Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:43]=[CH:44][CH:45]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 15 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 164B (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.033 g, 15%). 1H NMR (300 MHz, CDCl3) δ 9.5 (br, 1H), 8.63 (s, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.32-7.43 (m, 4H), 7.00 (dd, 1H), 6.31 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.91 (s and t, 5H), 3.50 (s, 3H); LC-MS (ESI) m/z 533 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.N1C=CC=CC=1.[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)=[O:32])=[CH:34][CH:35]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (0.34 g, 1.57 mmol) in methylene chloride (8 mL) was added pyridine (0.15 mL, 1.88 mmol) and 4-n-butylbenzoyl chloride (0.37 g, 1.88 mmol). The reaction mixture was stirred for 1 h then purified directly by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. The product fractions were combined and concentrated in vacuo. The residue was triturated with ethyl ether and the solids collected by filtration and rinsed with hexanes. 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (0.48 g; 81%) was obtained as white solid.
Reaction SMILES: [H][H].[CH3:3][CH:4]([OH:19])[CH:5]([OH:18])[C:6]1[N:11]=[C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]2=[N:8][CH:7]=1)=[O:13].[ClH:20]>[Pt]=O>[ClH:20].[CH3:3][CH:4]([OH:19])[CH:5]([OH:18])[CH:6]1[NH:11][C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]=2[NH:8][CH2:7]1)=[O:13]
Reactant: [H][H]
Reactant: CC(O)C(O)c1cnc2[nH]c(N)nc(=O)c2n1
Agent: O=[Pt]
Agent: Cl
Product: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1

Procedure:
There was dispersed 100 mg of platinum oxide into 100 ml of a 1N hydrochloric acid, and then the catalyst was activated with hydrogen gas. Then, 100 ml of 1N hydrochloric acid solution containing 1 g of biopterin was added to the above dispersion. After the catalytic reduction was conducted for 5 hours under normal temperature and normal pressure in a hydrogen atmosphere, the catalyst was filtered off from the reaction mixture to give a hydrochloric acid solution of tetrahydrobiopterin having a (6R)/(6S) ratio of 60/40 as measured by HPLC. Light yellow powder was produced by repeating the cycle of concentration of the solution and addition of ethanol. The powder was filtered off from the above solution to give 1.08 g of powder. The (6R)/(6S) ratio of the powder thus obtained was 57/43 as measured by HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:49][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NC1CCCCC1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC3CCCCC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and cyclohexylamine (13.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-cyclohexylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (35.0 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][N:25]=[CH:26]2>>[CH:26]1[C:27]2[C:22](=[C:21]([NH:20][C:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][N:7]=4)[CH2:14][CH2:13]3)=[O:17])[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][N:25]=1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: Nc1cccc2cnccc12
Product: O=C(Nc1cccc2cnccc12)C1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
Using the procedure outlined in Example 107, the title compound was prepared from 1-(5-trifluoromethylpyrid-2-yl)-piperidine-4-carboxylic acid (D101) (100 mg, 0.36 mmol) and 5-aminoisoquinoline (27 mg, 0.19 mmol) as an off white solid. MS(ES): MH+ 401, M-H+ 399.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH2:13][CH3:14])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CCOc1ccc(Nc2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 4-ethoxyaniline by a procedure similar to example 28 (32%). 1H NMR (CDCl3): 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 7.03 (m, 1H), 6.73 (m, 3H), 4.09 (q, J=7.2, 2H), 1.49 (t, J=7.2, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:47]=[CH:46][C:39]2[S:40][C:41](B(O)O)=[CH:42][C:38]=2[CH:37]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:41]3[S:40][C:39]4[CH:46]=[CH:47][C:36]([F:35])=[CH:37][C:38]=4[CH:42]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2cc(F)ccc2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc3cc(F)ccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (33 mg, 0.066 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (12.91 mg, 0.066 mmol) and tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined and dried over Na2SO4, and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (1:1, 10 mL). The mixture was stirred at room temperature for 60 minutes and then concentrated. The resulting crude material was reconstituted in MeOH and DCM (6.0 mL) and purified via preparative HPLC, eluting with a gradient of 25-30% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to yield a TFA salt of the title compound (12 mg, 44%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.82 (d, J=9.76 Hz, 1H), 2.15 (d, J=8.30 Hz, 1H), 3.59-3.70 (m, 1H), 3.82 (s, 1H), 3.91 (br s, 1H), 3.98-4.11 (m, 2H), 4.38 (br s, 1H), 4.43-4.55 (m, 2H), 7.23-7.33 (m, 1H), 7.42 (d, J=4.88 Hz, 1H), 7.76 (dd, J=9.76, 2.44 Hz, 1H), 7.93-8.03 (m, 3H), 8.62-8.74 (m, 1H), 9.41 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H18F2N4O2S, 417. found, 417.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[F:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[F:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C(C)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(OCCCC(=O)O)cc1F
Yield: 78.2 %

