Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][CH3:15])[C:7]1=[O:16])=O>CO.C(Cl)Cl>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:16])[C@@H:8]1[O:14][CH3:15])(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC)[C@H]1SC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1C(=O)N[C@@H]1SC(C)=O

Procedure:
A solution of 71.20 mg of 2[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-2-oxoacetic acid methyl ester (crude product) in 10 ml of 1% aqueous methanol is stirred overnight at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH3:2].[CH2:15]([O:17][C@H:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[CH:22][CH:21]=1)[CH3:16].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:15]([O:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=2)=[O:28])=[CH:29][CH:30]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:16]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCNCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of N-ethyl-N-[4-(trifluoromethyl)benzyl]amine (0.213 g, 1.05 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g, 1.00 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.337 g, 1.05 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (90 mL) and the organic phase was washed with 5% HCl (2×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.339 g (70%) of a colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([NH:25][CH3:26])=[O:24])[C:5]([CH2:18][OH:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([O:19][CH2:18][C:5]1[N:4]([C:20]2[CH:21]=[C:22]([C:23]([NH:25][CH3:26])=[O:24])[CH:27]=[CH:28][C:29]=2[CH3:30])[C:3](=[O:31])[C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:6]=1)(=[O:40])[CH3:39]
Reactant: CNC(=O)c1ccc(C)c(-n2c(CO)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(C)c(-n2c(COC(C)=O)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide, (225 mg, 0.50 mmol) stirred in CH2Cl2 was added pyridine (55 μL, 0.69 mmol). To the resulting homogeneous solution was then added acetic anhydride (47 μL, 0.51 mmol). The mixture was stirred at rt for 3 h. Additional pyridine (150 μL, 1.8 mmol) and acetic anhydride (100 μL, 1.05 mmol) were then added and the reaction was allowed to stir overnight at rt. The reaction was then quenched with 1N NHCl4 and diluted with CH2Cl2. The layers were separated and the organic layer was then extracted with CH2Cl2 (3×). The organics were then combined, dried, and concentrated in vacuo. The residue was then triturated with Et2O and filtered to give (150 mg, 61%) an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (br s, 1H), 7.87 (app d, J=7.8 Hz, 1H), 7.74-7.69 (m, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.40 (app t, J=8.1 Hz, 1H), 7.28-7.19 (m, 1H), 6.91 (s, 1H), 5.43 (s, 2H), 4.60 (s, 2H), 2.79 (s, 3H), 2.06 (s, 3H), 1.94 (s, 3H). ES-HRMS m/z 535.0676 (M+H calcd for C24H22N2F2BrO5 requires 535.0675).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[N:14]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1)=[O:12]>O1CCCC1>[I:1][C:16]1[CH:17]=[C:13]([C:11]([O:10][CH3:9])=[O:12])[N:14]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:25]([CH3:27])[CH3:26])[CH:15]=1
Reactant: COC(=O)c1cccn1[Si](C(C)C)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)cn1[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.4 %

Procedure:
N-Iodosuccinimide (653 mg, 2.9 mmol) was added to a stirred solution of 2-methoxycarbonyl-1-triisopropylsilylpyrrole (815 g, 2.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for two days. The solvent was then removed in vacuo and the oily residue suspended in hexanes (50 mL) with vigorous stirring. The insoluble solid was removed by filtration and the filtrate concentrated in vacuo. Purification of the residue by column chromatography using hexanes gave 3-iodo-5-methoxycarbonyl-1-triisopropylsilylpyrrole (1.044 g, 88%) as a white crystalline solid, mp 81-83° C.: 1H NMR (CDCl3) δ 7.18 (d, 1H, J=1 5 Hz), 7.09 (d, 1H, J=1.5 Hz), 379 (s, 3H), 1.74 (sept, 3H, J=7.6 Hz), 1.11 (d, 18H, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([CH2:20]O)[CH:17]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:15]=2)=[C:8]([O:30][CH3:31])[CH:7]=1.[CH3:33][O:34][C:35](=[O:49])/[C:36](/[C:47]#[N:48])=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([O:45][CH3:46])[CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:33][O:34][C:35](=[O:49])/[C:36](/[C:47]#[N:48])=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:20][C:18]2[CH:19]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:32])=[CH:7][C:8]=3[O:30][CH3:31])[CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:17]=2)=[C:40]([O:45][CH3:46])[CH:39]=1
Reactant: COC(=O)/C=C/c1ccc(OCc2cc(CO)cc(OCCCCCCCl)c2)c(OC)c1
Reactant: COC(=O)/C(C#N)=C/c1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(OCc2cc(COc3ccc(/C=C(\C#N)C(=O)OC)cc3OC)cc(OCCCCCCCl)c2)c(OC)c1
Temperature: 0 °C
Yield: 73.7 %

