Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[OH:20][C:21]([CH3:54])([CH3:53])[CH2:22][C@:23]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:28][CH2:27][N:26]([C@H:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH3:30])[C:25](=[O:46])[NH:24]1.O>C(O)C.C1(C)C=CC=CC=1.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>[OH:20][C:21]([CH3:53])([CH3:54])[CH2:22][C@:23]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:28][CH2:27][N:26]([C@H:29]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]4)=[N:6][CH:7]=3)=[CH:35][CH:36]=2)[CH3:30])[C:25](=[O:46])[NH:24]1
Reactant: NC(=O)C1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylic acid amide (120 mg), Na2CO3 (443 mg), and Pd(PPh3)4 (12 mg) were added to a solution of (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}tetrahydro-pyrimidin-2(1H)-one (200 mg; for preparation see WO 2009061498) in ethanol (6 mL), toluene (8 mL), and H2O (4 mL) at room temperature. The resulting mixture was stirred at 100° C. for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was concentrated, diluted with H2O (30 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were concentrated to afford an oil which was purified by preparative HPLC to give the title compound. Yield: 124 mg (58% of theory); LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=513 [M+H]+; 1H NMR (CDCl3, 400 MHz) δ 0.69 (s, 3H), 1.29 (m, 2H), 1.31 (m, 3H), 1.50 (d, 3H), 1.79 (m, 2H), 1.98-2.07 (m, 3H), 2.12-2.22 (m, 3H), 2.70-2.83 (m, 1H), 4.55 (s, 1H), 5.80-5.62 (m, 2H), 7.21 (m, 3H), 7.28 (m, 1H), 7.33 (m, 4H), 7.70 (m, 2H), 7.78 (m, 1H) 8.69 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([Li])CCC.[CH3:29][S:30]S(C)(=O)=O.Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]([S:30][CH3:29])[CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Reactant: CSS(C)(=O)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CSC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Reaction time: 0.67 h
Yield: 42.2 %

Procedure:
In 10 ml of a mixture of anhydrous tetrahydrofuran-hexamethylphosphoric acid triamide (7:3) was dissolved 1.00 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. To the resulting solution was added 10 ml of a tetrahydrofuran solution of 1,1,1,3, 3,3-hexamethylsilazane lithium salt consisting of 1.17 g of 1,1,1,3,3,3-hexamethylsilazane and 6.6 millimoles of n-butyllithium at -78° C., and the resulting mixture was stirred for 40 minutes, after which 500 mg of methyl methanethiolsulfate was added at the same temperature and the mixture was stirred for 15 minutes. Subsequently, the temperature of the reaction mixture was elevated to room temperature. The reaction mixture was introduced into 80 ml of 2N hydrochloric acid with ice-cooling and the resulting mixture was extracted with two 40-ml portions of ethyl acetate. The extracts were combined and washed with water and saturated aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the oily product obtained was purified by a column chromatography (eluant: toluene:ethyl acetate=50:1) to obtain 480 mg (yield: 39.6%) of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][C:6]([O:9][CH3:10])([CH3:8])[CH3:7].O1CCCC1.C(O)(=O)C(O)=O>O>[CH3:10][O:9][C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CCC(C)(C)OC)OC
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)CCC=O
Yield: 85.3 %

Procedure:
A mixture of 1,1,4-trimethoxy-4-methylpentane (3.2 g, 0.018 mol), tetrahydrofuran (100 mL), water (10 mL) and oxalic acid (1.0 g, 0.022 mol) was heated at reflux for 40 hours. Workup provided 4-methoxy-4-methylpentanal (2.0 g).
Reaction SMILES: C([O:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:42][CH3:43])C1C=CC=CC=1.[H][H]>C(N(CC)CC)C.CO.[Pd]>[OH:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:42][CH3:43]
Reactant: COc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 3 h

