Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([Br:13])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1>O>[Br:13][C:5]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:2][S:3][CH:4]=1
Reactant: CCCCCCc1c(Br)sc(Br)c1Br
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1cscc1Br
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Compound 51 (70 g, 0.173 mol) was mixed with dry THF (400 mL). To this mixture, 7-butyllithium (138 mL, 2.5M in hexane, 0.345 mol) was added dropwise at −78° C. under argon. The resulting mixture was stirred for 10 minutes, then water (30 mL) was added to quench the reaction. The THF was evaporated and the organic was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), water (70 mL) and dried over MgSO4. After evaporation of the solvent, the resulting crude product was purified by vacuum distillation (72-74° C. at 0.17 mbar) to yield 52 (35.3 g, 82.6% yield). GC/MS: 246 g/mol (M-1). 1H NMR (CD2Cl2): δ 7.22 (s, 1H), 6.96 (s, 1H), 2.57 (t, 2H), 1.61 (m, 2H), 1.32 (m, 6H), 0.88 (t, 3H). 13C NMR: 141.92, 122.87, 120.95, 112.89, 31.88, 30.07, 29.53, 29.20, 22.88, 14.14.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CSC.B>O1CCCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-iodobenzoic acid (22 g) in tetrahydrofuran (450 mL) was added borane dimethylsulfide complex (35.5 mL, 10M in tetrahydrofuran), and the solution was allowed to stir overnight. The reaction was quenched by addition of methanol, and the solvent was evaporated. The residue was dissolved in ethyl acetate and filtered. The solvent was evaporated to give a solid, which was recrystallized from ether to yield a white solid, which was chromatographed, eluting with ether, to give 4-iodobenzyl alcohol (15.1 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[O:43][CH3:44])[CH3:26]>>[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][C:29]=1[O:43][CH3:44])[CH3:26]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Product: CCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC)nc2C)c(=O)n4C)cc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 39 mg, 0.100 mmol) and 2-(4-ethoxy-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Stage 29.1.1, 34 mg, 0.123 mmol) to give the title compound as a white solid. (HPLC: tR 2.88 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.16 (s, 1H), 8.07-8.02 (m, 1H), 7.94-7.88 (m, 1H), 7.51-7.47 (m, 1H), 7.06-6.96 (m, 3H), 4.20-4.12 (m, 2H), 4.06-3.98 (m, 2H), 3.85 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H), 1.42-1.29 (m, 6H))
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[CH3:1][CH:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)CCC(=O)O
Product: CCC(C)CCC(=O)Cl

Procedure:
The acid from step A2 is converted into the acid chloride by interaction with thionyl chloride according to a standard method. After removal of the excess of thionyl chloride, the residual acid chloride is used in step C2 without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=2[N:5]([C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([O:30][CH3:31])=[CH:25][CH:24]=3)=[O:20])[CH2:4]1>C1COCC1.O=[Pt]=O>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([O:30][CH3:31])=[CH:25][CH:24]=4)=[O:20])[C:6]=2[CH:7]=1
Reactant: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(N)c3ccccc43)cc2c1
Yield: 95.5 %