Procedure:
1 g (2.2 mmol) (E)-3-[4-[3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]benzyloxy]-3-methoxyphenyl]acrylic acid methyl ester was added to a solution of 0.62 g (2.7 mmol) 2-cyano-(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid methyl ester and 0.73 g (2.7 mmol) triphenylphosphine in 10 ml tetrahydrofuran. The solution was cooled to 0°C. and then 1.1 ml (2.7 mmol) of a solution of azodicarboxlic acid diethyl ester in toluene were added dropwise. The mixture was allowed to react for 1 hour at 0° C. and then it was poured into an ice cold 1 M solution of HCl. The mixture was extracted three times with tert.-butyl-methylether/ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfates filtered and concentrated in vacuum. The solid residue was first treated with diethylether, filtered and then it was recrystallized twice from tert.-butyl-methylether to give 1.1 g (79%) of (E)-3-[4-[[3-[(6-Chlorohexyl)oxy]-5-[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]benzyl]oxy)-3-methoxyphenyl]-2-cyanoacrylic acid methyl ester in form of slightly yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=1>CN(C=O)C>[CH3:1][C:2]1([C:18]([NH:60][C:59]2[CH:61]=[CH:62][C:56]([CH3:55])=[CH:57][CH:58]=2)=[O:19])[CH2:3][CH2:4][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
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
Product: Cc1ccc(NC(=O)C2(C)CCN(c3ncnc4[nH]cc(C)c34)CC2)cc1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from example 6, step B, (0.020 g, 0.073 mmol) in DMF (1 mL) were added BOP reagent (0.065 g, 0.15 mmol), triethylamine (0.019 mL, 0.15 mmol), and 4-methylaniline (0.012 mL, 0.11 mmol). The reaction was stirred overnight and concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.0133 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)C(C)C)(C)C.[I-].[Na+].[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>C(O)C>[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: COCCN
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COCCNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 90 °C

Procedure:
To a solution of 2-chloro-5-(2-chloroethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.2 g) and N,N-diisopropylethylamine (0.27 ml) in ethanol (5 ml) was added sodium iodide (0.08 g) and 2-methoxyethylamine (0.11 g). The reaction vessel was sealed and the reaction mixture heated at 90° C. for 15 h before concentration under reduced pressure. The residue was partitioned between ethyl acetate and sodium hydrogencarbonate solution, and the aqueous phase extracted with additional ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by NPHPLC (eluting with 0-25% ethanol in dichloromethane) to afford 5-(N-(2-methoxyethyl)-2-aminoethyl)amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a semi-solid. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentrated under reduced pressure to leave the title compound as a white solid (0.085 g).
Reaction SMILES: [C:1]([C:4](C(OCC)=O)([CH2:15][CH2:16][CH2:17][CH:18]([O:28]C(=O)C)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:15][CH2:16][CH2:17][CH:18]([OH:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CC#CCCCC(=O)OC)(CCCC(COc1ccc(F)cc1)OC(C)=O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C(CC#CCCCC(=O)O)CCCC(O)COc1ccc(F)cc1

