Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[S:16][C:10]=2[NH:9][C:8]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26]([CH2:25][N:9]1[C:10]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:11]=2[C:12](=[O:13])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]1=[O:21])=[O:27])[CH3:30]
Reactant: CCCCCCn1c(=O)[nH]c2sc3c(c2c1=O)CCCC3
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCn1c(=O)c2c3c(sc2n(CC(=O)OCC)c1=O)CCCC3
Yield: 77 %

Procedure:
A 1.2 g quantity of 3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Compound III-9), 0.14 g of 50% sodium hydride and 1.0 g of ethyl bromoacetate were allowed to react with each other in the same manner as in Reference Example 5. The residue obtained by concentration was subjected to silica gel column chromatography using chloroform as an eluent. Then 1.2 g of 1-ethoxycarbonylmethyl-3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione was obtained in a yield of 77%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-(trifluoromethyl)phenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, chloroform-d) δ ppm 1.21 (t, J=7.1 Hz, 3 H) 2.71 (s, 6 H) 4.14 (q, J=7.2 Hz, 2 H) 7.31 (d, J=7.8 Hz, 2 H) 7.53 (d, J=7.8 Hz, 2 H) 7.61 (s, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:37])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:22]3[CH:23]=[C:19]([C:17]([NH:16][CH2:15][C:11]4[C:10]([CH3:37])=[N:9][C:8]([NH2:7])=[CH:13][C:12]=4[CH3:14])=[O:18])[N:20]=[CH:21]3)=[CH:26][CH:27]=2)[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4,6-Dimethyl-5-({[1-(4-pyrazol-1-ylmethyl-benzyl)-1H-imidazole-4-carbonyl]-amino}-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (260 mg, 0.37 mmol), 5 mL TFA and 10 mL DCM was stirred of room temperature for 1 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). Aq. NaHCO3-solution was added to the product containing fractions and after evaporation the aq. layer was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the title compound. 1H-NMR (DMSO-d6, 400 MHz) 7.80 (s, 2H), 7.66-7.69 (m, 2H), 7.45 (s, 1H), 7.28 (d, 2H), 7.20 (d, 2H), 6.26 (s, 1H), 6.21 (s, 1H), 6.04 (s, 2H), 5.31 (s, 2H), 5.19 (s, 2H), 4.30 (d, 2H), 2.34 (s, 3H), 2.21 (s, 3H); LCMS (method A) RtA=0.832 min; [M+H]+=416.0
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]Br)=[CH:16][CH:15]=1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.O.[OH-].[Na+]>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:21][CH2:22][CH2:23][N:10]2[CH2:11][CH2:12][CH:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:9]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)NC1CCNCC1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)NC1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
11 g (64 mmol) of 4-ethoxycarbonylaminopiperidine, 20.5 g (64 mmol) of 4,4-bis(4-fluorophenyl)butyl bromide, 12.9 g (128 mmol) of triethylamine and 0.18 g of potassium iodide were stirred in 180 ml of absolute dimethylformamide at 80° C. for 36 hours, the mixture was diluted with about 1.5 liters of water, 100 ml of 2N NaOH were added and the mixture was extracted twice with methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:28]([N:11]([CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[N:15][CH:14]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ncc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide (30 mg) in N,N-dimethylacetamide (0.6 mL) were added benzyl bromide (13 mg) and cesium carbonate (26 mg). The mixture was stirred overnight at r.t. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 1:1) to give N-benzyl-2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 534.8 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCOCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCOCCO)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-(2-aminoethoxy)ethanol (0.010 mL, 0.10 mmol) and sodium triacetoxyborohydride (48 mg, 0.23 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[2-(2-hydroxyethoxy)ethylaminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:10]([CH2:13][CH3:14])=[C:11]=S.C(N=C=NC(C)C)(C)C.C(OCC)(=O)C>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:11]([NH:10][CH2:13][CH3:14])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN=C=S
Reactant: Nc1cc(Br)cnc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCNc1nc2cc(Br)cnc2[nH]1
Temperature: 65 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a cooled (0° C.) solution of 5-bromopyridine-2,3-diamine (5.0 g, 27 mmol) in NMP (20 mL) was added isothiocyanatoethane (2.3 mL, 26 mmol). The resulting solution was heated (65° C.) for four hours and then cooled to ambient temperature before 1,3-diisopropylcarbodiimide (4.2 mL, 27 mmol) was added. The reaction mixture was stirred for 18 hours, diluted with water and the resulting suspension was collected by filtration. Trituration with ethyl acetate provided 6-bromo-N-ethyl-3H-imidazo[4,5-b]pyridin-2-amine (4.8 g, 75% yield) as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ 11.41 (bs, 1H), 7.91 (s, 1H), 7.53 (s, 1H), 7.17 (s, 1H), 3.33 (q, 2H), 1.17 (t, 3H); MS (ES) for C8H9BrN4: 241 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>CCOC(C)=O.O>[CH2:18]([O:17][C:15]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
To a suspension of piperazine-2-one (2.00 g, 20.0 mmol) in EtOAc (50 mL) and water (50 mL), were added sodium carbonate (6.36 g, 60.0 mmol) and 95% benzyl chloroformate (3.59 mL, 24.0 mmol) and the mixture was stirred for 3 days at rt. To the mixture were added EtOAc (50 mL) and water (20 mL) and then organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL×2). The combined organic layer was washed with brine (20 mL) and then dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether (50 mL) to give title compound (3.98 g, 85%) as a colorless solid.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([O:24][CH2:25][CH3:26])[N:16]=1.[N:27]([C@@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C@@H:32](N2C=C(C)C(=O)NC2=O)[CH2:31]1)=[N+:28]=[N-:29]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:32]2[O:33][C@H:34]([CH2:35][OH:36])[C@@H:30]([N:27]=[N+:28]=[N-:29])[CH2:31]2)=[C:17]([O:24][CH2:25][CH3:26])[N:16]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCOc1nc(N)nc2nc[nH]c12
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: CCOc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 50 °C