Procedure:
4-(4-Acetyl-3-fluorophenoxy)butanoic acid, ethyl ester (20 mg, 0.0745 mmol) is dissolved in 1 mL of methanol/water (3:2) and treated with 30.91 mg (0.22 mmol) of potassium carbonate according to the procedure described for Example 4 to give 14 mg (82%) of 4-(4-acetyl-3-fluorophenoxy)butanoic acid as a white powder: m.p. 110°-111° C.; The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 1710, 1670, 1610 cm-1 ; MS m/e calculated for C12H13O4FNa: 263.0695, found 263.0699.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.[N:26]1C=CC=[CH:28][C:27]=1CN>>[NH2:20][C:8]([NH:4][CH2:5][C:6]1[CH:2]=[CH:1][CH:28]=[CH:27][N:26]=1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: NCc1ccccn1
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CS(=O)(=O)O
Product: NC(=NS(=O)(=O)c1ccc(Cl)cc1)NCc1ccccn1

Procedure:
The compound of Example 21 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 327.79; found mol. wt. (M+H) 328.3; 655.6 (Dimer)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[SH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Sc1ccccn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol)and diisopropylethylamine (2.6 mL, 15 mmol)in dry dichloromethane (30 mL) was added anhydrous trifluoromethanesulfonic acid (1.0 mL, 6.0 mmol) at −78° C. The mixture was stirred for 1 minute under ice cooling, and cooled to −78° C. To the reaction mixture was added 2-mercaptopyridine (1.67 g, 15 mmol), and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 g, ethyl acetate-hexane 1:5) to give the titled compound as pale yellow oily substance (937 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C2C=C(C(OCC)=O)OC=2C2C=CC=C(C#N)C=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:28]1[CH:29]=[C:30]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[O:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=1>>[Cl:40][C:35]1[CH:34]=[C:33]([C:32]2[O:31][C:30]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:29][C:28]=2[C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Reactant: CCOC(=O)c1cc(Br)c(-c2ccc(F)c(Cl)c2)o1
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 11A starting with the compound from Example 6A. Purification is carried out using the mobile phase: cyclohexane/ethyl acetate (50:1). 1.07 g (63% of theory) of the title compound with a purity of 81% are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]5[CH:27]=[CH:28][S:29][C:25]=5[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]5[CH:27]=[CH:28][S:29][C:25]=5[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[CH:7][C:8](=[O:12])[N:9]2[CH2:31][C:32]([NH2:34])=[O:33])=[CH:4][CH:3]=1
Reactant: O=c1cc(CCN2CCN(c3nccc4sccc34)CC2)c2ccc(F)cc2[nH]1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Cn1c(=O)cc(CCN2CCN(c3nccc4sccc34)CC2)c2ccc(F)cc21
Temperature: 50 °C

Procedure:
66.9 kg of 7-fluoro-4-[2-[4-[thieno[3,2-c]pyridin-4-yl]piperazin-1-yl]ethyl]-quinolin-2(1H)-one (V), 18.4 kg of 2-chloroacetamide (1.2 eq.), 51.5 kg of potassium carbonate (2 eq.) and 335 l of DMF are introduced into a reactor. The mixture is stirred at 50° C. for twenty hours and then cooled to 25° C. and 1000 l of water are added. The suspension obtained is filtered and washed with water and a paste is re-formed in 307 l of ethanol. The solid is filtered off. 60.7 kg, estimated on a dry basis, of a white solid (II) are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:10]=32)[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:54][CH:55]([N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[NH2:66])[CH3:56].Br.C(N(CC)CC)C>CN(C=O)C>[CH3:20][C:2]1([CH3:1])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([NH:66][C:58]4[N:57]([CH:55]([CH3:56])[CH3:54])[C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=5[N:59]=4)=[O:18])=[CH:12][C:10]=32)[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1
Reactant: CC(C)n1c(N)nc2ccccc21
Reactant: CC1(C)CCNC(=O)c2nc3ccc(C(=O)O)cc3n21
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1c(NC(=O)c2ccc3nc4n(c3c2)C(C)(C)CCNC4=O)nc2ccccc21
Reaction time: 16 h
Yield: 50 %