Procedure:
Methyl 8-acetyl-8-ethoxycarbonyl-12-acetoxy-13-(4-fluorophenoxy)-5-tridecynoate (40.00 g., 0.079 mole) is added to a solution of sodium hydroxide (18.96 g.; 0.474 mole) in water (132.7 ml.) and methanol (462.9 ml.). The resulting solution is allowed to stand for 191/2 hours at 55°.
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([OH:3])=[O:2].Cl[C:29]1[N:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32]>>[C:1]([C@@H:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:29]2[C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=[CH:36][N:37]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(O)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 96, 2-[1-carboxy-2-(4-hydroxy-phenyl)-ethylamino]-6-chloro-quinoline-3-carboxylic acid is reacted with 2-chloronicotinic acid to provide the title compound in a form of diammonia salt after chromatography on silica (aq. ammonia containing eluent).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCCCCC(=O)O
Product: CCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and nonanoic acid to yield (3aR,4S,7aR)-4-nonanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+Na]=476; RT 9.818 min; LC-MS Method III
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:30]([O:34][C:35]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH:39]2[O:45][CH:43]([CH2:42][N:41]([CH2:16][CH2:15][N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][CH:28]=3)[C:11]([NH:13][CH3:14])=[O:12])[CH2:40]2)[CH2:44]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CNC(=O)N(CCOc1ccc(C#N)cc1)CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Temperature: 45 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]-3-methylureido}ethyl ester (1.35 g, 3.233 mmol; see Preparation I above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (1.48 g, 6.466 mmol; see WO 01/28992) and potassium carbonate (1.34 g, 9.7 mmol) in dry acetonitrile (15 mL) was stirred at 45° C. for 24 h. The reaction mixture was diluted with 20 mL water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel (using 2-2.5% methanol in dichloromethane) and further purification by preparative HPLC yielded 920 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22]Cl.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: ClCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl

Procedure:
80 g (0.28 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are dissolved in 220 ml of concentrated hydrochloric acid and chlorine gas is slowly conducted into the solution at -10° C. for 4 hours. The mixture is slowly poured on to a mixture of ice and sodium carbonate solution (250 g sodium carbonate dissolved in water) and extracted with methylene chloride. The extract is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 1.2 kg silica gel column using methylene chloride and then methylene chloride/ethyl acetate (10:1) as the eluting agent and crystallised from ethyl acetate/ether/n-hexane. There is obtained 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>O1CCOCC1.CCOC(C)=O.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>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][OH:17])=[CH:22][CH:23]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1ccc(-c2ccc(CCCO)cc2)cn1Cc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
According to Scheme 3 Method A: To a solution of 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 0.33 mmol, 0.10 g) in dioxane/saturated aqueous NaHCO3 (1:1, 6 mL) was added Pd(PPh3)4 (0.15 eq, 0.05 mmol, 58 mg) and 4-(3-hydroxypropyl)phenylboronic acid (1.5 eq, 0.50 mmol, 90.0 mg). The reaction was then stirred at 90° C. for 4.5 hours. The reaction was allowed to cool and diluted with AcOEt. The reaction washed with saturated NH4Cl solution, brine and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15 g SiO2) using pure AcOEt as the eluent to afford 1-(4-chlorobenzyl)-5-(4-(3-hydroxypropyl)phenyl)pyridin-2(1H)-one (0.22 mmol, 78 mg, 66%) as a white solid. M.p.: 165° C.; Rf=0.05 (CH2Cl2/AcOEt 80/20); LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=3.78 min; MS m/z (CI) [MH]+=354, 356; 1H NMR (300 MHz, DMSO-d6) δ 1.64-1.77 (m, 2H), 2.61 (t, J=7.3 Hz, 2H), 3.32-3.46 (m, 2H), 4.48 (t, J=5.1 Hz, 1H), 5.15 (s, 2H), 6.52 (d, J=9.5 Hz, 1H), 7.24 (d, J=8.1 Hz, 2H), 7.35-7.44 (4H), 7.47 (d, J=8.1 Hz, 2H), 7.83 (dd, J=2.6 Hz, 9.5 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CN1CCCCC1CCn1ccc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CCCCC1CCn1ccc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A solution of compound 61 (235 mg, 0.91 mmol) in EtOH (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (520 mg, 1.83 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then it was concentrated to give brownish oil. This residue was partitioned between CH2Cl2 (50 mL) with 10% MeOH and saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with an additional CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a brown residue which was subjected to flash chromatography on silica gel (MeOH:CH2Cl2, 5:95 to 2M NH3 in MeOH:CH2Cl2, 1:9) to give compound 62 (154 mg, 46.1%) as a yellow solid. 1H NMR (DMSO-d6) δ 7.71 (d, J=2.9 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.37-7.30 (m, 2H), 7.10-7.08 (m, 1H), 6.98 (s, 1H), 6.70 (dd, J=1.5, 6.9 Hz, 1H), 6.31 (d, J=3.0 Hz, 1H), 6.25 (brs, 2H), 4.15 (t, J=7.5 Hz, 2H), 2.79-2.75 (m, 1H), 2.19 (s, 3H), 2.05-1.15 (m, 10H); ESI-MS (m/z, %): 367 (M+1,50), 184 (M+2, 100); ESI-HRMS calculated for C21H27N4S (MH+): 367.1966, observed: 367.1937.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CC(O)C>[C:11]([N:18]1[CH2:19][CH2:20][N:21]([C:6]2[N:7]=[CH:2][C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc3cc[nH]c3n2)CC1
Reaction time: 18 h