Procedure:
A solution of 14d (140 mg, 0.32 mmol) in THF (10 mL) was hydrogenated over PtO2 at 50 psi for 2 h. After removal of the catalyst, the solution was concentrated to a small volume below 25° C. and diluted with iPr2O to give 15d (124 mg, 95%), mp 250-255° C. 1H NMR [(CD3)2SO] δ 11.56 (d, J=1.6 Hz, 1 H, NH), 8.08 (d, J=8.4 Hz, 1 H, H-6), 7.76 (d, J=8.2 Hz, 1 H, H-9), 7.70 (s, 1 H, H-4), 7.46 (t, J=7.6 Hz, 1 H, H-8), 7.40 (d, J=8.8 Hz, 1 H, H-7'), 7.28 (t, J=7.6 Hz, 1 H, H-7), 7.16 (d, J=2.4 Hz, 1 H, H-4'), 7.08 (d, J=1.8 Hz, 1 H, H-3'), 6.91 (dd, J=8.8, 2.5 Hz, 1 H, H-6'), 5.98 (s, 2 H, NH2), 4.73 (dd, J=10.8, 8.9 Hz, 1 H, H-2), 4.51 (dd, J=10.9, 1.7 Hz, 1 H, H-2), 4.17-4.08 (m, 1 H, H-1), 3.98 (dd, J=11.0, 3.1 Hz, 1 H, CHHCl), 3.78 (s, 3 H, OCH3), 3.75 (dd, J=11.0, 8.1 Hz, 1 H, CHHCl).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][CH2:17]1.[F:33][C:34]([F:40])([F:39])[CH2:35][C:36](O)=O.ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:36]([CH2:35][C:34]([F:40])([F:39])[F:33])=[N:24][N:23]=[C:20]2[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:18][CH2:17]1
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 18 h
Yield: 89.3 %

Procedure:
Triethylamine (0.259 mL, 1.86 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-ylcarbamate (548 mg, 1.55 mmol), 3,3,3-trifluoropropionic acid (0.205 mL, 2.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimmide hydrochloride (356 mg, 1.86 mmol), and 1-hydroxy-7-azabenzotriazole (253 mg, 1.86 mmol) in dichloromethane (55 mL). After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→96% dichloromethane/methanol) gave the title compound (618 mg). MS 447.1 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)[CH3:12].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (116 mg, 0.871 mmol), 1,1-dimethylethyl 4-acetyl-1-piperidinecarboxylate (110 mg, 0.484 mmol) and AcOH (1 μL, 0.017 mmol) in Chloroform (10 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (196 mg, 0.925 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the Isco Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 12 g column) to yield the desired product. This was further purified via reverse phase column chromatography on Gilson (C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) to obtain pure the pure title compound (67 mg, 22% yield) as a colorless oil: LC-MS (ES) m/z=345 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C=O)C.O>[Cl:24][CH2:23][CH2:22][CH2:21][N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:2]([F:12])([F:1])[F:13])=[N:4][N:5]=[C:6]2[CH2:11]1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCN(CCCCl)C2
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.90 g) in DMF (10 mL) was added K2CO3 (2.35 g) and 1-bromo-3-chloropropane (1.70 mL) at rt. The reaction mixture was heated at 80° C. for 3 h, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 for 1 h, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as transparent liquid (0.68 g, 30.00%).
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=O.[CH3:24][NH2:25]>>[CH3:24][NH:25][CH2:1][C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CN
Reactant: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Product: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid and methylamine (2M in THF)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1oc(C)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc(C)nc1CBr
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
10 mmol of ethyl 2,4-dimethyl-1,3-oxazole-5-carboxylate was dissolved in 30 ml of carbon tetrachloride, then 11 mmol of N-bromosuccinimide was gradually added with keeping the temperature at 20 to 30° C. After the end of the adding, 0.5 mmol of azobisiso butyronitrile was gradually added. Then stirring was continued for 30 minutes at a room temperature. The temperature was heated up to 80° C. to carry out the reaction for 3 hours. The reacted liquid was cooled down to a room temperature. A precipitated solid matter was eliminated by filtration. The filtrate was washed with 30 ml of water and the organic phase was separated and extracted and dried under sodium sulfate. Then the solvent was evaporated out, obtaining ethyl 4-(bromo methyl)-2-methyl-1,3-oxazole-5-carboxylate.
Reaction SMILES: C(OP([CH2:9][C:10](=[O:12])[CH3:11])(OCC)=O)C.[CH:13]([O:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[O:22])=[CH:19][C:18]=1[CH3:32])([CH3:15])[CH3:14]>O1CCCC1>[CH:13]([O:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([N:23]2[CH2:28][CH2:27][C:26](=[CH:9][C:10](=[O:12])[CH3:11])[CH2:25][CH2:24]2)=[O:22])=[CH:19][C:18]=1[CH3:32])([CH3:15])[CH3:14]
Reactant: Cc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Reactant: CCOP(=O)(CC(C)=O)OCC
Solvent: C1CCOC1
Product: CC(=O)C=C1CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To an oven dried flask was placed 60% sodium hydride in mineral oil (1.5 g, 36 mmol). To the flask was added tetrahydrofuran (90 mL) under a nitrogen atmosphere. The mixture was cooled to 0° C. and a solution of 1-diethoxyphosphorylpropan-2-one (7.1 mL, 37 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred at 25° C. for 30 min and treated with 1-(4-isopropoxy-3-methyl-benzoyl)piperidin-4-one (10 g, 36 mmol) in tetrahydrofuran (90 mL). The mixture was stirred at 25° C. for 24 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to afford 1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]propan-2-one (10.2 g) 1H NMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 6.12 (s, 1H), 4.60-4.51 (m, 1H), 3.66 (br d, 4H), 2.95 (br s, 2H), 2.50-2.33 (m, 2H), 2.19 (s, 6H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 315.18, found 316.0 (M+1)+; Retention time: 2.2 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>>[I:8][C:7]1[C:2]([NH:10][CH3:9])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: CN
Reactant: Clc1ncncc1I
Product: CNc1ncncc1I
Yield: 78 %

