Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=O.BrBr.[NH2:16][C:17]1[S:18][CH2:19][CH2:20][N:21]=1>C(Cl)Cl.O>[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[N:16]=[C:17]3[N:21]([CH:1]=2)[CH2:20][CH2:19][S:18]3)=[CH:5][CH:6]=1)(=[O:12])[CH3:13]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: NC1=NCCS1
Agent: BrBr
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2cn3c(n2)SCC3)cc1
Reaction time: 8 h

Procedure:
4-Acetamidoacetophenone (44 g, 0.25 mole) was suspended in 500 ml methylene chloride and treated with bromine (44 g, 0.275 mole). The reaction mixture was stirred overnight, then evaporated in vacuo. The residue was suspended in 200 ml of absolute EtOH and treated with 2-amino-4,5-dihydrothiazole (60 g, 0.59 mole). The reaction was stirred for 2 days, then taken up in water and extracted with methylene chloride. The organic phase was washed with water and then brine, and then dried over sodium sulfate. Flash column chromatography (silica, eluting with methylene chloride/methanol, 98/2) gave 6-(4-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:7][N:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])=[O:9])=[O:4].[I-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30].[OH-].[Na+].[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:46])=[C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=1>>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:46])=[C:38]([N:40]2[CH2:41][CH2:42][N:43]([C:3]([CH:5]3[CH2:7][N:6]([S:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)(=[O:9])=[O:10])[C:29](=[O:30])[N:28]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[O:4])[CH2:44][CH2:45]2)[CH:39]=1
Reactant: COC(=O)C1CN1S(=O)(=O)c1cccc(OC)c1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: O=C=Nc1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cc(Cl)ccc4C)CC3)N(c3ccccc3Cl)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-aziridine-2-carboxylic acid methyl ester (step 2 of example 1) was first reacted with sodium iodide and 2-chlorophenylisocyanate; subsequent ester hydrolysis using sodium hydroxide and coupling with 1-(5-chloro-2-methylphenyl)-piperazine gave the title compound as a colorless solid. MS: 603.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][O:32][C:31]4=[O:38])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.FC1C=C(C2C=NN3C=CC(N4[C@@H](C(C)C)COC4=O)=NC=23)C=CC=1C1N(COCC[Si](C)(C)C)N=CN=1.FC(F)(F)C(O)=O.N>ClCCl.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([CH:35]([CH3:36])[CH3:37])[CH2:33][O:32][C:31]4=[O:38])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)c(F)c3)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)c(F)c3)c2n1
Agent: N
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one and (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.137 g, 0.255 mmol) was dissolved in dichloromethane (0.55 mL). Trifluoroacetic acid (1.1 mL) was added and the mixture allowed to stir at ambient temperature for 18 hours. The reaction mixture was concentrated with multiple dichloromethane additions to give a crude residue. Acetonitrile (5 mL) and 28% aqueous ammonia (3 mL, 44 mmol) were added and the mixture concentrated with multiple acetonitrile additions to a yellow solid. Purification by normal phase chromatography, eluting with 50-100% EtOAc/dichloromethane, provided (S)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.032 g, 31%) as a yellow solid. LCMS (APCI+) m/z 408.5 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 11.24 (broad s, 1H), 8.61 (d, J=7.8 Hz, 1H), 8.43 (s, 1H), 8.26 (t, J=8.2 Hz, 1H), 8.09 (m, 2H), 8.00 (d×d, J=13.8, 1.0 Hz, 1H), 7.87 (d×d, J=8.4, 1.2 Hz, 1H), 4.99-4.96 (m, 1H), 4.50-4.41 (m, 2H), 2.94-2.86 (m, 1H), 1.10 (d, J=7.0 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[CH2:17][N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:24])=[CH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([C:10]1[C:9](=[O:25])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[N:12]([C:11]=1[OH:24])[C:20]1[C:19](=[O:21])[N:18]([CH3:22])[CH2:17][N:16]([CH3:23])[C:15]=1[N:14]=2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)cc(O)n3c2C1=O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)c(Cc4ccccc4)c(O)n3c2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 