Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(OCC)C>[C:19]([O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: C=CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A three-neck round-bottom flask fitted with an addition funnel, thermometer and a mechanical stirrer was charged with 100 ml of water, 40 g (0.20M) of p-hydroxybenzophenone and 8.8 g of sodium hydroxide. The flask was cooled in an ice bath to 8°-10° C., then 20 g (0.22) of acryloyl chloride were added dropwise while holding the temperature at 8°-10° C. When the addition was complete, the reaction mixture was stirred for an additional half hour. Then 150 ml of diethyl ether was added to dissolve the product of the reaction. The ether layer was separated from the water layer and washed twice with 3% sodium hydroxide and twice with water. The solution was dried over magnesium sulfate, filtered and stripped. An amount of 43.0 g of an oily product was obtained and purified by recrystallization from absolute ethanol, from which an amount of about 34.7 g of white crystalline product was isolated.
Reaction SMILES: [Cl:1][C:2]1[N:10]2[C:5]([C:6](=[O:12])[NH:7][C:8]([CH3:11])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.O>[CH2:19]([N:7]1[C:6](=[O:12])[C:5]2=[CH:4][CH:3]=[C:2]([Cl:1])[N:10]2[N:9]=[C:8]1[CH3:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nn2c(Cl)ccc2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred mixture of 7-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.10 g, 5.99 mmol) and Cs2CO3 (2.25 g, 6.9 mmol) in dioxane (20 mL) was added benzyl bromide (0.76 mL, 6.16 mmol) and heated at 95° C. under nitrogen for 3 h. The reaction mixture was cooled to rt, diluted with water and stirred for 1 h. The precipitated solid was collected and washed with water, dried in vaccum over P2O5 at 35° C. to give the title compound (1.41 g, 87%): 1H NMR (CDCl3) δ 7.26 (m, 2H), 7.20 (m, 1H), 7.13 (m, 2H), 6.98 (d, 1H, J=4.4 Hz), 6.40 (d, 1H, J=4.4 Hz), 5.19 (s, 2H), 2.35 (s, 3H); 3C NMR (CDCl3) δ 154.0, 148.0, 135.8, 129.0, 127.8, 126.5, 117.7, 116.5, 109.7, 108.2, 45.7, 20.1; MS (ESI+) 274.04, 276.06 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:31]=[CH:30][CH:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1cccc(C(=O)OCC)c1

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino) hexanoic acid (3.64 g) and ethyl 3-aminobenzoate (1.47 ml) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.57 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from toluene to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)hexanamide (1.85 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([O:5][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)=[O:4]
Reactant: O=C(O)[C@@H](O)CC1CC1
Reactant: COc1ccc(CCl)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](O)CC2CC2)cc1

Procedure:
The title compound was prepared from 1.0 g (7.6 mmol) of 2-(S)-hydroxy-3-(cyclopropyl)propanoic acid (from EXAMPLE 21, Step A), 1.6 mL (11.4 mmol) of TEA and 1.6 mL (11.8 mmol) of 4-(methoxy)benzyl chloride in 10 mL of DMF using a procedure analogous to that described in EXAMPLE 20, Step G to provide 1.70 g (88%, ee=97.5%) of the title compound: RF: 0.20 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) 8-0.01-0.09 (m, 2H), 0.40-0.45 (m, 2H), 0.84 (m, 1H), 1.55-1.67 (m, 2H), 2.82 (br m, 1H), 3.81 (s, 3H), 4.25 (br m, 1H), 5.14 (ABq, J=11.8, 2H), 6.90 (d, J=8.7, 2H), 7.29 (d, J=8.7, 2H). HPLC Conditions:
Reaction SMILES: Cl.[C@H:2]12[CH2:18][C@H:5]([N:6]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][CH:9]=3)[CH2:7]1)[CH2:4][NH:3]2.C(N(C(C)C)CC)(C)C.[C:28](Cl)(=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33]>ClCCl>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:6]2[CH2:7][C@@H:2]3[CH2:18][C@H:5]2[CH2:4][N:3]3[C:28](=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33])=[CH:9][CH:10]=1
Reactant: CCC/C=C/C(=O)Cl
Reactant: c1ccc2c(N3C[C@@H]4C[C@H]3CN4)ccnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC/C=C/C(=O)N1C[C@@H]2C[C@H]1CN2c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To 4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-5-yl]quinoline hydrochloride (26.2 mg, 0.1 mmol), dissolved in 0.5 ml anhydrous dichloromethane, polymer-supported diisopropylethylamine (80 mg, 3-4 mmol/g) was added followed by (E)-hex-2-enoyl chloride (19.9 mg, 0.15 mmol) dissolved in anhydrous dichloromethane (1 ml). The mixture was shaken at room temperature for 20 minutes, filtered and the filtrate evaporated to dryness under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 9 mg of a solid (0.028 mmol, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:3]=1.C(O)(=O)C.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:19]1([CH2:22][NH:1][C:2]2[CH:6]=[CH:5][N:4]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1
Reactant: N#Cc1ccc(-n2ccc(N)n2)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#Cc1ccc(-n2ccc(NCC3CC3)n2)cc1
Yield: 53.8 %