Procedure:
To 500 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-ethoxypurine (0.0895 g, 0.5 mmol) and 3'-azido-3'-deoxythymidine (0.668 g, 2.5 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 24 mL solution of trans-N-deoxyribosylase (Example 2b) at an activity of 1400 units/mL was added. The reaction was heated at 50° C. Four days later 0.089 g, 0.5 mmol, of 2-amino-6-ethoxypurine was added to the reaction. The reaction was terminated after eleven days. The reaction was heated to 80° C. to precipitate the enzyme and then filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered and the solvent removed in vacuo to give a foam. The foam was chromatographed on 180 g of silica gel (230-400 mesh) eluted with chloroform/methanol (98:2. v/v). The product containing fractions were combined and the solvent removed in vacuo to give the product as an oil. The oil was dissolved in water and lyophilized to give a solid (55% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.Cl.[CH2:28]([N:30]=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:23][C:15]1[CH:16]=[C:17]([C:18](=[O:19])[NH:30][CH3:28])[CH:21]=[CH:22][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a suspension of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzoic acid (2.0 g, 6.24 mmol), methanamine hydrochloride (0.506 g, 7.49 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.795 g, 9.36 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (1.434 g, 9.36 mmol) in DMF (Volume: 8.5 mL) was added 4-methylmorpholine (3.43 mL, 31.2 mmol) at 23° C. The reaction was stirred at 23° C. for 2 hr. The reaction mixture was diluted with water (100 mL) and the product was extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with 1N HCl (50 mL), saturated NaHCO3 (50 mL), H2O (50 mL), brine (50 mL) dried over MgSO4, filtered, rinsed with EtOAc, and dried in vacuo to provide tert-butyl 4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate (1.90 g, 5.70 mmol, 91% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9 H) 2.28 (s, 3 H) 2.75 (d, J=4.55 Hz, 3 H) 2.79-2.87 (m, 4 H) 3.42-3.52 (m, 4 H) 7.03 (d, J=8.34 Hz, 1 H) 7.62 (dd, J=8.34, 2.27 Hz, 1 H) 7.64-7.69 (m, 1 H) 8.26 (q, J=4.46 Hz, 1 H). ESI-MS: m/z 334.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:23][C@H:24]([CH3:46])[CH2:25][O:26]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)(=[O:14])=[O:15])[CH:9]=[C:8]([O:23][C@H:24]([CH3:46])[CH2:25][OH:26])[N:7]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)N2CCN(C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCN(C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-{2-[(2,3-difluorobenzyl)thio]-6-[(1R)-1-methyl-2-(trityloxy)ethoxy]pyrimidin-4-yl}-4-methylpiperazine-1-sulfonamide (the product from step (100 mg) in DCM (3 ml) was added TFA (3 ml) dropwise. The reaction was then allowed to stir at room temperature for the following 3 h until complete. The reaction was then reduced in vacuo and the resulting residue was purified by preparative HPLC to yield the title compound as a white solid. Yield: 45 mg
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 60 h
Yield: 94.1 %

Procedure:
A solution of allyl bromide (5.94 mL, 68.78 mmol) in acetone (20 mL) was added, over a period of 20 min, to a mixture of 4-hydroxybenzaldehyde (8.00 g, 65.50 mmol) and K2CO3 (9.96 g, 72.06 mmol) in acetone (100 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 60 h. After removal of the solvent, the crude residue was dissolved in EtOAc (100 mL) and washed twice with a mixture of water (100 mL) and NaOH (10% aqueous solution, 10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 10.00 g of 4-(allyloxy)benzaldehyde were obtained [Rf=0.5 (10% EtOAc/Hexanes), pale brown oil, 94% yield]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Cl:11][C:12]1[C:13]([N:17]=[C:18]=[S:19])=[CH:14][S:15][CH:16]=1>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:18]([NH:17][C:13]1[C:12]([Cl:11])=[CH:16][S:15][CH:14]=1)=[S:19]
Reactant: Nc1cc(F)c(F)cc1N
Reactant: S=C=Nc1cscc1Cl
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1NC(=S)Nc1cscc1Cl