7.1 g (0.021 mole) of 9-benzyl-2,3-dihydro-1,3-dimethyl-6-hydroxy-pyrimido[2,1-f]purine-4,8(1H,9H)-dione in 200 ml of acetone, add 2.3 g (0.023 mole) of triethylamine, and stir the mixture for 5 minutes at room temperature under a nitrogen atmosphere to obtain a clear solution. Add dropwise to the solution 4.7 g (0.027 mole) of benzyl bromide, and reflux the mixture for 5 hours under a nitrogen atmosphere. Remove the acetone under reduced pressure, and triturate the gummy residue with methanol. Filter off the resultant white solid, pour the filtrate into water, acidify to pH 4-5 with dilute hydrochloric acid, and decant the aqueous supernatant. Dissolve the gummy residue in the chloroform, wash the solution with water, and dry over anhydrous magnesium sulfate. Remove the drying agent by filtration, and evaporate solvent from the filtrate under reduced pressure. Chromatograph the residual oil on silica gel, eluting with chloroform(96)-methanol(4), to obtain the title compound as a solid with mp 176° -179° C.
Reaction SMILES: [C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31]Br)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Na+].[I-].[F:36][C:37]1[C:43]([F:44])=[CH:42][C:41]([F:45])=[C:40]([F:46])[C:38]=1[O-:39].[K+]>CC(C)=O.CCOC(C)=O>[C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][O:39][C:38]1[C:40]([F:46])=[C:41]([F:45])[CH:42]=[C:43]([F:44])[C:37]=1[F:36])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr
Reactant: [O-]c1c(F)c(F)cc(F)c1F
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of N-[(carbobenzyloxycarbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (3.36 g, 6.73 mmol) in acetone (20 ml) was added dry NaI (0.20 g, 1.35 mmol) and potassium (2,3,5,6-tetrafluoro)-phenoxide (1.37 g, 6.73 mmol) at room temperature and stirred for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The resultant solid was triturated with ether to provide the titled product as a white solid (3.53 g, 6.04 mmol, 89%). MS C28 H32N2O7, [M+Na]+ =607, [M−H]− =583.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:30])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-methyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 274°-277° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][C:6]2([CH3:14])[CH3:13].[CH:15](O)=[O:16].Cl.CN(C)CCCN=C=NCC>ClCCl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH:15]=[O:16])[CH2:7][C:6]2([CH3:14])[CH3:13]
Reactant: O=CO
Reactant: COc1ccc2c(c1)C(C)(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C)(C)CN(C=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 18, 3.2 g, 16.7 mmol) in anhydrous dichloromethane (40 mL) was treated with formic acid (1 mL, 26.5 mmol) followed 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9 g, 20.34 mmol) and the resulting solution was stirred at ambient temperature overnight. It was then diluted with chloroform and washed with water (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as pale brown viscous oil (3.26 g, 90%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CCOC(CN)OCC
Product: CCOC(CNCCC(=O)OC(C)(C)C)OCC
Yield: 25 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, (40 mmol) was reacted with tert-butyl 3-bromopropionate (3.34 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform only) to obtain the title compound (1.33 g, 25%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O=C(O)C(=O)c1cccs1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0.0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 0° C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was dissolved in CHCl3 (30 ml) and a solution of 3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added to this at 0° C. The mixture was stirred and allowed to warm at room temperature. After 1.5 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 3.14 g (92.6%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 