Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2c[nH]c3ncc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cc23)cnn1Cc1cccc(F)c1
Yield: 51 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (250 mg, 0.346 mmol) was hydrolyzed by lithium hydroxide (72.8 mg, 1.734 mmol), THF/Methanol/water (2/3/1 ml) to yield 100 mg (52% yield) of the titled compound. 1H NMR (CDCl3, 400 MHz): δ 9.28 (S, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.59-7.52 (m, 3H), 7.34-7.27 (m, 2H), 7.05-6.94 (m, 4H), 5.32 (s, 2H), 3.61-3.60 (m, 4H), 3.19 (s, 4H), 2.40 (s, 3H), 1.49 (s, 9H). MS: m/z=657.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:12]1([C:10]2[S:11][C:7]3[C:8](=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][CH:6]=3)[N:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1cccc2sc(-c3ccccc3)nc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc2sc(-c3ccccc3)nc12

Procedure:
26.5 g (0.11 mol) of the compound from Example III were dissolved in 400 ml of methylene chloride and the mixture was boiled under reflux with 50 g of manganese dioxide (active) overnight. After cooling, the solid was filtered off with suction and the filtrate was concentrated. Yield: 25 g (85% of theory) M.p.: 127°-128° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C:61]([O:65][C:66](=[O:75])[CH:67]=[C:68]1[CH2:71][CH:70]([C:72](O)=[O:73])[CH2:69]1)([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:72]([CH:70]2[CH2:69][C:68](=[CH:67][C:66]([O:65][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:75])[CH2:71]2)=[O:73])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Reactant: CC(C)(C)OC(=O)C=C1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C(=O)C1CC(=CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.4 %

Procedure:
HATU (148 mg, 0.39 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (138 mg, 0.35 mmol), DIEA (0.068 mL, 0.39 mmol) and 3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutanecarboxylic acid (83 mg, 0.39 mmol) in DMF (4 mL), and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture was added water to give pale-yellow precipitates. The precipitate was collected by filtration to give tert-butyl 2-(3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutylidene)acetate (138 mg, 0.236 mmol, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]([F:59])([F:58])[F:57])O1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[K+].ClCCl>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(#N)C>[CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[C:56]([F:59])([F:58])[F:57])[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccccc2C(F)(F)F)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)(F)F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Yield: 57.3 %

Procedure:
In a microwave vial was placed ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester (132.7 mg, 0.205 mmol), 4,4,5,5-tetramethyl-2-(2-trifluoromethyl-phenyl)-1,3,2-dioxaborolane (278.3 mg, 1.02 mmol, 5.0 eq.), sodium carbonate (65.0 mg, 0.61 mmol, 3.0 eq.), potassium acetate (60.2 mg, 0.61 mmol, 3.0 eq.), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexed with dichloromethane (1:1) (33.4 mg, 0.041, mmol, 0.20 eq), ACN (10 mL), and water (2.5 mL). The reaction mixture was degassed with N2 for 10 minutes and then subjected to microwave irradiation at 100° C. for 40 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and then filtered through a pad of Celite. The filtrate was washed with 50% brine/water, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via flash column chromatography eluted with 50 to 100% ethyl acetate/heptane to give 83.9 mg (57.4%) of desired product as a foam. MS (ESI) m/z: 714.4 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([C:28]([F:31])([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:32](OCC)=[O:33].[O-]CC.[Na+].Cl>C(O)C>[OH:33][CH:32]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([C:28]([F:31])([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c(C(F)(F)F)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c(C(F)(F)F)n1
Temperature: 78 °C
Yield: 81 %

Procedure:
1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.205 g, 0.548 mmol) and ethyl formate (0.132 mL, 1.64 mmol) were dissolved in anhydrous ethanol (1.1 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.00 mL, 2.74 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.178 g, 0.444 mmol, 81%).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH2:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3])(=[O:21])[CH3:20]
Reactant: C=Cc1ccc(C(C)(C)O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=Cc1ccc(C(C)(C)OC(C)=O)cc1
Yield: 48 %

Procedure:
A mixture of 6.7 g of 1-(1-hydroxy-1-methylethyl)-4-ethenyl-benzene and 4.0 g of pyridine in 100 ml of dichloromethane was stirred while 4.0 g of acetyl chloride in 20 ml of dichloromethane was added dropwise. After the addition was complete, the mixture was refluxed gently overnight. After cooling, an additional 30 ml of dichloromethane was added and the mixture was then washed with 50 ml of cold 5% aqueous HCl, and then several times with 30 ml portions of water. After drying over magnesium sulfate, filtering, and concentrating, the crude product was purified by HPLC using ethyl/acetate hexane as eluent. This method affords 4.05 g (47.5% yield) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C1COCC1.CCCCCC>[OH:17][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Reaction time: 0.67 h
Yield: 45.2 %