Procedure:
A solution of 4-chloro-5-iodopyrimidine 67A (2.03 g, 8.44 mmol) in 40% aqueous MeNH2 solution was stirred at RT for 17 h. The mixture was then extracted with DCM (2×150 ml). The combined organic phase were dried concentrated to give 5-iodo-4-methylaminopyrimidine 67B (1.55 g, 78%) as an orange solid which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:15]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
To a solution of 3-tert-butylphenol (5.0 g; 33.28 mmol) in N,N-dimethylformamide (166 mL) at room temperature under nitrogen was added sodium hydride (2.0 g; 49.92 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then iodomethane (6.2 mL; 99.84 mmol) was added. After stirring at room temperature overnight, the reaction mixture was quenched with water and aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 400 mL gradient elution) to yield the title product as a clear oil (6.19 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:6])[CH3:5].[S:7]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[NH:10]1)(=[O:9])=[O:8].[Na]>CN(C)C=O>[O:6]=[C:4]([CH2:3][CH2:2][N:10]1[C:11](=[O:12])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:7]1(=[O:9])=[O:8])[CH3:5]
Reactant: CC(=O)CCCl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)CCN1C(=O)c2ccccc2S1(=O)=O
Temperature: 80 °C
Yield: 86.1 %

Procedure:
9.0 g (76 millimoles) of 4-chlorobutan-2-one were slowly added dropwise to 10.0 g (50 millimoles) of sodium saccharin in 100 ml of absolute dimethylformamide, while stirring. The temperature was then gradually increased to 80° C., and the reaction mixture was stirred at this temperature for 5 hours, after which it was cooled. An excess of ice-water was added, and stirring was continued for a further hour. The precipitated solid was filtered off under suction, recrystallized from ethanol and dried in a drying oven under reduced pressure at 50° C. to give 10.9 g (86%) of N-(2-oxobut-4-yl)-saccharin of melting point 118°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[N:31]1[CH:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[N:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:37]([C:35]4[CH:36]=[N:31][CH:32]=[N:33][CH:34]=4)=[O:38])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: O=C(O)c1cncnc1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3cncnc3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with pyrimidine-5-carboxylic acid to yield the title compound as yellow solid. MS: 533.2 (MH+, 1Cl).
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([N:2]1[C:1](=[O:15])[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3]1=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)CCC2
Product: C=CCn1c(=O)c2cccc3c2n(c1=O)CCC3
Yield: 89 %

