Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCOCC>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCNc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 5 h

Procedure:
12 g (43 mmol) of 8-(4-methoxyphenylamino)-caprylic acid methyl ester are dissolved in 400 cc. of ether. 5.1 g (50 mmol) of triethylamine are added thereto. 7.3 g (43 mmol) of 4-methoxybenzoic acid chloride are added dropwise to the mixture with stirring and cooling with ice. After the addition, stirring is continued at 25° C. for 5 hours. The separated triethylamine-hydrochloride is filtered off with suction and the ethereal phase is washed in sequence with water, 5% bicarbonate solution, water, 2 n hydrochloric acid and water is dried over Na2SO4, and the solvent is distilled off. The crude product is used in the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([S:32][C:30](=[O:33])[CH3:31])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)Sc1ccc(C2CN(CCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a degassed solution of 3-[2-(4-trifluoromethanesulfonyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (2.55 g; 5.80 mmol) in toluene (50 mL) was added Pd2dba3 (0.27 g; 0.29 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]-ethyl]-2-(dicyclohexylphosphino)ferrocene (0.32 g; 0.58 mmol), followed, after 5 min. by, potassium thioacetate (1.33 g; 11.6 mmol). The resulting mixture was heated under reflux overnight. After cooling to RT the mixture was diluted with CH2Cl2, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/acetone 95:5) to afford 3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (1.70 g)
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32]CC3C=CC=CC=3)=[CH:28][CH:27]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(Nc3ccc(O)cc3)c(N)cn2)c1
Yield: 102.7 %

Procedure:
The product from Step 2 (16.4 g, 31.0 mmol) was hydrogenated with a balloon of H2 in the presence of 5% Pd/C (2 g) in MeOH (100 mL) over the weekend. The reaction mixture was then filtered through Celite and concentrated to give the title compound (13 g, quant.) which was used without purification. MS (ES+) m/e 409 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([O:12][CH3:13])[C:24]2[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=2[F:18])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CONS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1F)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 4-chloro-N-methoxy-3-(trifluoromethyl)benzenesulfonamide(0.58 g (2.00 mmol)) and 3,4-difluoronitrobenzene (0.66 ml (5.96 mmol)) in 5.0 ml of DMF, sodium hydride (60%, 0.09 g (2.25 mmol)) was added bit by bit with stirring under cooling with ice. The resulting mixture was stirred under cooling with ice for one hour and allowed to warm-up to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.32 g (37%) of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Cs+]>COCCOC.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>[F:10][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccccc2)cc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 4-bromo-2-fluorobenzonitrile (1.12 g, 5.6 mmol) in 1,2-dimethoxyethane (10 mL) were added Phenyl boronic acid (750 mg, 6.16 mmol), tetrakis(triphenylphosphine)palladium (0) (194 mg, 0.17 mmol) and Cesium fluoride (1.8 g, 12.3 mmol). The mixture of reaction was stirred at 100° C. under nitrogen for 3 h. Then, the mixture is cooled and filter through celite. Then added ethyl acetate and water and extracted (3×). The crude was purified by chromatography (silica gel, hexane-ethyl acetate 10:1) affordind 818 mg (74% yield)n of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F

Procedure:
150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 578.71 mg (1.77 mmol) of cesium carbonate, 99 μl (0.709 mmol) of 1-bromopinacolone and 10 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 12 min 4% B, t 15 min 4% B, t 30 min 10% B), 188 mg of (8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:4]([CH:16]=O)[CH2:3]1.Cl.[O:19]([NH2:21])[CH3:20]>C(O)(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:4]([CH:16]=[N:21][O:19][CH3:20])[CH2:3]1
Reactant: CN1CCC(c2ccc(Cl)c(Cl)c2)C(C=O)C1
Reactant: CON
Agent: Cl
Solvent: CC(C)O
Product: CON=CC1CN(C)CCC1c1ccc(Cl)c(Cl)c1
Yield: 40.2 %

Procedure:
To a solution of 1-methyl-3-formyl-4-(3,4-dichlorophenyl)piperidine (10 g, 33 mmol) in warm isopropanol (100 mL) was added methoxylamine hydrochloride (3 g, 36 mmol). The reaction was heated at reflux for 30 min. The solvent was evaporated off and the residue made basic (pH=9) using concentrated ammonia. Extraction with ether afforded 8.5 g of crude product. Purification by repeated column chromatography on silica using EtOAc/Et3N (95:5) as eleuent afforded 4 g of the title compound as an oil.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[O:25][CH3:26]>O>[CH3:26][O:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[O:6][CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(CO)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCC(=O)N1CCCC1
Reaction time: 18 h