Procedure:
To a solution of 1-bromo-2-(trifluoromethyl)benzene (1.18 g, 5.24 mmol) in THF (20 mL) cooled at −78° C. was dropwise added a 1.60 M solution of n-butyllithium in hexane (3.4 mL). After being stirred for 40 min; a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.0 mmol) in THF (3 mL) was added and the solution stirred for 1 h at −78° C. The reaction was quenched with saturated ammonium chloride. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated to give 0.78 g of a white solid which was used for the next reaction without purification. MS calculated for C17H22F3NO3: (M+H) 346; found 246.0 (M-Boc+1).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:4]=1.[H-].[Na+].[K].[I-].[K+].[Cl:22][CH2:23][CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:27]>CN(C)C=O>[ClH:22].[ClH:1].[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26](=[O:27])[CH2:25][CH2:24][CH2:23][NH:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([C:5]3[CH:4]=[C:3]([F:2])[CH:8]=[CH:7][C:6]=3[CH3:9])[CH2:11][CH2:12]2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(F)cc1[C@H]1CC[C@H](N)CC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1[C@H]1CC[C@H](NCCCC(=O)c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a suspension of 1.73 g. of trans 4-(p-fluoro-o-tolyl)cyclohexylamine hydrochloride (I) (prepared as in Example 51) in 40 ml. of dimethylformamide, 0.31 g. of 56% sodium hydride in mineral oil is added. After about 1 hour of stirring, 2 g. of potassium, 1.2 g. of potassium iodide and 1.82 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone are added successively. The mixture is stirred in an oil bath at about 90° C. for about 18 hours, allowed to cool and the solvent removed under vacuum by a rotary evaporator. The residue is dissolved in benzene and water; the organic layer is washed with water and brine and then taken to dryness. The residue is dissolved in 30 ml. of methanol, 15 ml. of 2.5N hydrochloric acid is added and the mixture stirred for about 1 hour, then concentrated under vacuum. The precipitated solid is collected on a filter and on recrystallization from methanol:2.5N hydrochloric acid gives pure trans 4'-fluoro-4-{[4-(p-fluoro-o-tolyl)cyclohexyl]amino}butyrophenone hydrochloride (I) melting at 215° to 218° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:21]2=[N:22][N:23]([CH3:25])[N:24]=[C:20]2[CH:19]=1>>[CH3:25][N:23]1[N:22]=[C:21]2[CH:26]=[CH:27][C:18]([CH2:17][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)=[CH:19][C:20]2=[N:24]1
Reactant: Cn1nc2ccc(CCl)cc2n1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Product: Cn1nc2ccc(CN(c3ccc([N+](=O)[O-])cc3)n3cnnc3)cc2n1

Procedure:
Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 5-chloromethyl-2-methyl-2H-benzotriazole
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[CH:6][N:7]=1.[CH:11]([NH:13][NH:14][CH:15]=O)=O.CN(C=O)C.C(OCC)(=O)C>O>[N:13]1[N:14]=[CH:15][N:1]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:11]=1
Reactant: Nc1cc2cc[nH]c2cn1
Reactant: O=CNNC=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1cc2cc(-n3cnnc3)ncc2[nH]1
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
5-Amino-1H-pyrrolo[2,3-c]pyridine (2 g, 15 mmol), diformylhydrazine (1.32 g, 15 mmol) and dry DMF (1.5 mL) were heated at 170° C. under nitrogen for 4 hours. After cooling, ethyl acetate (10 mL) and water (10 mL) were added. The mixture was stirred vigorously for 15 min. The resulting precipitate was collected by filtration, and chromatographed on silica eluting with a gradient of 5 to 7 to 10% MeOH in DCM to give a yellow solid. This was triturated with ether to give the title compound (1.65 g, 59%) as a yellow/green crystalline solid. mp 254°-257° C. 1H NMR (360 MHz, d6 -DMSO) δ 6.63 (1H, d, J=3.1Hz), 7.79 (1H, d, J=3.0Hz), 7.99 (1H, s), 8.71 (1H, s), 9.21 (2H, s) and 11.89 (1H, br s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:15]([N:14]([CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCCCCCBr
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCCCCN(C)Cc1ccccc1
Yield: 163.9 %