Procedure:
Dissolve 4-(3-amino-pyrazol-1-yl)-benzonitrile (200 mg) in 1,2-dichloroethane (12 mL). Add acetic acid (0.36 mL) and cyclopropanecarboxaldehyde (0.08 mL, 1.06 mmol) and stir the mixture at room temperature under a nitrogen atmosphere for 40 min. Add sodium triacetoxyborohydride (674 mg, 3.18 mmol) and stir for 3 h at room temperature. Quench the reaction with water. Extract the mixture three timed with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (136 mg, 54%) that was used without further purification.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1([CH3:17])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1.N>S(=O)(=O)(O)O>[CH3:6][C:7]1([CH3:17])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: CC1(C)Cc2ccccc2C=N1
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)Cc2ccc([N+](=O)[O-])cc2C=N1
Temperature: 60 °C
Yield: 89.8 %

Procedure:
To a stirred solution of potassium nitrate (2.53 g) in sulfuric acid (14 ml ) at 0° C. was added dropwise a solution of 3,4-dihydro-3,3-dimethyl isoquinoline (3.68 g; 23 mmol) [prepared according to the procedure of T. J. N. Watson, J. Org. Chem., 1998, 63, 406] in sulfuric acid (13.5 ml). The resultant solution was stirred at room temperature for 1.5 h and then heated to 60° C. for 4.5 h. The solution was then cooled to room temperature, and poured on to ice.; 0.880 ammonia was added until the solution was neutral, and the product was extracted into dichloromethane (×3). The combined organic phases were, dried over magnesium sulphate, and then evaporated in vacuo to afford the title compound (4.22 g). 1H NMR (CDCl3)δ: 1.27 (6H, s), 2.85 (2H, s), 7.34 (1H, d, J=8 Hz), 8.17 (1H, d, J=2Hz), 8.23 (1H, dd, J=8, 2Hz), 8.33 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:38]([CH:35]4[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]4)=[O:39])[CH2:21][CH2:20]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.5 %

