Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[S:9]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10]1.O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:15]([NH:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:16]
Reactant: O=C=Nc1ccsc1
Reactant: CN1CC(=O)N=C1N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccsc1
Temperature: 75 °C

Procedure:
To a stirred suspension of 2.6 (23 mM) of creatinine in 50 ml of anhydrous DMF was added a solution of 3.0 g (23 mM) of 3-thienyl isocyanate in 25 ml of toluene. The resulting mixture was heated at 75° C. for 4.5 hrs., cooled and added to 150 ml of water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.4 g of the above urea as a cream colored solid, m.p. 194°-195° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[N:18][N:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)O1.Br[C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH3:45])[S:34](=[O:44])(=[O:43])[CH2:35][C:36](=[N:39][O:40][CH2:41][CH3:42])[C:37]=2[N:38]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH2:41]([O:40][N:39]=[C:36]1[CH2:35][S:34](=[O:44])(=[O:43])[N:33]([CH3:45])[C:32]2[CH:31]=[CH:30][C:29]([C:16]3[CH:17]=[N:18][N:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:20]=3)=[N:38][C:37]1=2)[CH3:42]
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: CCON=C1CS(=O)(=O)N(C)c2ccc(Br)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCON=C1CS(=O)(=O)N(C)c2ccc(-c3cnn(-c4cccnc4)c3)nc21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To Na2CO3 (183 mg, 1.71 mmol) was added water (1.5 ml) and acetonitrile (2 ml) and the solution was degassed for 5 min with argon. 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridine (111 mg, 0.41 mmol), 6-bromo-N-ethoxy-1-methyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-imine (114 mg, 0.34 mmol) and Pd(dppf)Cl2 (25 mg, 0.034 mmol) were added sequentially followed by rinsing the flask with acetonitrile (2 ml). The mixture was stirred at 80° C. for 1.5 h followed by cooling to ambient temperature. Water and ethyl acetate were added then the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/heptane, gradient, afforded N-ethoxy-1-methyl-2,2-dioxo-6-[1-(3-pyridyl)pyrazol-4-yl]pyrido[3,2-c]thiazin-4-imine as a red solid as a single isomer.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][N:26]6[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]6)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:26]1([CH2:25][CH2:24][O:23][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:15]=2[C:14]2[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]34)[CH:11]=[CH:12][CH:13]=2)[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3c2c2cccc4c2n3C(c2ccccc2)CO4)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C2COc3cccc4c5c(OCCN6CCNCC6)cccc5n2c34)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a mixture of tert-butyl 4-{2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}-1-piperazinecarboxylate (0.406 g, 0.79 mmol) in CH2Cl2 (2 mL) is added trifluoroacetic acid (2 mL). The mixture is stirred at room temperature for 1 h then partitioned between CH2Cl2 and water. The organic layer is washed with saturated potassium carbonate, dried over anhydrous sodium sulfate and concentrated. Column chromatography (50 mL silica) using CH3OH/CH2Cl2 (8/92) with 2 drops per 100 mL of NH4OH gave 0.133 g (35%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl 2-(1-piperazinyl)ethyl ether; mp 72° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27](C)[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.BrC1C=CC(C(F)(F)[F:68])=CC=1F>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:26]=2[F:68])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1cc(C(F)(F)F)ccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 16 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine (Intermediate 74) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene in 16% yield.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:19]([SH:21])[CH3:20]>ClCCl>[OH:18][C:7]1[C:8]2[C:9](=[O:17])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH:2]([S:21][CH2:19][CH3:20])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Reactant: CCS
Solvent: ClCCl
Product: CCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (3.05 g) was dissolved in dichloromethane (100 ml) and ethanethiol (1 ml) was added. The solution was left stirring at room temperature for 6 hours, during which time the red-brown solution became yellow-green. Removal of the solvent gave a yellow solid which, recrystallised from hexane, gave 1,8-dihydroxy-10-ethylthio-9-anthrone (2.63 g, 91%) as bright yellow needles, melting point 117°-118° C. (Found: C 67.3, H 5.1, S 11.1; C16H14O3S requires C 67.1, H 4.93, S 11.2%.)
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CN
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CNc1ncc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 154a from 6-chloro-5-nitro-nicotinic acid and 2 M methylamine solution in THF.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:7]=1Cl)([O-:5])=[O:4]>>[CH3:1][NH:2][C:7]1[C:6]([N+:3]([O-:5])=[O:4])=[CH:11][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
Following the above procedure, two grams of 40% aqueous solution of methyl amine was reacted with 2.6 grams of 2,6-dinitro-4-t-butyl-chlorobenzene to give N-methyl-2,6-dinitro-4-t-butylaniline as orange needles melting at 129°-130° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>CCOCC.O>[NH2:2][CH2:1][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][OH:7]
Reactant: COC(=O)c1ccccc1CC#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: NCCc1ccccc1CO
Temperature: -20 °C
Reaction time: 5 h

