Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:5]>C1COCC1.O.CO>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)([CH3:5])[C:3]([OH:20])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 94.1 %

Procedure:
A solution of 2,2-bis-(4-chloro-phenyl)-propionic acid methyl ester (210 mg, 0.67 mmol) in THF/water/methanol (1:11, 18 mL) was stirred at room temperature for 5 days then concentrated in vacuo. The residue was partitioned between ethyl acetate and 2N hydrochloric acid, then the organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (186 mg, 93%) as a yellow solid which was used without further purification. LCMS (PS-B3) Rt 2.40 min [M−CO2H]− 249.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)OCC1.[C:12]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:12]([C:14](=[C:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)[C:15]([OH:17])=[O:16])#[N:13]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C(=O)O)=C1CCC(=O)CC1
Temperature: 25 °C

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-one (7.00 g, 44.8 mmol), tert-butyl 2-cyanoacetate (6.96 g, 49.3 mmol), ammonium acetate (0.28 g) and acetic acid (1.4 mL) in toluene (90 ml) was refluxed using Dean-Stark water separator to isolate water formed for 48 hours. The reaction mixture was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo. To the crude material was added 140 ml of a 2% aqueous sulfuric acid solution and the mixture was refluxed for 1 hour. The reaction mixture was then cooled to room temperature and filtered to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.36-2.55 (m, 4H), 3.04 (dd, J=7.6, 5.8 Hz, 2H), 3.30 (d, J=13.6 Hz, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([CH:9]=1)[NH2:8].[C:16](#[N:20])[CH:17]([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([NH:8][C:16](=[NH:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=1
Reactant: CC(C)C#N
Reactant: CSc1ccc(N2CCOCC2)c(N)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(N2CCOCC2)c(NC(=N)C(C)C)c1
Temperature: 140 °C

Procedure:
A mixture of 5-methylthio-2-morpholinoaniline (1.8 g), isobutyronitrile (1.66 g) and anhydrous aluminium chloride (3.2 g) was heated at 140° C. for 2 hours to give N-(5-methylthio-2-morpholinophenyl) isobutyramidine (m.p. 155° C.) which was recrystallised from hexane.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)=[C:13]([F:23])[CH:12]=2)[CH2:6]1.C[C:25]1[O:26][C:27]([CH:30]=S(=O)=O)=[N:28][N:29]=1.O>CS(C)=O>[CH3:30][C:27]1[O:26][C:25]([O:3][CH2:4][C@@H:5]2[O:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH2:18][CH2:19][O:20][CH2:21][CH:22]=4)=[C:13]([F:23])[CH:12]=3)[CH2:6]2)=[N:29][N:28]=1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Reactant: Cc1nnc(C=S(=O)=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nnc(OC[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)o1
Temperature: 110 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
Sodium hydride (28 mg of a 60% suspension in mineral oil, 0.69 mmol) was added to a solution of 5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one (0.2 g, 0.69 mmol) in DMSO (5 ml) and the mixture was stirred for 1 hour. 2-Methyl-5-sulfonylmethyl-1,3,4-oxadiazole (RB Woodward et al, (Journal of the American Chemical Society 105, 904 [1983]) (0.11 g, 0.69 mmol) was added and the solution heated at 110° C. for 9 hours. Water (40 ml) was added and the mixture extracted three times with EtOAc. The combined extracts were dried by filtration through phase separation paper (Whatman 1PS) and evaporated. The residue was purified by flash column chromatography, eluting first with EtOAc and then with EtOAc/MeOH (20:1) to give the title product (23 mg, 9%) as a solid (mp 146-147° C.). MS: 376 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:12]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])[CH3:13]