Procedure:
To a stirred solution of DMF (20 mL) containing 2-hydroxy-1-(pyrrolidin-1-yl)ethanone (2.00 g, 15.5 mmol) under N2 was added 60% NaH/paraffin (640 mg, 16 mmol). Once gas evolution ceased, 2-chloro-5-nitroanisole (1.9 g, 10 mmol) was added. After stirring for 18 hr at 20°, the reaction was diluted with H2O prior to being extracted with EtOAc 3×. The organic layers were washed twice with aq. Na2CO3, brine and dried over Na2SO4 prior to concentration. Chromatography on silica gel using 25% EtOAc/CH2Cl2 eluted 2.06 g of 2(2-methoxy-4-nitrophenoxy)-1-(pyrrolidin-1-yl)ethanone (52%). 1H NMR (DMSO-d6) δ 1.73-1.79 (m, 2H), 1.86-1.92 (m, 2H), 3.29-3.32 (m, 2H), 3.43-3.46 (m, 2H), 3.04 (s, 3H), 4.93 (s, 2H), 7.02 (d, J=8.80 Hz, 1H), 7.73 (d, J=2.74 Hz, 1H), 7.84 (dd, J=8.80 Hz, 2.20 Hz, 1H); 13C NMR (DMSO-d6) δ 23.22, 25.35, 44.27, 45.30, 55.76, 66.23, 106.35, 111.93, 116.99, 140.51, 148.25, 153.28, 164.33; HPLC a) column: PHENOMENEX® C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.2% H3PO4 to 90% MeOH/10% H2O/0.2% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 2.24 min retention time, (100%); HPLC b) column: PHENOMENEX® C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.29 min retention time; MS (ES): m/z 281 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31](O)=[O:32].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(Cl)Cl.CO>[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:32]
Reactant: Cc1ccccc1CCC(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccccc1CCC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 12.7 %

Procedure:
Preparation of example 50 from the title compound of Example 7 (30 mg, 0.11 mmol), 3-(2-methylphenyl)propanoic acid (27 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) in N,N-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gel chromatography (3% methanol in CH2Cl2 increasing to 5% methanol in CH2Cl2), also in an analogous manner, followed by methanol trituration afforded the title compound (6 mg, 0.014 mmol) as a yellow powder in 13% yield.
Reaction SMILES: [C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2].[C:27](=O)([O-])[O-].[K+].[K+]>CC(C)=O.CI>[C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([O:25][CH3:27])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2]
Reactant: CC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C=O)cc2c1C(COC(N)=O)C1(O)ON2CC2C1N2C(C)=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
11-Acetyl-4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (55 mg) was dissolved in a mixture of acetone (2 ml) and methyl iodide (2 ml). To the solution was added potassium carbonate (150 mg), and the mixture was stirred at 45° C. overnight under nitrogen atmosphere. The mixture was cooled to room temperature and filtered, and the filter cake was washed with a mixture of chloroform and acetone (1:1, v/v, 10 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to column chromatography on silica gel, and elution was carried out with a mixture of chloroform and acetone (4:1, v/v). The desired fractions were collected and evaporated to dryness. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (1:1, v/v) to afford 11-acetyl-4-formyl-9-hydroxy-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (11 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: Cc1cccc(F)c1B(O)O
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(C)cccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-methylphenyl)boronic acid gave 269. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.88 (s, 1H), 7.48-7.33 (m, 3H), 7.25-7.13 (m, 2H), 5.05 (t, J=5.3 Hz, 1H), 3.77-3.63 (m, 5H), 3.34-3.25 (m, 1H), 3.26-3.17 (m, 1H), 2.83 (s, 3H), 2.44 (s, 3H), 1.68-1.50 (m, 4H). LCMS (ES+) m/z 475 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[N:18][CH:19]=1
Reactant: Fc1ccc(CBr)nc1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cn2)cnn1C1CCCCO1
Yield: 26.9 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.62 g, 13.4 mmol) (this compound was prepared in accordance with the procedure of Stenkamp et al., WO 2008022979), 2-(bromomethyl)-5-fluoropyridine (7.6 g, 40.2 mmol) and K2CO3 (9.24 g, 67 mmol) were stirred in DMF (40 ml) and CH2Cl2 (40 ml) for 48 h. The mixture was diluted with CH2Cl2, washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (1.1 g, 27%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.73 (d, J=2.9 Hz, 1H), 7.47-7.43 (m, 2H), 6.19 (d, J=2.9 Hz, 1H), 6.03-5.98 (dd, J=10.7, 2.0 Hz, 1H), 5.12 (s, 2H), 4.18-4.08 (m, 1H), 3.78-3.69 (td, J=11.6, 2.6 Hz, 1H), 2.21-2.00 (m, 2H), 1.75-1.60 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:25]1[CH:29]=[CH:28][S:27][C:26]=1[C:30]1[O:35]C(C)(C)[O:33][C:32](=O)[CH:31]=1)#[N:24]>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:32](=[O:33])[CH2:31][C:30]([C:26]1[S:27][CH:28]=[CH:29][C:25]=1[C:23]#[N:24])=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2sccc2C#N)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1C#N
Yield: 52.3 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (302 mg, 1.0 mmol) and 6-(3-cyano-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J3) (250 mg, 1.06 mmol) according to the general procedure K. Obtained as a light yellow solid (251 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH2:23][C:22]([CH3:26])([CH3:25])[C:21]=2[CH:27]=1>CCCCCC.C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:20]2[O:24][CH2:23][C:22]([CH3:25])([CH3:26])[C:21]=2[CH:27]=1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCC(=O)c1cc(Br)cc2c1OCC2(C)C