Procedure:
One hundred and fifty (150) grams of methyl 2-cyanomethylbenzoate ("Yakugaku Zasshi", Vol. 86, p. 544, 1966) was added dropwise to a suspension of 60 g of lithium aluminum hydride and 211 g of aluminium chloride in ether while maintaining the suspension at -20° C. The mixture was stirred at room temperature for 5 hours, and the aluminum complex was decomposed with 520 ml of a 10 N aqueous solution of sodium hydroxide and 140 ml of water. The residue was extracted with tetrahydrofuran, dried, and distilled under reduced pressure to afford 45 g of 1-amino-2-(2-hydroxymethylphenyl)ethane as a colorless oil having a boiling point of 125° C./0.5 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][N:5](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[CH:3]=1.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:11]=[N:10][C:9]2[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5][C:4]=2[CH:3]=1
Reactant: CC(=O)N1c2ncc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Agent: O=S(=O)(O)O
Product: CC(=O)N1c2ncc(Br)cc2NC[C@@H]1C
Temperature: 0 °C
Yield: 50.2 %

Procedure:
A 50-mL round bottomed flask was charged with (S)-1-(7-bromo-3-methyl-1-tosyl-2,3-dihydropyrido[3,2-b]pyrazin-4(1H)-yl)ethanone (1.2 g, 2.83 mmol) and sulfuric acid (5.79 mL, 109 mmol). A slight exotherm was observed. The mixture was stirred until all the substrate dissolved (ca. 20-30 min). After a total of 30-45 min, the pale yellow solution was carefully pipetted onto crushed ice (50 g). The flask was rinsed with a small portion of water (ca. 2 mL), which was also added to the crushed ice. The crushed ice/aqueous solution mixture was then stirred as 10 N aqueous sodium hydroxide solution was slowly added while maintaining the internal temperature below 9° C. (with the aid of an external crushed ice/water bath). The pH was adjusted to 11-12 (a total of ca. 22 mL 10 N aqueous sodium hydroxide solution was added). After the addition was complete, the mixture was poured into a separatory funnel and extracted with dichloromethane. The dichloromethane layer was washed with water (2×30 mL) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:1 dichloromethane-ethyl acetate) to afford (5)-1-(7-bromo-3-methyl-2,3-dihydropyrido[3,2-b]pyrazin-4(1H)-yl)ethanone (384 mg, 50%) as a colorless foam. MS (ESI, pos. ion) m/z 270, 272 [M+1]+.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:1](=[O:4])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Acetic acid (1.321 g, 22.000 mmol) was dissolved in DMF (10 ml), 1-(4-fluorophenyl)methanamine (2.478 g, 19.800 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (7.770 g, 24.200 mmol) and N-ethyl-N,N-diisopropylamine (5.971 g, 46.200 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporations. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation and gave 1.344 g of N-(4-fluorobenzyl)acetamide (yield 36.5%).
Reaction SMILES: O[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH2:14])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH2:14])=[CH:4][N:3]=1
Reactant: Nc1cnc(O)c(N2CCOCC2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1cnc(Cl)c(N2CCOCC2)n1

