Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:18]1[C:19](C2C=CC=CC=2)=[C:20]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=2C2C=CC=CC=2)[CH:21]=[CH:22][CH:23]=1>CN1CCCC1=O>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([S:14][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([S:24][C:20]4[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=4)[CH:30]=3)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1cccc(Sc2ccccc2)c1
Reactant: Clc1cccc(Sc2cccc(Cl)c2-c2ccccc2)c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: c1ccc(Sc2cccc(Sc3cccc(Sc4ccccc4)c3)c2)cc1
Temperature: 210 °C

Procedure:
436 g of m-phenylmercapto thiophenol and 78 g of potassium hydroxide were dissolved in 500 ml of N-methyl-2-pyrrolidone, then 376 g of m-chlorophenyl phenylsulfide was added and the resultant mixture was heated to 170° C. After removing the water content, 20 g of cuprous chloride was added and heated to 210° C. and maintained at that temperature for 10 hours while stirring. After the reaction was over, the product was treated by the method as in Example Z-1 and bis(m-phenylmercaptophenyl)sulfide was obtained as a fraction at 255° C.-265° C./5 Torr by vacuum distillation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:10]=1)=[O:8].N[C:25]1SC=C(C)N=1>>[CH3:25][C:4]1[N:3]=[C:2]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:10]=2)=[O:8])[S:1][CH:5]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(Nc1nccs1)c1cn(CC2CC2)c2cc(CO)ccc12
Product: Cc1csc(NC(=O)c2cn(CC3CC3)c3cc(CO)ccc23)n1

Procedure:
The compound was prepared according to the procedure given for 1-Cyclopropylmethyl-6-hydroxymethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide using 2-amino-4-methyl-thiazole.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:10]C2N[C:7](=O)[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].CI.[CH3:25][N:26]([CH3:29])[CH:27]=[O:28]>O>[Br:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:10][C:25]2[N:26]([CH3:29])[C:27](=[O:28])[N:8]([CH3:7])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Br)c(Oc3ccc(F)cc3F)cc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)n(C)c2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of 5-bromo-6-(2,4-difluorophenoxy)-1,3-dihydro-2H-benzimidazol-2-one (0.106 g, 0.311 mmol) in N,N-dimethylformamide (2.2 mL) was treated with sodium hydride (0.0273 g, 0.684 mmol) and stirred at 20° C. for 30 min. The reaction mixture was treated with methyl iodide (0.0426 mL, 0.684 mmol) and stirred 20° C. for 30 min. The reaction mixture was diluted with water which resulted in the formation of a precipitate. The solid was filtered and washed with water to give the desired product (108 mg, 94%) which was used without further purification. LCMS calculated for C15H12BrF2N2O2 (M+H)+: m/z=369.0, 371.0. found: 368.9, 371.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([O:22]CC)=[O:21])[CH:4]=1.CO.[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([OH:22])=[O:21])[CH:4]=1
Reactant: CCOC(=O)Cc1cc2c(c(OC)c1)C(=O)c1ccccc1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(CC(=O)O)cc2c1C(=O)c1ccccc1CC2

Procedure:
Ethyl 4-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-acetate is refluxed in water (20 ml) and methanol (5 ml) containing sodium hydroxide (0.5 g) for 2 hours. The solution is cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated. The residue is recrystallized from ethyl acetate-hexane to afford 4-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl acetic acid, mp 189°-199°.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:18][C:19]1[C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[OH:27])=[C:21]([Cl:25])[S:22][C:23]=1[Cl:24].[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:18][C:19]1[C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:27][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)=[C:21]([Cl:25])[S:22][C:23]=1[Cl:24]
Reactant: OC(c1cccc(Cl)c1)c1c(Cl)sc(Cl)c1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1cccc(C(OC2CCCCO2)c2c(Cl)sc(Cl)c2Br)c1
Reaction time: 3.5 h