Reactant: O=Cc1c(O)cccc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cccc(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-fluoro-6-hydroxybenzaldehyde (2.500 g; 17.80 mmol), iodoethane (5.566 g; 35.70 mmol), and K2CO3 (2.959 g; 21.40 mmol) in anh. DMF (50 ml) was heated to 80° C., under nitrogen, for 2 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-6-fluorobenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.66 min.; [M+H]+: 169.14 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(C1C=CC(OC2N=CC(N[C:32]([C@H:34]([NH:37][C:38](=O)[O:39]C(C)(C)C)[CH2:35]C)=[O:33])=CC=2)=CC=1C(C)C)#N.Cl>ClCCl>[CH3:35][C@H:34]1[NH:37][C:38](=[O:39])[N:13]([C:12]2[CH:14]=[CH:15][C:9]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:10][CH:11]=2)[C:32]1=[O:33]
Reactant: Cc1cccc(Oc2ccc(N)cc2)c1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 4-[(3-methylphenyl)oxy]aniline (90 mg, 0.45 mmol) in dichloromethane (1 mL) was added with shaking at 35° C. an aliquot of approximately ⅓ of solution 1 slowly via syringe (over ca. 1 min). After 30 min, HCl (ca. 0.8 mL) was added and the heterogeneous mixture was heated at 100° C. for 2 hours with shaking, allowing the dichloromethane to distill off through a glass capillary. After cooling to room temperature the aqueous HCl was pipetted off and the residue dried under vacuum. The residue was purified by silica gel chromatography (Biotage instrument, 10 g column) eluting with 0-100% EtOAc/cHex to give after drying the title compound as a solid (30 mg).
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([NH:26]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:11]([O:13]C(C)(C)C)=[O:12])(C)(C)C>C(O)=O>[NH2:26][C@@H:7]([CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:11]([OH:13])=[O:12])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=CO
Product: N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)O)C(=O)O
Temperature: 63 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
(2S)-2-tert.-Butoxycarbonylamino-5-(4-hydroxy-benzyl)-hexanedioic acid di-tert.-butyl ester (159 mg, 332 μmol) was solved in formic acid (20 ml) and the solution was stirred at 63° C. for one hour. The solvent was removed under reduced pressure and the residue was taken up in methanol and concentrated and dried in vacuo. The product was taken up in water and lyophilized to yield 78 mg (79%) of the title compound (contains 0.4 eq formic acid and traces of methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]([CH2:21][CH2:22]OS(C)(=O)=O)[N:15]=[CH:14][C:13]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:28]#[N:29].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]([CH2:21][CH2:22][C:28]#[N:29])[N:15]=[CH:14][C:13]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
To a solution of methanesulfonic acid 2-((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydroindazol-1-yl)-ethyl ester (850 mg, 2.16 mmol) in dimethyl sulfoxide (20 mL) was added sodium cyanide (540 mg, 10.8 mmol). The mixture was stirred at 55° C. for 4 hours. After cooling, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate (20 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (10% methanol in dichloromethane) to afford [(R)-1-(2-cyano-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (600 mg, 85%) as a white solid. MS calcd. for C18H20N4O2 324, obsd. (ESI+) [(M+H)+] 325.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].[Cl:26]CCl>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([Cl:26])=[O:25])[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a suspension of 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid (15e) (0.21 g, 0.57 mmol) in dichloromethane (2.5 ml) oxalyl chloride (0.15 ml, 1.71 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.21 g, 95%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([N+:23]([O-:25])=[O:24])=[C:13]([F:26])[CH:12]=2)[CH2:6][S:5](=[O:28])(=[O:27])[CH2:4]1.[C:29]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[C:14]([N+:23]([O-:25])=[O:24])=[C:13]([F:26])[CH:12]=2)[CH2:6][S:5](=[O:27])(=[O:28])[CH2:4]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cccc(C=O)c1
Reactant: N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c2)[C@@H]1O
Agent: Cl
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c3)[C@@H]2O)c1