Procedure:
Treatment of the 2-hydroxy-3-morpholino-5-aminopyrazine with phosphorus oxychloride by the method described in Preparation 13, Step B, gives the desired 2-chloro-3-morpholino-5-aminopyrazine.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:36][N:2]([CH3:1])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:34][CH3:35])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 87 %

Procedure:
A mixture of N-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 149, 230 mg, 0.47 mmol), iron (158 mg, 2.83 mmol), NH4Cl (17.7 mg, 0.33 mmol), ethanol (9 mL) and water (3 mL) was heated at reflux for 50 minutes. The reaction was judged to be incomplete so further iron (158 mg, 2.83 mmol) and NH4Cl (17.7 mg, 0.33 mmol) was added and the mixture was heated at reflux for a further 0.5 h. After cooling, the mixture was filtered and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7M methanolic ammonia in CH2Cl2 gave the title compound (187 mg, 87%) as a grey foam; 1H NMR: 1.78 (1H, m), 2.06 (1H, m), 2.20 (6H, s), 2.86 (1H, d), 2.90-3.01 (2H, m), 3.12 (1H, m), 3.15-3.23 (1H, m), 3.76 (3H, s), 3.88 (3H, s), 4.27 (2H, s), 6.72 (1H, s), 7.14 (1H, d), 7.15-7.21 (1H, m), 7.22-7.34 (1H, m), 7.50 (1H, s), 7.52 (1H, d), 7.74 (1H, s), 8.26 (1H, s), 8.28 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 458.75.
Reaction SMILES: [C:1]1([C:7]2[NH:18][C:10]3=[N:11][CH:12]=[C:13]([C:15]([OH:17])=O)[CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:1]1([C:7]2[NH:18][C:10]3=[N:11][CH:12]=[C:13]([C:15]([NH:28][C:24]4[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=4)[C:21]([O:20][CH3:19])=[O:29])=[O:17])[CH:14]=[C:9]3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnc2[nH]c(-c3ccccc3)cc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc(NC(=O)c2cnc3[nH]c(-c4ccccc4)cc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a solution of 2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (238 mg, 1 mmol, compound B of Example 1) in dimethyl formamide (5 mL) were added sequentially, methyl-3-aminobenzoate (151 mg, 1 mmol), triethylamine (0.1 mL) and BOP (500 mg, 1.2 mmol). After stirring the mixture at RT for 16 h, water was added and the solid formed was filtered, washed sequentially with water, 1N HCl, NaHCO3 and water to afford methyl 3-(2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamido)benzoate (100 mg) as a beige solid. LC/MS; (M+H)+=372.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[C:12]=1[F:26])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@@H:8]([C:11]1[C:12]([F:26])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[C:14]([Cl:17])=[CH:15][CH:16]=1)[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 18 h
Yield: 125.9 %

Procedure:
Step 2 To a solution of {(R)-1-[4-chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propyl}-carbamic acid tert-butyl ester (16.0 g, 40.7 mmol) in DCM (300 mL) was added 4M HCl in dioxane (41 mL, 162 mmol, 4 eq) and the reaction stirred for 18 h. The mixture was concentrated and then triturated with diethyl ether (˜200 mL) and the pale green solid filtered off and dried in a vacuum oven to give [3-((R)-1-Amino-propyl)-6-chloro-2-fluoro-phenyl]-pyridin-3-yl-methanone (15.0 g) as the HCl salt. Material contains about 1.3 g dioxane (from NMR ratio), which was not removed from vacuum oven drying.
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.[CH3:27][O:28][C:29]([C:31]1[N:32]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:33]=[C:34](I)[CH:35]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:27][O:28][C:29]([C:31]1[N:32]([S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])[CH:33]=[C:34]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]=2[O:8][CH3:7])[CH:35]=1)=[O:30]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2OC)cn1S(=O)(=O)c1ccc(C)cc1
Yield: 48.3 %