Procedure:
Under an inert atmosphere ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(2-piperidin-4-yl-ethyl)-propyl-amine (200 mg, 0.61 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (139 mg, 0.61 mmol), EDCl (117 mg, 0.61 mmol), HOBT (82 mg, 0.61 mmol), triethylamine (0.17 mL, 1.2 mmol), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in-vacuo. The residue was taken-up in EtOAc (50 mL) and washed with water (30 mL), 1 N NaOH (30 mL), brine (30 mL), and dried (MgSO4). The solution was filtered and concentrated to afford an oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (260 mg) which was deprotected with 10 mL trifluoroacetic acid, as described herein, to afford (4-{2-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-ethyl}-piperidin-1-yl)-piperidin-4-yl-methanone (200 mg) 116[M+H]+=478.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH2:39][CH2:40][CH2:41][OH:42]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:39][CH2:40][CH2:41][OH:42])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: NCCO
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(NCCO)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting material: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and 2-aminoethanol.
Reaction SMILES: C([O:5][P:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:16]=1)[F:14])(=[O:12])[O:7]C(C)(C)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:17]2[CH:16]=[C:15]([CH:13]([P:6](=[O:5])([OH:7])[OH:12])[F:14])[CH:20]=[CH:19][CH:18]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=P(O)(O)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
The above fluoromethylphosphonic acid di-tert-butyl ester (1.29 g, 2-7 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2.5 ml) was added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml) and a solid was formed in the aqueous phase. This was filtered off and dried in vacuo at 50° C. affording 55 mg (6%) of the title compound as a solid,
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([S:28]([CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:30])=[O:29])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:32]([CH2:31][S:28]([C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:30])=[O:29])[CH:33]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)(=O)Cc1cccc(N)c1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Product: CC(C)(C)S(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1

Procedure:
Example 4 was prepared under similar conditions as described in the preparation of Example 3 using 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and 3-[(tert-butylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The batch was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N+:7]([CH3:10])([CH3:9])[CH3:8])(=O)[OH:2].C(O)(=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[Na+]>>[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[C:1]([O:4][CH2:5][CH2:6][N+:7]([CH3:10])([CH3:9])[CH3:8])(=[O:2])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]
Reactant: O=C(O)c1ccccc1O
Reactant: C[N+](C)(C)CCOC(=O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: C[N+](C)(C)CCOC(=O)c1ccccc1O

Procedure:
To an aqueous solution containing 28.5 grams of choline carbonate is added 13.8 grams of salicylic acid and 12.6 grams of sodium sulfite. The mixture is stirred until complete solution is achieved and the ebullition of gases cease. The solution of choline salicylate sodium sulfite thus formed is sufficiently pure to be used for further pharmaceutical manufacture. The compound choline salicylate sodium sulfite may be obtained by removing the solvent under high vacuum with the aid of gentle warming. The compound is a colorless crystal, that is highly hygroscopic, rapidly absorbing water on exposure to the atmosphere. An 0.1 molar solution of choline salicylate sodium sulfite has a specific electrical conductivity of 8.16× 10-3.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(F)c1F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(F)c1F
Yield: 87.4 %

Procedure:
2,3-Difluorobenzoic acid (11.6 g, 0.07 mol), thionyl chloride (37.5 ml, 61.1 g, 0.5 mol) and toluene (80 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (10.8 g) as a clear yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.C[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25]C2.C(NC1C=CC=CC=1)C>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([N:27]([CH2:26][CH3:25])[C:28]1[CH:29]=[CH:30][CH:21]=[CH:22][CH:23]=1)=[O:9]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Solvent: CCNc1ccccc1
Product: CCN(C(=O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)c1ccccc1