Procedure:
Pyridinium p-toluenesulfonate (74.0 mg, 0.293 mmol) was added to (4-bromo-2,5-dichloro-3-thienyl)(3-chlorophenyl)methanol from Example 8, Step 1 (1.09 g, 2.93 mmol) and 3,4-dihydro-2H-pyran (2.67 mL, 29.3 mmol) in CH2Cl2 (12 mL). After 3.5 h, the reaction mixture was diluted with CHCl3 and washed with 5% aq. NaHCO3, water and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (30-50% CHCl3/hexane in 20 min.) to afford the desired product as a colorless gum.
Reaction SMILES: Br[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:7]=1)[CH3:3].[NH2:20][OH:21]>CN1CCCC1=O.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH:2]([NH:20][OH:21])[CH3:3])[CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: NO
Reactant: CC(Br)C#Cc1cccc(Oc2ccc(F)cc2)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The 2-bromo-4-[3-(4-fluorophenoxy)phenyl]-3-butyne prepared in step 2 was taken up in N-methyl-2-pyrollidinone (27 kg) and 50% aqueous hydroxylamine (21 kg) was added. The reaction mixture was agitated for 2.5 hours at ambient temperature and then was diluted with distilled water (18 kg). The layers were separated and the organic phase was concentrated in vacuo to give N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]hydroxylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[CH2:5]2.[C:16]([O:19][C:20](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])/[C:5]/2=[CH:16]/[O:19][CH3:20]
Reactant: COc1cc2c(cc1Br)CC(=O)NC2=O
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21

Procedure:
A mixture of 6-Bromo-7-methoxy-4H-isoquinoline-1,3-dione (275 mg, 1.02 mmole), 7 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (0.8 mL, 7.28 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed and the solid collected with ether. A brown solid, 202 mg, (63%), mp 245-248° C. dec, MS (ESI): m/z 310.1, 312.1 (M−H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#N)=[CH:18][CH:17]=1)([F:14])[F:13].[O:24]1CCOCC1.Cl>C(OCC)C.O>[F:11][C:12]([F:14])([F:13])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:24])=[CH:18][CH:17]=1
Reactant: C1COCCO1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 3 h

Procedure:
Diisobutylaluminium hydride (11.8 ml. 1M solution in toluene) was added to a stirred solution of 4-cyanophenyl trifluoromethyl ether (2.0 g., Fairfield) in dry diethyl ether (100 ml.). The mixture was refluxed with stirring for 3 hours. The mixture was cooled and dioxane (5 ml.) containing water 1.0 ml.) was added. Dilute hydrochloric acid was added (60 ml. of 10% solution). The mixture was stirred for 30 minutes and extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography on silica, eluting with 9:1 hexane:diethyl ether. 4-Trifluoromethoxybenzaldehyde was obtained as a colourless liquid (1.65 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12](Cl)([Cl:14])=[O:13]>C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:12]([Cl:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2cccnc12
Solvent: ClCCl
Product: O=C(Cl)Nc1cccc2cccnc12

Procedure:
8-Aminoquinoline (2.0 g., Pfaltz & Bauer, A28560) in methylene chloride (10 ml) was added dropwise to a 0° C. solution of 2.2M phosgene in methylene chloride (12 ml). The resulting precipitate was filtered and dried. The dark solid thus obtained is unstable and in practice it was immediately used in the next reaction.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:17]([NH:19][C:20]1([C:31]#[N:32])[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21]1)=[O:18]>>[C:31]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:24][CH2:23][N:22]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:21]1)#[N:32]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: N#CC1(NC(=O)C(N)CC2CCCCC2)CCN(C2CCCCC2)C1
Agent: Cl
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CCN(C2CCCCC2)C1

