Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1>CN(C)C=O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:6]2[CH2:5][CH2:4][N:3]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[C:2]2=[O:1])=[CH:26][CH:25]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(N2CCNC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(Cc3ccc(C(C)(C)C)cc3)C2=O)cc1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of methyl 4-(2-oxoimidazolidin-1-yl)benzoate (440 mg, 2.0 mmol) in N,N-dimethylformamide (10 ml) at 0° C. was added sodium hydride (96 mg-60% in oil, 2.4 mmole). The resulting mixture was stirred for 1 hour followed by addition of 1-(bromomethyl)-4-tert-butylbenzene (545 mg, 2.4 mmol). After stirring 24 hours at room temperature, the mixture was quenched with 1 ml water and the solvents were removed under reduced pressure. The residue was diluted with ethyl acetate (50 ml) and washed with water (50 ml) and brine (50 ml). Removal of the solvent gave the residue which was purified on ISCO system (1% methanol in dichloromethane) to give a pure product as a white solid (593 mg, 81%): 1H NMR (400 MHz, CDCl3) δ 8.25 (d, 2H), 7.68 (d, 2H), 7.36 (d, 2H), 7.23 (d, 2H), 4.46 (s, 2H), 3.90 (s, 3H), 3.83 (dd, 2H), 3.43 (dd, 2H), 1.31 (s, 9H). MS (ESI) m/z: Calculated: 366.19; Observed: 367.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C(Cl)Cl.O1CCOCC1>[CH2:30]1[CH2:31][CH:29]1[C:32]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:9][CH:8]=2)[N:6]=1)=[O:33]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2csc(N)n2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(-c2csc(NC(=O)C3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a mixture of 4-(2-aminothiazol-4-yl)-N-(tert-butoxycarbonyl)-benzylamine (2.98 g, 9.76 mmol) in DCM/dioxane (2:1, 150 mL) at room temperature, add triethylamine (2.0 mL, 15 mmol) and cyclopropanecarbonyl chloride (1.1 mL, 12 mmol). Stir at room temperature overnight and partition the reaction mixture between EtOAc (500 mL) and saturated aqueous NaHCO3 (250 mL). Dry the organic extract over Na2SO4, filter and concentrate in vacuo. Combine the residue with DCM and silica gel (12 g) and concentrate to a powder. Load powder on to a dry column attached to an Analogix® column (330 g) and purify by preparative liquid chromatography (0:1 to 1:4 EtOAc/hexane over 33 min, 1:4 EtOAc/hexane over 33 min, 1:4 to 1:1 EtOAc/hexane over 33 min, 1:1 EtOAc/hexane over 66 min; 35 mL/min) to afford the desired intermediate (2.381 g, 65%) as a yellow solid. MS (ES+) m/z: 374.2 (M+H)+.
Reaction SMILES: [C:1]1([PH:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Cl-].[Zn+2].[Cl-]>[C:8]1([PH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 164 °C
Yield: 44 %

Procedure:
101 g (0.5 mol) of diphenylphosphine oxide and 0.4 g of zinc chloride are mixed and heated to 164° C., the pressure being reduced simultaneously (14 mbar). Diphenylphosphine distills off through a descending condenser at a transition temperature of 148° C. The internal temperature is finally raised to 183° C. 41 g of diphenylphosphine are obtained. That corresponds to a yield of 88% of theory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:23](=[O:28])[CH2:24][CH2:25][C:26]#[CH:27])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([C:23](=[O:28])[CH2:24][CH2:25][C:26]#[C:27][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:14]=1
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 54.5 %

