 mL) was treated with carbonydiimidazole (6.1 g, 2 equivalents) at 25° C. for 2 hrs. The mixture was quenched with 10% citric acid, the organic layer was separated, washed with water, brine, dried over Na2SO4, filtered, and the solvents were evaporated A solution of the residue (3.3 g) in dioxane (20 mL) was treated with 1M LiOH (20 mL) at 25° C. for 2 hrs. The solvents were evaporated, and the residue was acidified with 10% HCl, extracted with dichloromethane/2-propanol (3:1), the organic layer was separated, dried over Na2SO4, filtered, and the solvents evaporated to give 1.5 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28](O)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[C:2]([F:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=2)[CH2:13][CH2:14]1)=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCNCC1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3F)CC2)c1

Procedure:
The title compound was prepared in analogy to example 5 from 1-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine (compound 5.5) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 538.4 (MH+, 100%)
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])[CH:13]=3)[C:8]([CH2:22][CH3:23])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[O:25]([NH2:27])[CH3:26]>>[CH3:26][O:25][NH:27][C:19]([CH2:18][NH:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:22][CH3:23])=[N:7][N:6]2[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)=[O:16])=[O:21]
Reactant: CON
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)NCC(=O)O)ccc12
Agent: Cl
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCC(=O)NOC)ccc12
Yield: 16.1 %

Procedure:
This compound was prepared according to the method of Example 37, using 222 mg (0.704 mmol, 1.0 equiv)[(1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl)-amino]-acetic acid and 59 mg (0.704 mmol, 1.0 equiv) methoxylamine hydrochloride as starting materials to give 39 mg of a clear oil, which was crystallized from ether/hexanes to give 34 mg (14%) of white crystals: mp 135-136° C.; Anal. calcd for C18H24N4O3: C, 62.77; H, 7.02; N, 16.27. Found: C, 62.64; H, 6.87; N, 16.47.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:14]\[C:15]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:17][CH2:16]2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:17][CH2:16]2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C\C2(c3ccc(Cl)cc3)CC2)COC1(C)C
Agent: O=[Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CCC2(c3ccc(Cl)cc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a stirred solution of (S)-4-{(Z)-2-[1-(4-chloro-phenyl)-cyclopropyl]-vinyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.55 g) at room temperature in methanol (2 ml) under an argon atmosphere was added platinum oxide (31 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 1 hour. The catalyst was filtered off, the filtrate was concentrated and purified by column chromatography (SiO2; heptane/EtOAc) to give (S)-4-{2-[1-(4-chloro-phenyl)-cyclopropyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g) as a white solid. MS (ISP): 380.4 ([M+H]+))
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([CH2:44][C:45]3[O:46][CH:47]=[CH:48][CH:49]=3)[C:28]2=[O:50])[CH:24]=[CH:25][CH:26]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:46]1[CH:47]=[CH:48][CH:49]=[C:45]1[CH2:44][N:29]1[CH2:30][C:31]2[C:32](=[N:33][C:34]([NH:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:35][CH:36]=2)[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][OH:18])[CH:22]=2)[C:28]1=[O:50]
Reactant: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(Cc3ccco3)Cc3cnc(Nc4ccccc4)nc32)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccco2)Cc2cnc(Nc3ccccc3)nc2N1c1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of 320 mg (0.47 mmol) of 1-[3-(2-tert-butyldiphenylsilyloxyethyl)-phenyl]-3-(furan-2-yl-methyl)-7-phenylamino-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one in dry tetrahydrofuran (5 ml) was treated with 0.6 ml (0.6 mmol) of tetrabutylammonium fluoride (1M solution in tetrahydrofuran) then stirred at room temperature for 2 hours. The solvent was evaporated and the crude material purified by flash chromatography on silica gel, eluting with 4:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 170 mg (82%) of 3-(furan-2-yl-methyl)-1-[3-(2-hydroxyethyl)-phenyl]-7-phenylamino-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one as a pale pink solid of melting point 195° C. [Mass spectrum (ESI) MH+ =442].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([C:26]3([CH3:39])[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[O:25])=[C:16]2[N:15]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([C:26]3([CH3:39])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])=[C:16]2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To (R)-tert-butyl 4-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-4-methylpiperidine-1-carboxylate (Example 48; 28 mg, 0.05 mmol), was added 1 mL 4 N HCl solution in dioxane and stirred at ambient temperature for 10 minutes. The reaction was concentrated, treated with ether, and filtered, giving the final product (HCl salt) as a fine beige powder. MS (apci) m/z=457.1 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:22])[CH:10]=1)C1C=CC=CC=1.[BrH:31].CCOCC>C(O)(=O)C>[BrH:31].[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[C:9](=[O:8])[CH:10]=[C:11]([C:21]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:22])[NH:12]2
Reactant: CCN(CC)CCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCN(CC)CCOC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 48 h