Procedure:
To a solution of 15 mL of 1,4-dioxane and 5 mL of water was added 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (2.05 g, 5.5 mmol) followed by 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (2.03 g, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenylphosphine)palladium (144 mg, 0.125 mmol). Upon completion of the addition, the reaction mixture was reacted at 80° C. for 30 minutes under microwave. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was diluted with 20 mL of water. After mixing well, the mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-1-(p-tolylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, yield 48%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([O:18]C)[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].Cl.CCCCCC>C1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5]
Reactant: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Temperature: 0 °C
Yield: 89.4 %

Procedure:
To a solution of 38.5 g (0.13 m) of 2,3-dichloro-4-methoxy-2'-fluorobenzophenone of Example 2A in 250 ml of dry benzene, 34.67 g (0.26 m) of AlCl3 is added. The mixture is refluxed 5 hours, poured over 100 ml concentrated HCl and 100 ml ice. The mixture is extracted with ethyl acetate, dried (Na2SO4) and evaporated to give 35 g. Trituration with hexane gives 32.8 g (89%) of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone. Analytical sample is recrystallized from ether-hexane, m.p. 128°-131° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(Br)cc1
Yield: 63.9 %

Procedure:
In 100 ml of acetone, 8.0 g of 4-bromophenol, 8.9 g of n-octylbromide, and 13 g of potassium carbonate were heated to reflux for 12 hours. After the solvent was distilled off under a reduced pressure, the residue thus obtained was extracted with isopropyl ether, washed with a 5% aqueous sodium hydroxide solution and water in turn. The ether was distilled off, and the residue was purified by a silica gel column chromatography using a mixed solvents of n-hexane and diethyl ether (10:1) and subjected to distillation to obtain 8.4 g of 4-bromo-1-n-octyloxybenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:27]([O:31][C:32](=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([NH2:42])[CH:36]=1)([CH3:30])([CH3:29])[CH3:28].O>C1COCC1.C(OCC)(=O)C>[C:27]([O:31][C:32](=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([NH:42][C:9](=[O:10])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH:36]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)CCc1ccc(Cl)c(N)c1
Reactant: C[C@H]([C@H](C(=O)Cl)c1ccc(Cl)cc1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]([C@H](C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
18 g (70.38 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl chloride were dissolved in 500 ml of THF, 18.4 ml (105.57 mmol) of N,N-diisopropylethylamine were added and the mixture was cooled to −10° C. 20.07 g (70.38 mmol) of tert-butyl-3-(3-amino-4-chlorophenyl)-propanoate, dissolved in 500 ml of THF, were then added slowly, while care was being taken not to exceed a reaction temperature of 0° C. during the addition. The mixture was then stirred for another 1 h. Water and ethyl acetate were then added to the reaction solution, the organic phase was separated off and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 30.13 g (59.74 mmol, 85% of theory) of the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9].[C:16]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.OCC(CO)(CO)CO.[Sn+2]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9].[C:16]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C[C@H](O)C(=O)O
Agent: C=C(CC(=O)O)C(=O)O
Agent: O=C1CCCCCO1
Agent: OCC(CO)(CO)CO
Product: CC(O)C(=O)O
Reaction time: 26 h

Procedure:
The polymerisation was performed like in Example 1, but the amounts of the ingredients were 846.3 g of aqueous L-Iactic acid (86 mole-%), 66.2 g of itaconic acid (6 mole-%), 67.4 g of ε-caprolactone (6 mole-%), 20.1 g of pentaerythritol (2 mole-%) and 0.39 g of tin(II) octoate, and the polymerisation time was 26 hours.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(O)=C(C(CS(C2C=CC([F:49])=CC=2)(=O)=O)=CC=1)C(OC)=O.O1C=CC(B(O)O)=C1>>[F:49][C:4]1[CH:5]=[CH:6][C:1]([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(-c2ccoc2)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(4-fluorobenzenesulphonylmethyl)-2-hydroxybenzoate (Intermediate 55) and furan-3-yl boronic acid.