1.40-1.50 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.80 (m, 1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05 (m, 5H), 3.30-3.40 (m, 1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H), 8.10 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:23]([O:35][CH3:36])=[CH:24][C:25]2[N:31]([CH3:32])[C:30](=[O:33])[O:29][CH2:28][CH2:27][C:26]=2[CH:34]=1.C(O)(C)C>Cl.O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[C:23]([O:35][CH3:36])=[CH:24][C:25]3[N:31]([CH3:32])[C:30](=[O:33])[O:29][CH2:28][CH2:27][C:26]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCOC(=O)N2C
Yield: 37.7 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (60.0 mg, 0.177 mmol), 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (39.3 mg, 0.177 mmol) and 5 drops of HCl/dioxane were stirred in isopropyl alcohol (2.00 mL, 26.1 mmol) at 120° C. in a sealed tube. After 24 hours the reaction mixture was concentrated and then extracted with DCM (20 mL) and washed with sat. NaHCO3 (20 mL) followed by water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on ISCO flash system (0-10% DCM:MeOH) to obtain one peak by LC/MS. When analyzed by HPLC, two peaks were shown. The fractions were concentrated and the residue was chromatographed on ISCO flash system (0-100% Hex:EtOAc) to obtain the product and the decarboxylated side product. The product was isolated as a pale blue solid (35.0 mg, 37.7%). mp: 160-162° C., MS (ESI+): 525 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.15 (d, 1H), 7.01 (s, 1H), 6.85 (d, 1H), 4.36 (m, 2H), 3.88 (s, 3H), 3.30 (s, 3H), 2.90 (br s, 5H), 1.99 (br s, 3H), 1.7 (d, 2H), 1.5-1.1 (m, 5H).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.O>CN(C=O)C>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:4]([CH3:3])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)(=[O:7])=[O:6])=[CH:20][CH:21]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)nn2)cc1
Yield: 47.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.42 g (10.5 mmol)) in 10.0 ml of DMF, N-methyl-p-toluenesulfonamide (1.85 g (9.99 mmol)) was added under ice-cooling and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3,6-dichloropyridazine (1.49 g (10.0 mmol)) was added. The reaction mixture was stirred at room temperature for one hour, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 1.41 g (47%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C@@:2]([C:8]1[C:13]([F:14])=[C:12]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=[C:10]([Br:22])[N:9]=1)([CH:5]([F:7])[F:6])[CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Br:22][C:10]1[N:9]=[C:8]([C@@:2]([NH:1][C:31](=[O:32])[CH2:30][Cl:29])([CH2:3][OH:4])[CH:5]([F:6])[F:7])[C:13]([F:14])=[C:12]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@@](N)(CO)C(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](CO)(NC(=O)CCl)C(F)F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of (R)-2-amino-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3,3-difluoro-propan-1-ol (2.15 g, 5.38 mmol) in dichloromethane (14.55 ml) was added an aq. sodium carbonate solution (14.55 ml, 10% aq. solution) at 0° C. 2-Chloroacetyl chloride (0.518 ml, 6.46 mmol) was added dropwise at 0° C. and the ice bath was removed after the addition. The reaction mixture was stirred at rt for 15 min. Methanol was added and the reaction mixture was stirred at 50° C. for 10 min. The reaction mixture was diluted with dichloromethane and water. The mixture was extracted with dichloromethane, dried over sodium sulfate, filtered and evaporated. The crude light yellow oil (2.91 g) was chromatographed over silica gel (40 g redisep column, cyclohexane/ethyl acetate 10-70%) to give the title compound. 2.32 g (91% yield).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([CH3:7])[CH2:5][OH:6].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>C1C=CC=CC=1>[ClH:8].[NH2:3][CH:4]([CH3:7])[CH2:5][O:6][C:12]1[N:11]=[N:10][C:9]([Cl:8])=[CH:14][CH:13]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(N)COc1ccc(Cl)nn1
Product: Cl
Yield: 61.4 %