Procedure:
Following General Procedure I and using aluminum chloride 1.76 g, 13.2 mmol), 20 mL of anhydrous dichloromethane, hexanoyl chloride (1.76 g, 13.2 mmol) and 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 1.5 g, 6.61 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 3% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil. It was used as such for the next step.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:5]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[N:3]=1.C(ON=O)(C)(C)C.O.C(Cl)(Cl)(Cl)[Cl:41]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:4]2[CH:5]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=3)[N:7]=[C:2]([Cl:41])[N:3]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: Nc1nc(Oc2ccc(F)c(C(F)(F)F)c2)cc(Oc2ccc(F)c(C(F)(F)F)c2)n1
Reactant: ClC(Cl)(Cl)Cl
Agent: CC(C)(C)ON=O
Solvent: O
Product: Fc1ccc(Oc2cc(Oc3ccc(F)c(C(F)(F)F)c3)nc(Cl)n2)cc1C(F)(F)F
Temperature: 30 °C

Procedure:
2-Amino-4,6-bis(4-fluoro-3-trifluoromethylphenoxy)pyrimidine (3.0 g, 6.7 mmol) was dissolved in carbon tetrachloride (75 ml) and the resulting solution was treated with t-butylnitrite (1.2 ml, 13.4 mmol). The mixture was heated at 30° C. for 48 hours and then poured into water. The product was extracted in dichloromethane, dried over sodium sulphate, filtered and concentrated under reduced pressure. The product, 4,6-bis(4-fluoro-3-trifluoromethyl-phenoxy)-2-chloro-pyrimidine, was obtained as an oil by column chromatography (eluting with 5:1, hexane:ethyl acetate). Yield 0.3 g (10%); mass 471 (M+ +H); N.m.r: 7.3-7.5 (6H, m, aromatics), 6.35 (1H,s,H-5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17]CC)=[O:16].CC(O)C.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]2[C:3]=1[NH:12][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:20]2=[O:22]
Reactant: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate (6B) (1200 g, 3.754 mol) was charged into a vessel followed by the addition of 2-propanol (1.200 L) and water (7.200 L) and stirred. NaOH (600.6 g, 7.508 mol) and water (1.200 L) were mixed and allowed to cool to room temperature. The resulting NaOH solution was charged into the reaction vessel. The reaction mixture was heated to 80° C. and stirred for 3.5 h generating a dark and homogenous mixture. After an additional hour, acetic acid (9.599 L [of a 20% w/v solution], 31.97 mol) was added via dropping funnel over 45 min. The reaction mixture was cooled to 22° C. at a rate of 6° C./h with stirring. The resulting solid was filtered, washed with water (3 L) to generate a wet cake of (1436 g). The filtrate was dried in a vacuum oven with nitrogen bleed over Drierite® to generate 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid as a brown solid. The 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid was purified by slurrying in 1.5 L methanol, with stirring, for 6 h. It was then filtered and dried to furnish 968.8 g of purified 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (6D).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH:16][C:17](=[O:19])[CH3:18])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:23]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH:16][C:17](=[O:19])[CH3:18])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1)#[N:24]
Reactant: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(=O)Nc1c(OCc2ccccc2)cc(C#N)cc1[N+](=O)[O-]
Temperature: 170 °C
Yield: 99 %

Procedure:
A mixture of N-{4-bromo-2-nitro-6-[(phenylmethyl)oxy]phenyl}acetamide (6.5 g, 17.8 mmol, STEP 1), zinc cyanide (4.18 g, 35.6 mmol), and tetrakis(triphenylphosphine)palladium (2.06 g, 1.78 mmol) in N,N-dimethylformamide (100 mL) was heated to 170° C. for 20 minutes in the microwave synthesizer (Biotage, Emrys Optimizer). After cooling to room temperature, the suspension was filtered, and washed with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, and concentrated in vacuum. The residual solid was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:1) to afford the title compound as a white solid (5.5 g, 99%).