Procedure:
A solution containing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.6 mmol), Boc-piperazine (15 g, 81 mmol), and DIEA (19.8 mL, 114 mmol) in 130 mL IPA was stirred at 80 C for 18 hours, after which the reaction was concentrated. The crude was flashed on silica gel (20:1 DCM:MeOH) to give a yellow powder, which was recrystallized from MeOH/minimal DCM to give 4-Boc-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine as a white crystalline solid (3 crops). 1H NMR (CDCl3, 400 MHz) δ 11.37 (br s, 1H), 8.34 (s, 1H), 7.12 (d, J=3.3 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H), 4.01-3.94 (m, 4H), 3.64-3.56 (m, 4H), 1.48 (s, 9H). HPLC Rt 2.05 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:6]=1)=[O:4].[OH-].[Na+].O1CCOCC1>CO>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:9]=1
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(C(F)(F)F)c(-c2ccc(Cl)cc2Cl)nc1C(=O)O

Procedure:
3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (0.9 g, 2.465 mmol) was suspended in MeOH (15 ml) and NaOH 2M (2.465 ml, 4.93 mmol) was added under stirring. 1,4-Dioxane (15.00 ml) was added and the solution was left standing at RT over night. The solvent was removed in vacuo and the resulting residue was dissolved in water (10 ml) and carefully acidified to pH4 with slow addition of 2M HCl (2 ml) whilst stirring. The mixture was extracted with EtOAc (20 ml) and the organic portion was washed with brine and concentrated in vacuo. The residue was purified by reverse phase chromatography (130 g C18 column) eluting with water/MeOH to afford the title compound; LS-MS Rt=1.57 mins[M+H]+ 351.0 (Method 2 min LC_v002).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13]C)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]2[CH:12]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=[CH:9][C:10]2=[O:13])=[CH:18][CH:19]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1ccc(C2CCCCC2)cn1
Product: O=c1ccc(C2CCCCC2)cn1Cc1ccc(Cl)cc1
Yield: 66.7 %

Procedure:
According to Scheme 26 Step 4: The title compound was prepared according to Example 6 Step 2, from 5-cyclohexyl-2-methoxypyridine (1 eq, 0.30 mmol. 57 mg) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 0.44 mmol, 92 mg), then purified by chromatography over silicagel (AIT Flashsmart prepacked column 5 g SiO2, CH2Cl2/MeOH 98/2) then recrystallized in pentane/diisopropyl ether, yielding the title compound (0.20 mmol, 0.09 g, 68%) as a beige solid.