Procedure:
To a solution of CuI (7.7 mg, 0.041 mmol) in triethylamine (2.28 mL) were added 2-bromopyridine (129 mg, 0.82 mmol) and (PPh3)2PdCl2 (28.7 mg, 0.041 mmol). The reaction mixture was cooled to 0° C. and tert-butyl 4-chlorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated under reflux for 3 h at 70° C. Triethylamine was evaporated, water was added and the aqueous phase was extracted twice with DCM. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (prepacked 25 g silicagel column/Cyclohexane/AcOEt: 70/30 as eluent) to afford 172 mg (Yield: 55%) of tert-butyl 4-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.O.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(Cl)Cl>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=[C:2]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[CH:3]=1)=[O:16]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 110 °C
Yield: 78.8 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (90 mg, 0.23 mmol) and 3-pyridinylboronic acid (42.8 mg, 0.35 mmol) in dioxane/water (3:1 mL). PdCl2(dppf)-CH2Cl2 adduct (9.47 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium carbonate (58.5 mg, 0.7 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave to 110° C. for 20 min. Upon cooling, water was added and solids that precipitated were filtered, dissolved in DCM and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The product containing fractions were evaporated and suspended in EtOH/EtOAc (1:1). The contents were sonicated, solids that precipitated were filtered, washed with hexanes and dried to afford the title compound as a white solid (78 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1 H) 9.39 (d, J=1.52 Hz, 1 H) 8.76 (t, J=5.05 Hz, 1 H) 8.69 (dd, J=4.67, 1.64 Hz, 1 H) 8.57 (dt, J=8.27, 1.80 Hz, 1 H) 7.78 (s, 1 H) 7.57 (dd, J=8.08, 5.56 Hz, 1 H) 5.89 (s, 1 H) 5.28 (quin, J=6.69 Hz, 1 H) 4.41 (s, 1 H) 4.39 (s, 1 H) 2.46 (s, 3 H) 2.25 (s, 3 H) 2.12 (s, 3 H) 1.52 (s, 3 H) 1.51 (s, 3 H); LC-MS (ES) m/z=431.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (250 mg, 0.62 mmol) according to the general procedure M. Obtained as a yellow oil (257 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24]([OH:26])=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[C:41]([CH2:43]O)[CH:40]=[CH:39][N:38]=1)=[O:36]>>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[C:41]([CH2:43][O:25][C:24]([C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)=[O:26])[CH:40]=[CH:39][N:38]=1)=[O:36]
Reactant: COC(=O)c1cc(CO)ccn1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Product: COC(=O)c1cc(COC(=O)c2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccc(S(C)(=O)=O)cc2)ccn1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (330 mg) and 4-hydroxymethylpyridin-2-carboxylic acid methyl ester. A colorless powder (410 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:14][C:13](=[O:15])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:16]=1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:17])[C:13](=[O:15])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:16]=1
Reactant: O=C1C[C@H]2CCCN2c2nc(Cl)ncc2N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C[C@H]2CCCN2c2nc(Cl)ncc21
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of 0.4 g (0.0017 mole) of (R)-9-chloro-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one (VI-102) in 10 mL of dimethylformamide was added 1.1 g (0.0034 mole) of cesium carbonate, followed by 0.32 mL (0.0051 mole) of iodomethane. After stirring overnight, the mixture was filtered and the filtrate concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (40:60-0:100) gave 0.35 g of (R)-9-chloro-6-methyl-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one (VII-102) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[H-].[Na+].Cl.Cl[CH2:40][C:41]1[NH:45][CH:44]=[N:43][CH:42]=1.N1C=CN=C1>CN(C=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]4[N:3]([CH2:40][C:41]5[NH:45][CH:44]=[N:43][CH:42]=5)[C:2](=[O:1])[CH2:7][O:6][C:5]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: ClCc1cnc[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3cnc[nH]3)C(=O)CO4)cc2)CCC1
Yield: 8 %

Procedure:
In a round bottom flask was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (150 mg, 0.318 mmol) in DMF (Volume: 8 ml) to give a brown solution.sodium hydride (30.5 mg, 0.763 mmol) and 5-(chloromethyl)-1H-imidazole hydrochloride salt (58.4 mg, 0.501 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. further sodium hydride (15.2 mg) and imidazole (29 mg) were added and the resulting mixture stirred for another hour. The reaction mixture was concentrated to dryness. The residue was partitioned between ethyl acetate (35 ml) and water (30 ml). The organic phase was separated and washed with water (2×25 ml), brine and concentrated. The residue was purified by column (biotage 25 g) to give product (14 mg). LCMS (Method A) RT=4.58 min, M+H+=552.1.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].P(O)(O)O>>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[CH:2]=[C:3]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:4]=[N:5]1
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: OP(O)O
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1

Procedure:
Ethyl 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate, was diazotised and treated with phosphorous acid to give ethyl 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate, m.p. 70°-73°. This was reduced to [1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-4-yl]methanol, m.p. 57°-59°
Reaction SMILES: [Cl:1][Si:2]([Cl:12])([Cl:11])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6]1.[Cl:13][SiH:14]([Cl:16])[Cl:15]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][Si:2]([Cl:11])([Cl:12])[CH2:3][CH2:4][C:5]1([Si:14]([Cl:16])([Cl:15])[Cl:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cl[SiH](Cl)Cl
Reactant: Cl[Si](Cl)(Cl)CCC1CC=CCC1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cl[Si](Cl)(Cl)CCC1([Si](Cl)(Cl)Cl)CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 121.8 g (0.50 mol) of 4-(2-trichlorosilylethyl)-1-cyclohexene and 0.1 g of a 20 wt % isopropanol solution of chloroplatinic acid, which were heated at 80° C. After the internal temperature became constant, 74.5 g (0.55 mol) of trichlorosilane was added dropwise over 10 hours. After the completion of addition, the reaction solution was stirred for 8 hours at 80° C. The reaction solution was distilled, collecting 157.3 g of (2-trichlorosilylethyl)trichlorosilylcyclohexane as a fraction having a boiling point of 122-126° C./0.1 mmHg (yield 83.0%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7]Br)[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:25][C:24]2[C:16]([F:15])=[C:17]([C:21]([F:26])=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])[S:5][CH:6]=1
Reactant: BrCc1nc(Br)cs1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(Br)cs2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of 4-bromo-2-(bromomethyl)thiazole (1.57 g, 6.10 mmol) in DMF (15 ml) was added dried K2CO3 (2.95 g, 21.38 mmol) followed by addition of 2,6-difluoro-3-hydroxybenzamide (1.05 g, 6.10 mmol). The resulting reaction mass was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), ice-cold water was added (50 ml) followed by extraction with EtOAc (3×100 ml). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was washed with ether and the solid thus obtained was filtered to get the desired product (1.56 g, 74%).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.CC1(C)OC2C(N3C=NC4C3=NC=NC=4[NH:40][C:41]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:42])OC(C(NC3C=C(C=CC=3)C(O)=O)=O)C2O1>>[C:44]1([NH:43][C:41]([NH2:40])=[O:42])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC1(C)OC2C(C(=O)Nc3cccc(C(=O)O)c3)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Solvent: O=C=Nc1ccccc1
Product: NC(=O)Nc1ccccc1