Procedure:
To 1,2-diamino-4,5-difluorobenzene (1.02 g) in THF abs. (15 ml) 4-chloro-3-thienylisothiocyanate (1.25 g, example 52c) dissolved in THF abs. (15 ml) was added. Following the analogous description in example 54a) the desired product was obtained (773 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:26][N:25]=[C:24]([C:27]([O:29]C)=[O:28])[CH:23]=4)[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[O:7][N:6]=1)=[O:4]>[OH-].[Na+].CO.O>[C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:26][N:25]=[C:24]([C:27]([OH:29])=[O:28])[CH:23]=4)[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[O:7][N:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2cccc(-c3cccc(-c4cc(C(=O)OC)no4)c3)c2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2cccc(-c3cccc(-c4cc(C(=O)O)no4)c3)c2)on1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
The ester from Example 10C (65 mg, 0.16 mmol) was dissolved in 4M NaOH (5 mL) in MeOH/H2O (5:3). After 2 hours no starting material was visible by TLC. When the reaction mixture was acidified to pH 1, the product precipitated out. The titled compound (22 mg, 36%) was obtained after reverse phase HPLC (0–70% acetonitrile in 0.1% aqueous TFA) as a white solid. MS (DEI) positive ion; m/z 376 (M)+: negative ion; m/z 751.1 (2M−H)−, 375.1 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 7.6 (s, 2H), 7.7 (t, J=7.8 Hz, 2H), 8.0 (dd, J=8.1, 1.5 Hz, 4H), 8.3 (s, 2H), 14.0 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([N:14]=[O:15])[C:9]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C1NCCN1c1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCN(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a solution of glacial acetic acid (2750 ml) and water (250 ml) was dissolved 150 g (0.75 mol) of 1-(4-chlorophenyl)-2-imidazolidinone with heating. The solution was cooled to room temperature, and sodium nitrite (70 g, 1.0 mol) in water (200 ml) was added dropwise over 1 hour. The mixture was stirred for another 6 hours, diluted with water (1.5 l.) and the product (137 g, 81%) was collected, m.p. 154°-156°.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][CH:11]1[CH2:18][OH:19])=[O:9])[CH:5]=[CH2:6].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(OCC)(=O)C.O>[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][CH:11]1[CH2:18][O:19][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:9])[CH:5]=[CH2:6]
Reactant: C=CCOC(=O)N1CC(C(C)=O)=CC1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC(C(C)=O)=CC1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.5 %

Procedure:
To a methylene chloride solution (50 ml) of 1-allyloxycarbonyl-4-acetyl-2-hydroxymethyl-3-pyrroline (2.5 g) and imidazole (1.51 g) was added tert-butyldimethylsilyl chloride (2.5 g) under ice-cooling. The mixture was then stirred at room temperature for one day, followed by addition of water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate twice. The organic layers were combined, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 1-allyloxycarbonyl-4-acetyl-2-tert-butyldimethylsilyloxymethyl-3-pyrroline (1.45 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13](C(OCC)=O)[C:14]([CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Mg]Br>C1COCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:8]([OH:7])([CH3:17])[CH3:9])[C:14]([CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(OCc3ccc(F)cc3)cc2nc1C
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc2cc(OCc3ccc(F)cc3)ccc2cc1C(C)(C)O
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of ethyl 7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate (Example 22, 65 mg, 0.19 mmol) in THF was added methyl magnesium bromide (3 M in Et2O, 0.5 mL, 1.5 mmol). The reaction was stirred for 30 minutes before being quenched with a sat. NH4Cl (aq.) solution. The aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a yellow solid (28 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.44 (dd, J=5.5, 8.2 Hz, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.18 (dd, J=2.3, 9.0 Hz, 1H), 7.07 (t, J=8.6 Hz, 2H), 5.13 (s, 2H), 2.95 (s, 3H), 1.75 (s, 6H). [M+H]=326.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].CC1(C)COB([C:21]2[CH:26]=[CH:25][C:24]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)OC1.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:31])[CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(C3(O)CCC3)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)cc3)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (6.15 g, 23.8 mmol), 1-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-cyclobutanol (8.35 g, 32.1 mmol), 2 M aqueous potassium carbonate (47.5 mL, 95.0 mmol) in EtOH (33 mL) and toluene (86 mL) was degassed with N2 for 25 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.93 g, 2.64 mmol). The reaction mixture was heated to 110° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, poured into a 3:1 mixture of saturated aqueous NH4Cl solution/water (450 mL) and extracted with EtOAc (10×150 mL), followed by 9:1 CH2Cl2/i-PrOH (4×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (0-100% EtOAc/heptane, with 0.03% formic acid modifier) to afford the title compound (4.98 g, 64%) as a red solid. MS (ES+) 326.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.21 (br. s., 1 H), 9.91 (s, 1 H), 8.35 (s, 1 H), 8.02 (s, 1 H), 7.67 (s, 1 H), 7.54 (d, J=8.00 Hz, 2 H), 7.38 (d, J=8.20 Hz, 2 H), 5.50 (s, 1 H), 2.36-2.45 (m, 2 H), 2.22-2.33 (m, 2 H), 1.92 (m, 1 H), 1.61-1.71 (m, 1 H).