Procedure:
The title compound was prepared starting from 3-chloro benzo[d]isothiazol 1,1-dioxide and 2-amino-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 10, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 40% acetonitrile in water to acetonitrile. MS, m/z 512=M+1.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:17]([CH:20]=[CH2:21])[CH2:18]O)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][N:9]([C@H:17]([CH:20]=[CH2:21])[CH2:18][N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@H](CO)N(OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C[C@H](CN1C(=O)c2ccccc2C1=O)N(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
A suspension of (R)-tert-butyl benzyloxy(1-hydroxybut-3-en-2-yl)carbamate (Intermediate 154, 74 g, 252.25 mmol), phthalimide (66.8 g, 454.02 mmol) and triphenylphosphine (119 g, 453.70 mmol) in toluene/THF (200/200 mL) was cooled under nitrogen with ice. DIAD (91.8 g, 453.98 mmol) was added dropwise over 20 minutes and the mixture was stirred at 0° C. for 20 minutes, without cooling for 2 hr. The mixture was filtered and the filtrate was evaporated. The residue was taken up in ether and filtered. The filtrate was evaporated and the residue was purified by silica gel column and eluted with EtOAc/hexane (0-50%) to give the title compound (74 g, 79%) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:18])=O.N#N>C(Cl)Cl.CN(C=O)C>[C:1]1([CH2:11][C:12]([Cl:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
1-Naphthylacetylchloride was synthesized from 1-naphthylacetic acid (20.0 g, 107.4 mmol) which was dissolved in CH2Cl2 (200 mL) and the solution was cooled to 0° C. Oxalylchloride (11.20 mL, 128.90 mmol) was added to the solution dropwise over 20 min. under the atmosphere of N2 then followed by one drop of DMF. The mixture was then allowed to warm to room temperature where it was stirred for 12 hours. The reaction mixture was concentrated under vacuum, the resulting residue was redissolved in CH2Cl2 (200 mL) and the solvents were evaporated in vacuo to give 1-naphthylacetylchloride 21.90 g (99%) as a dark oil: 1H-NMR (400 MHz, CDCl3) δ 7.92-7.84 (m, 3H), 7.61-7.42 (m, 4H), 4.58 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.[CH3:13][O:14][CH2:15]Cl>C(#N)C.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1
Reactant: COCCl
Reactant: COC(=O)Cc1ccc(S)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: COCSc1ccc(CC(=O)OC)cc1
Yield: 78.9 %