Procedure:
Phenyl isocyanate was coupled with the amide product using a method similar to those described above, affording the intermediate phenylurea compound. MW calculated for C30H29N7O7 (MH+) 600. found 600 by LCMS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([O:16]C)=O)=[C:12]([CH2:18][NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[NH:11][C:10](=[O:29])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].N=C=N>CO.O.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10](=[O:29])[NH:11][CH:12]3[CH2:18][N:19]([C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[CH:23]5)[C:14](=[O:16])[CH:13]23)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(CNc2ccc3[nH]ncc3c2)NC(=O)NC1c1ccc(F)cc1
Agent: N=C=N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C1NC2CN(c3ccc4[nH]ncc4c3)C(=O)C2C(c2ccc(F)cc2)N1
Temperature: 60 °C
Yield: 3.3 %

Procedure:
The product of step (b) (132 mg, 0.334 mmol, 1.00 equiv) and NaOH (2.5 N, 0.5 mL) were dissolved in methanol (2 mL) and heated to 60° C. in a sealed tube for three hours. The reaction mixture was diluted with water (˜50 mL) and EtOAc (˜50 mL), stirred, and separated. The aqueous layer was adjusted to pH 1 with 2N HCl and extracted with EtOAc. The organic layer was concentrated en vacuo and the residue (39 mg, 0.102 mmol, 1 equiv) was dissolved in DMF (5 mL). PS-carbodiimide resin (140 mg, 0.153 mmol, 1.5 equiv) was added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was filtered and washed twice alternately with methanol and methylene chloride. The filtrate was concentrated en vacuo and the residue was purified by silica gel column (0-10% MeOH in CH2Cl2). The residue was triturated with CH2Cl2/Hexane to give 4 mg of the title compound as a beige powder (11%). MS (ES+) m/e 364 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 8-amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as an orange foam (103 mg, 50%). LCMS (m/e) 507 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.10 (s, 1H), 7.55 (d, 1H, J=7.8 Hz), 7.47-7.33 (m, 3H), 7.26-7.17 (m, 2H), 7.07 (s, 1H), 6.79 (d, 1H, J=8.4 Hz), 6.59-6.50 (m, 1H), 4.19-4.15 (m, 2H), 2.38 (t, 2H, J=6.9 Hz), 2.25-2.20 (m, 1H), 2.08-2.04 (m, 2H), 1.37 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:9]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=1)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:1][O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[C:10]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)[CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=2)[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)Cc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C

Procedure:
A solution of (5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (100 mg, 0.2 mmol), 4-chlorophenyl boronic acid (41 mg, 0.24 mmol), K2CO3 (2 M solution in H2O, 220 μL, 0.4 mmol) in DME (2.0 mL) was heated to 80° C. in the presence of bis(tri-t-Butylphosphine) palladium (0) (cat) for 2 hrs. The mixture was cooled to room temperature filtered, diluted with EtOAc, washed with Na2CO3, dil HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give an off white solid. The residue was purified by flash column chromatography (EtOAc:petroleum ether), 1H NMR (CDCl3) δ 7.71 (s, 4H), 7.65-7.68 (m, 1H), 7.42 (d, 2H), 7.52-7.48 (m, 2H), 7.36 (d, 2H), 3.77 (s, 2H), 3.74 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>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].O1CCOCC1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:35][CH:36]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])=[N:11]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
5-(4-Bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole prepared in Step 3 of Preparation 1 (760.0 mg, 1.68 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (622.0 mg, 2.01 mmol), potassium carbonate (695.0 mg, 5.03 mmol), and Pd(dppf)Cl2 (137.0 mg, 0.17 mmol) were added to a mixed solvent of 1,4-dioxane (24.0 mL) and distilled water (6.0 mL). The reaction mixture was stirred for 15 minutes, additionally at 90° C. for 16 hours, and cooled to room temperature. Distilled water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 630.0 mg of the titled compound as a white solid.