Procedure:
Starting from 6,7-dihydropyrido[3,2,1-ij]quinazoline-1,3 (2H,5H)-dione (prepared according to WO 2010/079206) and allyl bromide and using Procedure E, the title intermediate was obtained as a colourless solid (0.393 g; 89% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].CC(C)([O-])C.[K+].[Br:18][C:19]1[N:23]2[N:24]=[C:25](Cl)[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[N:23]2[N:24]=[C:25]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COc1ccc(N)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc3ncc(Br)n3n2)cc1OC
Temperature: 60 °C
Reaction time: 15 h
Yield: 50.2 %

Procedure:
To a solution of 3,4-dimethoxyaniline (178 mg, 1.16 mmol, 2.0 equiv) in THF (5 mL) was added potassium tert-butoxide (131 mg, 1.16 mmol, 2.0 equiv) and heated to 60° C. for 30 min. The reaction mixture was cooled to room temperature then 3-bromo-6-chloroimidazo[1,2-b]pyridazine (135 mg, 0.582 mmol, 1.0 equiv) was added and stirred at room temperature for 15 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 102 mg of the dark brown solid, 50%.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][S:13][C:4]1[N:3]=[C:2]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=1
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Reactant: NC(CO)CO
Product: O=c1cnc2c(NC(CO)CO)nc(SCc3cccc(F)c3F)nc2[nH]1
Yield: 69.4 %

Procedure:
The titled compound (57 mg) was prepared from the product of step (b) (80 mg) and 2-amino-1,3-propanediol (29 mg) using the method of Example 2 step (f).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[N:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:15][C:16]1[CH:17]=[C:18]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[N:20][CH:21]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Cl)c1
Yield: 54.7 %

Procedure:
(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.75 g, 8.71 mmol, prepared as in Example 15a) and 5-chloro-3-pyridinol (1.69 g, 13.10 mmol, Aldrich Chemical Co.). were allowed to react in the presence of triphenylphosphine and DEAD as described in Example 2a. The crude product was purified by chromatography over silica gel eluted with hexane/EtOAc to provide 1.49 g (60%) of the title compound as a pale yellow oil. TLC Rf 0.75 (1:1 EtOAc/Hex). MS (DCI/NH3) m/e 313 (M+H)+ with 35Cl and m/e 315 (M+H)+ with 37Cl.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1c[nH]nc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccc(Cl)cc2)nc1C
Yield: 61.7 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.25 g) synthesized in Example 1(3), 4-chlorophenylboronic acid (13.9 g), copper acetate (16.3 g) and pyridine (14.4 mL), and in the same manner as in Example 17(1), the title object compound (6.9 g, 62%) was obtained as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][OH:8].[CH2:9](OCC(=O)C)C1C=CC=CC=1>>[CH3:9][C:2]1([CH2:7][OH:8])[O:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: OCC1OCCCO1
Reactant: CC(=O)COCc1ccccc1
Product: CC1(CO)OCCCO1
Yield: 37 %

Procedure:
The same procedure as in the steps (32a) and (32b) of Example 32 was repeated using 1-benzyloxy-2-propanone to obtain the title compound (1.51 g, total yield: 37%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[CH:17](O)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:17]=[N:16][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1NCC1CCOCC1
Reactant: O=CO
Product: Clc1ccc2ncn(CC3CCOCC3)c2n1

Procedure:
A solution of the crude product of Example 7B (0.979 g, 4.05 mmol) in formic acid (2 mL, 52.1 mmol) was heated at 95° C. for 1 hour. After cooling, the mixture was concentrated and dissolved in ethyl acetate. The mixture was washed with dilute potassium carbonate and brine, dried over magnesium sulfate, filtered and concentrated. Recrystallization from ethyl acetate/hexane afforded the title compound. MS (ESI) m/z 252 (M+H)+.