Procedure:
A solution of 5,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate C, 45 mg, 0.16 mmol) and PyBOP (145 mg, 0.28 mmol) in DMF (1.5 mL) is stirred for 10 min. 1-(Propan-2-yl)-1H-benzimidazol-2-amine; hydrobromide (Intermediate M, 71 mg, 0.28 mmol) and triethylamine (0.08 mL, 0.56 mmol) are added and the reaction is stirred for 16 h. The mixture is purified via preparative HPLC to afford the title compound (35 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH2:42])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH:42][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:27])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4nc(C)c(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 635.0 [(M+H)+]; mp 272° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[N:3][CH:4]=1)#[N:7]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C(N)=O)cc2)nc1
Temperature: 120 °C
Yield: 94.4 %

Procedure:
Combine 6-chloro-nicotinonitrile (1.0 g, 7.22 mmol), 4-hydroxybenzamide (1.09 g, 7.94 mmol), and potassium carbonate (1.49 g, 10.83 mmol) in toluene (8 mL). Add DMA (24 mL) to the reaction mixture. Heat the reaction mixture for 1.5 hour at 120° C. Let the reaction mixture cool to room temperature. Pour the reaction mixture onto water and filter the precipitate washing with water. Dry the solid under vacuum to provide the title compound (1.63 g, 94%)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([NH2:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C)C=O>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([NH:71][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:18])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1COc2ccc(C(=O)c3ccccc3C(=O)NCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 211.7 %

Procedure:
To a solution of 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)carbonylbenzoic acid (100 mg, 033 mmol) in N,N-dimethylformamide (2.00 mL) was added N-methylmorpholine (0.14 mL 1.32 mmol) followed by addition of HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.33 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of benzylamine (36 uL, 0.33 mmol). The reaction mixture was then heated to 60° C. for 18 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate the organic layer was washed with brine, 1.0 M aq. hydrochloric acid, brine, saturated aq. sodium-hydrogencarbonate and brine. The organic layer was separated dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford the title compound (0.27 g, 80%). MS (EI) for C23H18N2O4: 387 (M+H).
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][CH:22]=[O:23])[C@H:4]1[S:3]2.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][CH:22]=[O:23])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]1S2
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenyl-2-formyloxyacetamido)penam-3-carboxylate (1.52 g.) in dimethylformamide (7.5 ml.) were added acetic acid (2.3 ml.) and zinc powder (1.8 g.) under ice-cooling, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to the distillation of ethyl acetate to give oily 2-methyl-2,3-methylene-6-(2-phenyl-2-formyloxyacetamido)penam-3-carboxylic acid (1.1 g.).
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]([C:14]1[CH:15]=[C:16]([CH:44]=[C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:46]=1[OH:47])[CH2:17][C:18]1[C:19]([CH3:43])=[C:20]([OH:42])[C:21]([CH3:41])=[C:22]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=2)[C:23]=1[CH3:24])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:32]([C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[OH:36])[CH2:25][C:22]1[C:21]([CH3:41])=[C:20]([C:19]([CH3:43])=[C:18]([CH2:17][C:16]2[CH:15]=[C:14]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:46]([OH:47])=[C:45]([C:48]([CH3:50])([CH3:49])[CH3:51])[CH:44]=2)[C:23]=1[CH3:24])[O:42][P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: Cc1c(O)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)COP(Cl)OC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(OP2OCC(C)(C)CO2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 8.45 g of 2-chloro-5,5-dimethyl[1,3,2]dioxaphosphinane in 50 ml of toluene is added dropwise, in the course of 15 minutes and at a temperature between 20° and 30° C., to a solution of 28.65 g of 3,5-bis-[3',5'-ditert.-butyl-4'-hydroxybenzyl]-2,4,6-trimethylphenol and 25.3 g of triethylamine in 150 ml of toluene. The reaction mixture is heated under reflux for 24 hours. After cooling to room temperature, the residue is filtered off and the filtrate is evaporated to dryness. This gives 35 g of a colourless product having a melting point of 190° C.