Procedure:
To 2-diethylaminoethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.55 g) at room temperature was added hydrogen bromide in acetic acid (15 ml of a 48% solution) and the solution was stirred in a sealed flask for 48 hours. The reaction mixture was poured into dry ether (50 ml) to give a pale yellow solid which was filtered off and recrystallised from ethanol to yield 2-diethylaminoethyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate hydrobromide (0.36 g), m.p. 220° C. (dec). δ (360 MHz, DMSO-d6), 1.25 (6H, t, CH3), 3.28 (4H, m, NCH2CH3), 3.57 (2H, m, OCH2CH2N), 4.66 (2H, t, OCH2CH2), 6.86 (1H, s, 3-H), 7.47 (1H, d, 6-H), 8.05 (1H, d, 8-H), 9.37 (1H, bs, NH) and 12.1 (1H, vbs, NH). (Found: C, 40.20; H, 4.15; N, 5.86%. C16H18Cl2N2O3. 1.5HBr requires C, 40.15; H, 4.10; N, 5.85%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CO)n1
Reactant: C1CCNC1
Agent: CS(=O)(=O)Cl
Product: Cc1cccc(CN2CCCC2)n1

Procedure:
By reaction of 6-methyl-2-pyridyl methanol [prepared as described in Helv. Chim. Acta, 2429 (1957)], g 7.1 (0.058 moles), with methanesulfonyl chloride and then with pyrrolidine as in Description 1, g 7.5 of yellow oil (b.p. 62°-65° C. 80 mmHg) were obtained.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][C:9]([CH:11]2[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:19]=[C:13]1[O:12][CH:11]([C:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:10])[CH:15]([C:16]([O:18][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])[CH2:14]1
Reactant: CC(C)(C)O
Reactant: O=C1CC(C(=O)O)C(C(=O)OC(c2ccccc2)c2ccccc2)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.9 %

Procedure:
163 mg of (2RS,3SR)-2-diphenylmethoxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid, 59 mg of 4-dimethylaminopyridine and 36 mg of tert-butanol, were dissolved in 4 ml of methylene chloride, and 110 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto, followed by stirring at room temperature for 13 hours. The reaction solution was diluted with methylene chloride, then sequentially washed with a 10% citric acid aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and 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 silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 148 mg of the above-identified compound as colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].S(=O)(=O)(O)O.[CH2:29](O)[CH2:30]CC>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:29][CH3:30])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CCCCO
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 82.5 °C
Reaction time: 168 h

Procedure:
To a solution of ethyl 6-[N-(2,4difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 3 (Compound 3, 180 mg) in 1-butanol (5 ml), a concentrated sulfuric acid (0.12 ml) was added and the mixture was stirred at 80 to 85° C. for 7 days. After cooling, the reaction mixture was diluted with ethyl acetate (60 ml) and washed with water (60 ml). The ethyl acetate layer was washed with water (60 ml×5), dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to dryness. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/4) and then crystallized from diisopropyl ether to yield butyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 33, 52 mg) as white crystals.