Procedure:
A solution of (4-mercapto-phenyl)-acetic acid methyl ester (500 mg, 2.7 mmol) and chloromethyl methyl ether (331 mg, 4.1 mmol) in acetonitrile (3 mL) and pyridine (1 mL) was heated under reflux for 16 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in ethyl acetate (10 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×25 mL) and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded (4-methoxymethylsulfanyl-phenyl)-acetic acid methyl ester (482 mg, 77.6%) as a clear oil: EI-HRMS m/e calcd for C11H14O3S (M+) 226.0664, found 226.0664.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[C:16]([F:35])[C:17]([O:27][C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[C:18]([CH:26]=1)[C:19](N(CC)CC)=[O:20]>C1COCC1>[Br:13][C:14]1[CH:26]=[C:18]2[C:17](=[C:16]([F:35])[CH:15]=1)[O:27][C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][C:33]=1[C:19]2=[O:20]
Reactant: CCN(CC)C(=O)c1cc(Br)cc(F)c1Oc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=c1c2cc(Cl)ncc2oc2c(F)cc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium, 2.5 M (44.8 mL, 112 mmol) was added slowly to a solution of diisopropylamine (19.16 mL, 134 mmol) in THF (400 mL) at −78° C. The resulting solution was stirred at 0° C. for 15 minutes before cooling to −78° C. A solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-3-fluorobenzamide (30 g, 74.7 mmol) in THF (400 mL), cooled to −78° C., was added dropwise via cannula under positive pressure. The resulting solution was stirred 3 hours at −78° C. before being quenched with saturated ammonium chloride (200 mL). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to provide an off white solid that was triturated with methanol. The derived solid was dried under a stream of nitrogen to provide 7-bromo-3-chloro-9-fluoro-5H-chromeno[2,3-c]pyridin-5-one. MS m/z=330.1 [M+H].
Reaction SMILES: OC1C=CC=C(O)C=1[C:9]1[C:10]2[NH:14][C:13]([C:15](C3C(O)=CC=CC=3O)=[C:16]3[N:48]=[C:19]([C:20](C4C(O)=CC=CC=4O)=[C:21]4[NH:39][C:24](=[C:25](C5C(O)=CC=CC=5O)[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:10]12[CH:9]=[C:29]3[N:30]=[C:26]([CH:27]=[CH:28]3)[CH:25]=[C:24]3[NH:39][C:21]([CH:22]=[CH:23]3)=[CH:20][C:19]3=[N:48][C:16]([CH:17]=[CH:18]3)=[CH:15][C:13]([NH:14]1)=[CH:12][CH:11]=2
Reactant: Oc1cccc(O)c1-c1c2nc(c(-c3c(O)cccc3O)c3ccc([nH]3)c(-c3c(O)cccc3O)c3nc(c(-c4c(O)cccc4O)c4ccc1[nH]4)C=C3)C=C2
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
Then, a solution of 5,10,15,20-tetra(2',6'-dihydroxyphenyl)porphyrin in dry tetrahydrofuran is refluxed at the boiling point in an atmosphere of nitrogen, pivalic anhydride (40 times of the molar quantity) is added and then a small quantity of 4-dimethylaminopyridine is added. The mixture is refluxed for 10-24 hours. The reaction mixture is extracted by a suitable organic solvent (such as dichloromethane, chloroform, ether or the like), and the resulting solution is washed with dilute hydrochloric acid and with water. The organic layer is collected and the solvent is distilled away. The residue obtained is purified by, for example, silica gel chromatography to obtain a porphyrin coordinating no metal M (in the above process, the compound represented by H2T2,6 -dipivPP).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(diethyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J9) (310 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (530 mg).
Reaction SMILES: [F:1][C:2](=[CH2:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([N:15]([CH2:19][Si](C)(C)C)[CH2:16]OC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]([N:15]1[CH2:16][CH2:7][C:2]([F:1])([C:3]([O:5][CH3:6])=[O:4])[CH2:19]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=C(F)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(F)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
A 0.3 M solution of methyl 2-fluoroacrylate (4.37 g, 41.99 mmol) and DCM (140 mL) was stirred under nitrogen and cooled to 0° C. The reaction mixture was then treated with N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (10.47 g, 44.09 mmol) followed by TFA (1.56 mL, 20.99 mmol). The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was then concentrated in vacuo. The crude product was purified by SiO2 Biotage chromatography (hexanes/acetone) to afford 4.24 g (42.6%) of methyl 1-benzyl-3-fluoropyrrolidine-3-carboxylate (72a): 1H NMR (400 MHz, DMSO-d6) δ=7.35-7.23 (m, 5H), 3.72 (s, 3H), 3.63 (s, 2H), 2.97-2.80 (m, 3H), 2.54-2.48 (m, 1H), 2.43-2.30 (m, 1H), 2.18-2.04 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: COB(OC)OC
Solvent: CC#N
Solvent: O
Product: COc1c(N2CCOCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.85 g of morpholine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.30 g of the objective compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2F)[N:7]=[C:6]([C:16]([O:18]CC)=[O:17])[CH:5]=1.[OH-:21].[Na+]>O1CCOCC1>[C:9]1([N:8]2[C:4]([NH:3][C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:21])=[CH:5][C:6]([C:16]([OH:18])=[O:17])=[N:7]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
145.3 mg (3.63 mmol, 1.2 Eq) of a 60% suspension of NaH in mineral oil are suspended in 25 ml of dioxane, 700 mg (3.03 mmol) of ethyl 5-amino-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylate are added and the resulting mixture is stirred for 10 minutes at RT: Then phenylisocanate (360.6 mg, 3.03 mmol, 1 Eq) is added and the resulting mixture is heated to 80° C. for 5 hours. After cooling 7 ml of 1M NaOH are added and the resulting mixture is stirred overnight at RT. The solvent is evaporated in vacuo and the obtained crude product is subjected to HPLC chromatography. 257 mg (26%) of the pure product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][CH:13]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].CCN(C(C)C)C(C)C.[CH2:30](Cl)[O:31][CH2:32][CH2:33][O:34][CH3:35]>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:8]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][CH:13]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCCl
Reactant: Cc1onc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Yield: 60.5 %

Procedure:
The title compound was prepared by the method of Example 4(A) using N-(4-chloro-5-methyl-3-isoxazolyl)thieno[2,3-b]pyridine-3-sulfonamide (0.30 g, 0.91 mmoles), EtOAc (30 ml), DIEA (0.24 ml, 1.4 mmoles) and MEM-Cl (0.11 ml, 1.0 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.23 g (59%) of the title compound as a light yellow oil.