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (Example 80, Step 1) and 6-methyl-1,2,3,4-tetrahydro-quinoline with ethyl-phenyl-amine ([CAS RN 103-69-5]). MS (ISP): 405.0 [M+H]+.
Reaction SMILES: C(O[CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[O:6]1)(=O)C.[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:24]([O:23][P:22]([O:26][CH2:27][CH3:28])([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[O:6]1)=[O:29])[CH3:25]
Reactant: CC(=O)OC1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Reactant: CCOP(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of (±)-2-acetoxy-5-(p-toluenesulfonoxymethyl)-tetrahydrofuran (example 59) (1.63 g, 5.19 mmol) and triethyl phosphite (1.16 mL, 6.75 mmol) in methylene chloride (75 mL) at −35° C. was added titanium (IV) chloride (0.57 mL, 5.19 mmol) dropwise. The yellow solution was then stirred at −35° C. for 30 min and then at 0° C. for 30 min. Saturated NaHCO3 (75 mL) was then added to the reaction mixture and the suspension was then filtered through a CELITE diatomaceous earth. The mixture was then partitioned followed by extraction of the aqueous phase with methylene chloride (2×50 mL). The combined extracts were then washed with brine (100 mL), dried (MgSO4) and concentrated. The residue was then purified by chromatography eluting with 75% EtAc/hexanes-EtAc giving the title compound as 1:1 mixture of cis and trans isomers (1.42 g, 78%).
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[C:35]([CH3:36])=[C:34]2[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]2[C@@H:37]2[CH2:39][C@@H:38]2[F:40])=[CH:28][CH:27]=1>CS(C)=O>[F:40][C@H:38]1[CH2:39][C@H:37]1[N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([N:15]3[CH2:16][CH2:17][C@@H:13]([C:10]4([NH:8][CH3:9])[CH2:11][CH2:12]4)[CH2:14]3)[C:35]=2[CH3:36])[C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32]1
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3C)C2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (118 mg, 436 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml, 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (122 mg, 436 μmol) was added thereto and heated under reflux in an oil bath of 100° C. for 18 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (2 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by a preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 72.8 mg (42%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[I:8][C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH2:18])=[CH:11][CH:10]=1.O>C(O)(=O)C>[I:8][C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH:18][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)c2c1OCO2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(I)c2c1OCO2
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Acetic anhydride (14.25 ml) was added dropwise to a mixture of intermediate (2-a) (36.6 g) in acetic acid (500 ml), stirred at room temperature. The reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured out into water (500 ml). The precipitate was filtered, washed with water, then dried, yielding 39.29 g (92.6%) of N-(7-iodo-1,3-benzodioxol-4-yl)acetamide (intermediate 2-b).
Reaction SMILES: C([CH:3]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1)[C:4]([OH:6])=[O:5])C.[H-].[Na+].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1.CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[CH:9]=[C:8]2[CH2:7][CH2:3][C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(Cc1c[nH]c2ccc(OC)cc12)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32926.4 %

Procedure:
In THF(640 ml)-DMF(130 ml) was dissolved ethyl 3-(5-methoxy-1H-indol-3-yl)propionic acid (99.3 g, 0.4 mol). To the solution was added in limited amounts, under ice-cooling, a suspension of 60% sodium hydride in oil (18.4 g, 0.46 mol) in THF(50 ml)-DMF(10 ml). The mixture was stirred at room temperature for one hour, and the mixture was again cooled with ice. To the mixture was gradually added p-toluenesulfonyl chloride (83.9 g, 0.44 mmol), followed by stirring for a further 3 hours at room temperature. The reaction mixture was poured into an ice-saturated NH4Cl solution (180 ml). The upper layer was subjected to extraction with ethyl acetate (100 ml+500 ml). The extract solution was washed with a saturated aqueous saline solution (300 ml×2), followed by drying over Na2SO4. The residue was purified by means of silica gel chromatography (eluent: hexane-ethyl acetate (2:1)) and then were added hydrochloric acid (100 ml) and acetic acid (400 ml), and was refluxed for 1 hour. The reaction mixture was concentrated and the resulting crystals were washed with water, dried under reduced pressure and washed with methanol-isopropyl ether (1:3) to obtain the title compound (54.1 g: m.p. 172°-174° C.)
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C@H:6]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[C:7]([O:9]CC1C=CC=CC=1)=[O:8])=[O:2]>C(OCC)(=O)C.[H][H].[Pd]>[CH:1]([CH2:3][CH2:4][CH2:5][C@H:6]([N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])[C:7]([OH:9])=[O:8])=[O:2]
Reactant: O=CCCC[C@@H](C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=CCCC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 102.4 %

Procedure:
Benzyl 5-formyl-2(S)-phthalimidopentanoate (4.72 g) was dissolved in 230 ml of ethyl acetate and hydrogenated at 5 psig of hydrogen over 0.82 g of 10% palladium on carbon. After the uptake of 1 equivalent of hydrogen, catalyst was removed by filtration. Removal of solvent afforded 3.64 g of 5-formyl-2(S)-phthalimidopentanoic acid.