Procedure:
The title compound was prepared in analogous manner as described for example 1h) from (3R,4S,5S)-3-Amino-5-[4-nitro-3-fluoro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol hydrochloride salt (1.26 g, 2.78 mmol) and 3-tert-butyl benz-aldehyde (0.361 g, 2.26 mmol); ESIMS [M+H]+=563, UPLC RtD=1.576 min, 1H NMR (600 MHz, DMSO-d6): δ 7.35 (s, 1H), 7.27-7.21 (m, 2H), 7.15 (m, 2H), 7.10 (d, 1H), 5.32 (d, 1H), 5.01 (q, 2H), 3.81 (m, 1H), 3.63 (m, 1H), 3.38 (m, 1H), 3.20 (m, 1H), 3.10 (m, 1H), 3.05-2.98 (m, 2H), 2.80 (m, 2H), 2.63 (m, 1H), 2.41 (s, 1H), 2.14 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1.C(O)C.O.N>C(OCC)(=O)C.ClCCl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[I:1]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc2[nH]nc(I)c2c1
Yield: 25.7 %

Procedure:
5-Amino-3-iodo-1H-indazole can be obtained as described in Example 4 from 1 g of 3-iodo-5-nitro-1H-indazole, 20 ml of ethanol, 6.9 g of ferrous sulfate, 10.8 ml of distilled water and 8.2 ml of 32% aqueous ammonia. 230 mg of 5-amino-3-iodo-1H-indazole are thus obtained in the form of a yellow foam (Rf=0.12, silica gel thin layer chromatography, eluent: ethyl acetate/dichloromethane (2/8 by volume)).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][C:9]1[C:10]([O:25][C:26](=[O:28])[CH3:27])=[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=13)[O:15][C:14]([CH3:24])([CH3:23])[CH2:13][CH2:12]2)=[O:7].[ClH:36]>O1CCOCC1>[ClH:36].[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][C:9]1[C:10]([O:25][C:26](=[O:28])[CH3:27])=[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=13)[O:15][C:14]([CH3:24])([CH3:23])[CH2:13][CH2:12]2)=[O:7]
Reactant: CC(=O)Oc1c2c(c3ccccc3c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)OC(C)(C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Oc1c2c(c3ccccc3c1OC(=O)[C@@H]1CCCN1)OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[5-(acetyloxy)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl] 1-tert-butyl (2S)-pyrrolidine-1,2-dicarboxylate (11) (1.2 g, 2.5 mmol) in 1,4-dioxane (5 mL) is added a solution of hydrogen chloride gas in anhydrous 1,4-dioxane (4.0 M, 10 mL). The reaction is stirred at room temperature for 4 hours. The reaction is dried under reduced pressure. The desired product is obtained as a white solid (1.015 g, 93%) M.p.=125-130° C.; 400 MHz 1H NMR (CDCl3) δ: 8.81 (br. s, 2H), 8.18 (d, J=8.8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.44 (m, 2H), 4.81 (br. s, 1H), 3.8-3.6 (m, 1H), 3.46 (br. s, 2H), 2.65-2.5 (m, 1H), 2.57 (t, J=6.4 Hz, 2H), 2.4-2.3 (m, 1H), 2.38 (s, 3H), 2.15-2.00 (m, 2H), 1.85-1.70 (m, 1H), 1.77 (t, J=6.4 Hz, 2H), 1.36 (s, 3H), 1.35 (s, 3H); LCMS: 384 [M+H]; Calc. for C22H25NO5.1.58 HCl: C, 59.86; H, 6.07; N, 3.18; Found C, 59.91; H, 6.09; N, 2.91.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.CO>O1CCCC1>[NH2:7][CH2:6][C:5]1[C:4]([Cl:11])=[CH:3][C:2]([NH2:1])=[C:9]([I:10])[CH:8]=1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc(I)c(N)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A dried 25 ml of two-neck round bottom flask was filled with argon gas. The solution of 4-amino-2-chloro-5-iodo-benzonitrile (63.8 mg, 0.23 mmol) in tetrahydrofuran was put into the flask and cooled to 0° C. To the solution was added Borane-THF complex (2 eq, 0.46 mmol, 0.4 ml) slowly. The temperature of the mixture was raised and heated to reflux for 12 hours. After confirming the completion of the reaction with TLC, to the solution was added methanol slowly (generation of bubbles) and stirred for 2 hours. The methanol was removed under reduced pressure and the residue was extracted with ethylacetate. The ethylacetate layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a yellow syrup (46.5 mg, 71.85%).
Reaction SMILES: OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([N:51]3[C:55]4=[N:56][CH:57]=[CH:58][CH:59]=[C:54]4[CH:53]=[CH:52]3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:60][CH2:61][N:62]([CH:65]([CH3:67])[CH3:66])[C:63](=[O:64])[C:39]=12)C1C=CC=CC=1>>[OH:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([N:51]3[C:55]4=[N:56][CH:57]=[CH:58][CH:59]=[C:54]4[CH:53]=[CH:52]3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:60][CH2:61][N:62]([CH:65]([CH3:67])[CH3:66])[C:63](=[O:64])[C:39]=12
Reactant: CC(C)N1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(O)c2C1=O

Procedure:
9-Hydroxy-2-isopropyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (412) was prepared following the same method as described for 9-hydroxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (408) from 9-benzyloxy-2-isopropyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (411) (40 mg, 0.08 mmol) and was obtained as an off-white solid (30 mg, 91%).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.[OH-].[Na+].C1C(S(O)(=O)=O)=CC2C(C3C=C(S(O)(=O)=O)C=CC=3C(=O)C=2C=1)=O.OO>O.CO>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=C1c2ccc(S(=O)(=O)O)cc2C(=O)c2cc(S(=O)(=O)O)ccc21
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 23.5 °C
Reaction time: 0.17 h