Procedure:
To a suspension of 1.5 g of 61% sodium hydride in 40 ml of benzene was added dropwise 2.5 g of 2-amino-1-propanol at room temperature. Then, a solution of 5 g of 3,6-dichloropyridazine in 15 ml of benzene was added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was washed with water, and dried over magnesium sulfate. After evaporating the solvent, the residue was treated with hydrogen chloride-ether solution to give 2.31 g of 3-(2-aminopropoxy)-6-chloropyridazine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[CH2:11][C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Solvent: ClC(Cl)Cl
Product: OCCN1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
4-(2-Hydroxyethyl)-piperazine (7.2 ml; 58.7 mmol) was added to a suspension of 5-chloromethyl-8-hydroxyquinoline (5.413 g; 23.5 mmol) in CHCl3 (80 ml) at 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was subsequently washed with a saturated NaHCO3 solution and brine, then dried with Na2SO4 and evaporated to dryness. Crystallization of the residue from a mixture of CHCl3-Hex gave 4.05 g (60%) of title product. M.p. 123-4° C. The mother liquor was evaporated and the residue was crystallized to yield 1.5 g of title product. Overall yield: 5.55 g (82%). A highly pure product was obtained by soxleth extraction using hexane as the extractant. TLC (CHCl3 MeOH NH3=8:2:0.5). Rf=0.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:23](=[O:25])[CH3:24])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 600 mg of the compound [1-1], 75 mg of dichlorobis(triphenylphosphine)palladium (II), 743 μL of tributyl (1-ethoxyvinyl)tin, and 3 mL of 1,4-dioxane, was stirred overnight at 100° C. After standing to cool, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/2) to obtain 367 mg of tert-butyl[(1S)-1-(4-acetylphenyl)ethyl]carbamate [1-2] (hereinafter, referred to as the compound [1-2]) as a colorless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:16]([NH2:18])=[O:17])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1.CS(O[CH:24]1[CH2:30][CH:29]2[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[CH:26]([CH2:27][CH2:28]2)[CH2:25]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[C:16]([C:13]1[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[N:12][C:3]([S:2][CH3:1])=[N:4][C:5]=3[C:6]=2[N:15]([CH:24]2[CH2:30][CH:29]3[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:38])([Cl:39])[Cl:37])=[O:33])[CH:26]([CH2:27][CH2:28]3)[CH2:25]2)[N:14]=1)(=[O:17])[NH2:18]
Reactant: CSc1ncc2ccc3c(C(N)=O)n[nH]c3c2n1
Reactant: CS(=O)(=O)OC1CC2CCC(C1)N2C(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2ccc3c(C(N)=O)nn(C4CC5CCC(C4)N5C(=O)OCC(Cl)(Cl)Cl)c3c2n1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
8-(Methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 50 mg (0.193 mmol) in DMF (8 ml), were reacted with 2,2,2-trichloroethyl 3-[(methylsulfonyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 200 mg (0.52 mmol) and cesium carbonate 140 mg (0.43 mmol) at 90° C. for 4 hours. The mixture was cooled at r.t. and portioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The crude was purified by column chromatography eluting with DCM/EtOH 9/1 to provide 2,2,2-trichloroethyl 3-[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate as a off-white solid 73 mg (70%). The compound (134 mmol) was dissolved in THF (5 ml), acetic acid (5 ml) and zinc dust 35 mg (0.536 mmol) were added. The mixture was heated up to 50° C. and stirred 18 hours. The volatiles were removed in vacuum and the residue was purified by chromatography eluting with DCM/MeOH 95/5. A further purification was required and was performed by prep-HPLC method 1, to obtain the title compound 25 mg (50%). LC/MS (254 nm) HPLC method 2 Rt 4.08 min. 1H NMR (401 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.25 (d, J=8.67 Hz, 1H), 7.62-7.79 (m, 3H), 7.52-7.60 (m, 1H), 6.21-6.54 (m, OH), 3.68 (br. s., 2H), 2.76 (s, 2H), 2.22-2.36 (m, 2H), 2.02 (br. s., 2H), 1.78-1.98 (m, 5H). HRMS (ESI) calcd for C18H20N6OS [M+H]+ 369.1492 found 369.15.