Procedure:
Ethyl 7-bromoheptanoate (6.00 g, 25.3 mmol) was dissolved in acetonitrile (30 mL), N-methyl-benzylamine (6.53 mL, 50.6 mmol) and potassium carbonate (13.99 g, 101 mmol) were added at room temperature, and the mixture was heated to reflux for 6 hours. The mixture was left to stand for cooling, and the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give crude ethyl 7-[benzyl(methyl)amino]heptanoate (11.5 g) as a light yellow oily substance. The resulting crude product was dissolved in 60 mL of ethanol, 10% palladium-carbon (0.72 g) was added, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 16 hours. The mixture was left to stand for cooling, insoluble matter was removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (ethyl acetate:methanol=10:0→10/1, v/v) to give the title compound (4.67 g; yield, 98%) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:30]([C:29]4[CH:28]=[C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:24])=[O:25])[CH:35]=[CH:34][CH:33]=4)=[O:31])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Product: O=C(c1cccc(NS(=O)(=O)c2ccccn2)c1)N1CCN(c2nc3ccc(Cl)cc3s2)CC1

Procedure:
Compound 11 is prepared using synthesis method 2 using intermediates 3g and 5a (yield: 60%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:12]=1)[C:5](O)=[O:6].S(Cl)([Cl:28])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:12]=1)[C:5]([Cl:28])=[O:6]
Reactant: CCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2F)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2F)nc1

Procedure:
3-Fluoro-4-(5-n-octyloxypyrimidine-2-yl)benzoic acid (1.70 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 3-fluoro-4-(5-n-octyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:23](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([C@H:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccs1)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(2R)-2-(tert-Butoxycarbonylamino)-3-(thiophen-2-yl)propionic acid (5.00 g; 18.4 mmol) was dissolved in tetrahydrofuran (60 ml). Methyliodide (9.2 ml; 147 mmol) was added and the solution was cooled to 0° C. Sodiumhydride (60% in oil; 1.90 g; 55.3 mmol) was added in portions and the reaction mixture was stirred at room temperature for two days. Ethyl acetate (50 ml) and water (20 ml) were added dropwise. The solvent was removed in vacuo and the residue was dissolved in ether (30 ml) and water (30 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium hydrogencarbonate (30mi). The aqueous phase were mixed. Citric acid (5% (aq)) was added to pH 3 and the aqueous phase was extracted with ethyl acetate (4×30 ml). The combined organic phases were washed with water (2×30 ml), aqueous sodium thiosulfate (5%; 30 ml), water (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in ether (10 ml) and dicyclohexylamine (8.5 ml) was added and the mixture was left in a refrigerator overnight. The precipitate was filtered and washed with ether (2×15 ml) and then redissolved in methylene chloride and washed with a mixture of water (15 ml) and sodium hydrogensulfate (15 ml; 10%(aq)). The aqueous phase was washed with methylene chloride (3×15 ml). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo to give 5.10 g of (2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(thiophen-2-yl) propionic acid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:22])[C:13]([OH:21])=[CH:14][N:15]3[CH:18]([CH3:20])[CH3:19])=[CH:10][C:9]=2[F:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:22])[C:13]([O:21][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:14][N:15]3[CH:18]([CH3:20])[CH3:19])=[CH:10][C:9]=2[F:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: CC(C)n1cc(O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cn(C(C)C)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5.0 ml DMF solution of 144 mg of 7-(cyclohexylamino)-6-fluoro-3-hydroxy-1-isopropylquinolin-4(1H)-one were added 313 mg of potassium carbonate and 100 μl of ethyl bromoacetate in that order, followed by overnight stirring at room temperature. Aqueous saturated ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 159 mg of ethyl {[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetate.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O)C.C(=O)([O-])O.[Na+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 12.9 parts of 4-(1-piperazinyl)phenol dihydrobromide, 40 parts of ethanol and 50 parts of water are added 12.6 parts of sodium hydrogen carbonate. Then there are added dropwise 6.4 parts of methanesulfonyl chloride at 0° C. Upon completion, stirring is continued overnight. The precipitated product is filtered off and taken up in water. The whole is alkalized with a sodium hydroxide solution and stirred for 30 minutes at room temperature. The mixture is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and dried, yielding 2.8 parts of 1-(4-hydroxyphenyl)-4-(methylsulfonyl)piperazine; mp. 204.9° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].N1C(C)=CC(C)=CC=1C>CCCCCC.CC(C)=O>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
Methyl pheophorbide-a (100 mg, 0.17 mmol) was added to commercially available 2,4,6-collidine (25 mL, Aldrich) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 10 min, the reaction was shown to have reached 100% completion by HPLC peak area. The solution was cooled to room temperature and solvent removed under reduced pressure. Hexane (10 mL) was added to the flask and the precipitated residue collected by filtration and rinsed with hexane to give methyl pyropheophorbide-a (71 mg, 78%).