Procedure:
A one-liter flask equipped with a thermometer, stirrer and condenser is charged with 50 g 6,13-dihydroquinacridone, 180 ml methanol, 1 g polyvinyl pyrrolidone powder (Luviskol® K-30/BASF) are stirred at 20 to 27° C. for 10 minutes. 73 g 50% aqueous sodium hydroxide are added. The mixture is stirred under a slow flow of nitrogen at 50-53° C. for 50 minutes then heated to reflux. 1.2 g 2,7-anthraquinone disulfonic acid is added as catalyst. 76 g of an aqueous 18.9% hydrogen peroxide solution is added into the reaction mixture with a peristaltic pump at a pumping rate of 0.4 ml/minute. The resulting pigment suspension is further stirred for 10 minutes at reflux then diluted with 100 ml cold water and filtered. The presscake is washed with hot water then dried, yielding a bronze colored large particle size beta quinacridone.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:10]3[CH:11]=[C:12]([S:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.C(N1C=CC([C:42](=[NH:44])[NH2:43])N1C(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:10]3[CH:11]=[C:12]([S:16][CH2:17][CH2:18][NH:19][C:42]([NH2:44])=[NH:43])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C=CC(C(=N)N)N1C(=O)OC(C)(C)C
Reactant: CN1CCC(OC(c2cccc(SCCN)c2)c2nc3cc(F)ccc3[nH]2)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(OC(c2cccc(SCCNC(=N)N)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine (example 437B, 230 mg) in acetonitrile (15 mL) is added is added N,N′-bis-Boc-guanylpyrazole (172 mg) and diisopropylethylamine (1 equivalent) at room temperature. The mixture is stirred at room temperature for 3 h. The solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol from 100/0 to 95/5). The residue is then dissolved in 5N aqueous hydrochloric acid (8 mL) and the solution is stirred overnight at room temperature. The solvent and volatiles are removed under reduced pressure and the residue is triturated with diethyl ether and filtered to afford N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl) guanidine trihydrochlorhide as a white crystalline solid melting at 170° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH:19]=[CH:20][CH:21]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:28][C:26]([CH2:25][O:24][CH2:23][CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:29])[F:30])[CH:17]=3)=[N:27][C:2]=2[N:3]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1cccc(OC(F)(F)F)c1
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(OC(F)(F)F)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-acetamidine hydrochloride (example 81.2). Light brown solid. MS: m/e=384.1 [M+H+].
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]([O:17][CH:18]([CH3:20])[CH3:19])(=[O:16])[CH2:9][C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].Br[CH2:22][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:24]Br>O>[CH:18]([O:17][C:8]([C:9]1([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[CH2:24][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:22]1)=[O:16])([CH3:20])[CH3:19]
Reactant: COC(CBr)(CBr)OC
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Temperature: 145 °C

Procedure:
Following the procedure of Pigou and Scheisser (J. Org. Chem. 1988, 53, 3841), a 500 mL, 3-neck flask, fitted with a reflux condenser and thermocouple, was charged with NaH (60% in mineral oil, 4 g, 0.210 mol). DMF (100 mL) was added via syringe and the slurry was stirred under N2. Diisopropyl malonate was added at a rate so that the internal temperature did not rise above 70° C. After the H2 evolution had ceased, the flask was briefly opened and 1,3-dibromo-2,2-dimethoxypropane was added. The bath temperature was raised to 145° C. The reaction mixture was maintained at this temperature for 48 h. After this time the dark brown mixture was allowed to cool to rt. Water (50 mL) was added and the solvents were removed in vacuo. The residue was partitioned between ether (200 mL) and sat'd aq NH4Cl (200 mL) and the mixture filtered through a pad of Celite to remove solid impurities. The aqueous layer was extracted with ether (2×100 mL). The combined ether extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography (SiO2, O-25% EtOAc in hexanes) gave semi-pure diisopropyl-3,3-dimethoxycyclobutane-1,1-dicarboxylate (28.5 g), which was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](F)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>CCO>[CH3:12][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CN
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4-Aminobenzenesulphonylfluoride (200 mg, 1.14 mmol) was dissolved in a solution of methylamine in EtOH (3 mL, excess) and heated to 80° C. for 45 minutes, then cooled to room temperature and left to stir overnight. The solvent was evaporated in vacuo and azeotroped with ether to yield the title compound as a solid (160 mg, 75%). NMR: 2.12 (s, 3H), 5.85 (s, 2H), 6.59 (d, 2H), 7.37 (d, 2H); m/z 187.
Reaction SMILES: [CH3:1][NH-:2].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10](Cl)=[O:11])[CH:5]=1.C(=O)([O-])O.[Na+]>O1CCCC1.[OH-].[Na+].ClCCl>[CH3:1][NH:2][C:10]([C:6]1[CH:5]=[C:4]([Cl:3])[N:9]=[CH:8][N:7]=1)=[O:11]
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: C[NH-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)ncn1
Temperature: 25 °C

Procedure:
0.5 ml of a 2 M methylamide solution in tetrahydrofuran and 1 ml 1 N sodium hydroxide solution are added to 177 mg 6-chloro-pyrimidin-4-carboxylic acid chloride in 5 ml dichloromethane under an argon atmosphere and while cooling with a bath of ice/acetone. The reaction mixture is heated overnight with stirring to ambient temperature and then combined with some saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic phases are washed with 0.1 N hydrochloric acid and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down.