Procedure:
A suspension of 7.60 g (12.98 mmol) (S)-2-(4-benzyloxy-3-methoxy-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 0.76 g 10% Pd/C in 2 mL triethylamine and 150 mL MeOH was hydrogenated at RT and 2620 hPa hydrogen pressure for 16 h. To complete the reaction a further 0.38 g 10% Pd/C were added and the mixture was again hydrogenated for 3 h at RT. The catalyst was filtered off through Celite and the filtrate was concentrated by evaporation i.vac. The product was further reacted without purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[N:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([B:28]([OH:33])[OH:29])[C:24]([F:27])=[N:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(OCc2ccccc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1cc(OCc2ccccc2)cnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of diisopropylamine (Aldrich) (0.33 mL, 2.16 mmol) in THF (5 mL) was cooled to 0° C. and treated with n-butyllithium (Aldrich) (0.94 mL, 2.36 mmol). The resulting mixture was stirred at 0° C. for 30 min and then cooled to −78° C. 5-(Benzyloxy)-2-fluoropyridine (Aldrich) (0.200 g, 0.982 mmol) in THF (3 mL) was added dropwise and the solution was stirred at −78° C. for 40 min before being treated with triisopropyl borate (Aldrich) (0.50 mL, 2.16 mmol) in THF (2 mL). After the addition, the cooling bath was removed and the reaction mixture slowly warmed up to rt and was stirred for 1 h. The reaction mixture was quenched with 5% NaOH (10 mL). The aqueous layer was separated and acidified to pH 5 using 5N HCl. The resulting mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the crude product as yellow solid (0.210 g). m/z (ESI, +ve ion) 248.0 (M+H)+. 1H NMR (300 MHz, d4-MeOH) δ 6.60 (br s., 1H); 6.36 (br. s., 1H); 6.00-6.24 (m, 5H); 3.87 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[N:13][CH:12]=1)=[O:10].[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[N:13][CH:12]=1)([OH:10])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Solvent: ClCCl
Product: Cc1cccc(C(O)(Cc2ccccc2)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (2,3-dimethylphenyl)(l-trityl-1H imidazol-5-yl)methanone (450 mg, 1.01 mmol) in dichloromethane (25 mL) at room temperature was treated with benzyl magnesium bromide (1.51 mmol) and allowed to react at room temperature and the reaction mixture was then stirred at room temperature for 5 hours. The mixture was quenched with water (10 mL) and a sat. solution of ammonium chloride (10 mL). The residue was isolated in a typical aqueous to give 1-(2,3-dimethylphenyl)-2-phenyl-1-(1-trityl-1H-imidazol-5-yl)ethanol (Intermediate 8) crude, which was taken to the next step without any purification.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[OH:7][C:8]1[C:9]([CH3:43])=[C:10]([CH:36]=[CH:37][C:38]=1[C:39](=[O:42])[CH2:40][CH3:41])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)C(O)=O)=[CH:15][CH:14]=1.[N+](=C)=[N-]>O1CCCC1.CN(C)C=O>[Cl:6][CH2:1][C:2]([C:22]1[CH:21]=[C:20]([CH:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]3[CH:36]=[CH:37][C:38]([C:39](=[O:42])[CH2:40][CH3:41])=[C:8]([OH:7])[C:9]=3[CH3:43])=[CH:18][CH:17]=2)[CH:28]=[CH:27][CH:26]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)CCl)c3)cc2)c(C)c1O
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Add oxalyl chloride (0.660 mg, 5.20 mmol) to a solution of 3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoic acid (2.50 g, 5.00 mmol) in tetrahydrofuran (0.20M). Add dimethylformamide (5 drops). Add ethereal solution of diazomethane (15.0 mmol) and stir for 2 hours. Add hydrochloric acid (4N in dioxane) to quench unreacted diazomethane and evaporate solvents to afford the title compound (2.25 g, 4.19 mmol, 85%): MS (m/z): 536 (M−H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:10])[CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a stirred solution of 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid (0.36 g, 1.00 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.50 mmol) and 4-dimethylaminopyridine (0.28 g, 2.30 mmol). The reaction was stirred at ambient temperature for 10 minutes, methanesulfonamide (0.15 g, 1.56 mmol) was added and the stirring was continued at ambient temperature for 17 hours. 5% aqueous hydrochloric acid solution (10 mL) were added and diluted with ethyl acetate (100 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.27 g, 62%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (br s, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 4.12 (s, 2H), 3.39 (s, 3H), 2.03-1.88 (m, 3H), 1.76-1.63 (m, 5H), 1.48-1.23 (m, 3H), 0.94-0.87 (m, 2H), 0.64-0.58 (m, 2H); MS (ES−) m/z 436.2 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12]/[N:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:11].C(N(CC)CC)C.Cl[CH2:45][C:46](=[O:48])[CH3:47].O>CC(=O)CC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:46]([CH3:47])([OH:48])[CH2:45][S:11]/[C:10]/1=[N:12]/[N:13]=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: Fc1cccc(F)c1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCC(C)=O
Product: CC1(O)CS/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N1c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
To a solution of (E)-N-(2,6-difluorophenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (253 mg, 0.49 mmol) in butanone (4.9 mL) was added triethylamine (0.14 mL, 0.98 mmol) and chloroacetone (0.055 mL, 0.68 mmol), and the reaction was stirred at 80° C. for 15 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel containing water (5 mL), and extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes) to afford the title compound as a yellow solid (248 mg, 88%): mp 105° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.25-8.12 (m, 3H), 7.88-7.72 (m, 4H), 7.39 (d, J=8.5 Hz, 3H), 7.06 (td, J=8.9, 4.4 Hz, 2H), 3.58 (d, J=11.5 Hz, 1H), 3.37 (d, J=11.5 Hz, 1H), 3.24 (d, J=2.7 Hz, 1H), 1.59 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02, −113.71, −115.83, −115.84; ESIMS m/z 576 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[Br:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Br:17][C:18]1[C:19]([NH:1][CH:2]([CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH3:3])=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(Cl)ncc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To the solution of tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (5 g, 21.9 mmol) in ethanol (50 ml) were added 5-bromo-2,4-dichloropyrimidine (5.97 g, 26.3 mmol), and N-ethyl-N-isopropylpropan-2-amine (8.48 g, 65.7 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum, and the crude product was added to water (100 ml). The aqueous layer was extracted with ethyl acetate (50 mL×4) and organic layer was dried over sodium sulfate and concentrated to give crude product tert-butyl 4-(1-((5-bromo-2-chloropyrimidin-4-yl)amino)ethyl)piperidine-1-carboxylate (7 g, yield: 97.2%) as a yellow oil. LRMS (M+H+) m/z: calcd 418. found 419.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1.Cl[S:24]([OH:27])(=O)=[O:25].[CH3:28][NH2:29]>ClCCl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:24](=[O:27])(=[O:25])[NH:29][CH3:28])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1
Reactant: CN
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccccc2)CC1
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(N2CCC(C(=O)OC)=Cc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In dichloromethane (20 ml) was dissolved methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1 g). Under ice-cooling, to the solution was added dropwise chlorosulfonic acid (0.93 ml). The mixture was stirred at room temperature for 1 hour, and the reaction solution was added dropwise to 40% methylamine solution in water (25 ml) under ice-cooling. The mixture was stirred at room temperature overnight, concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][CH2:18][OH:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1>C(O)C1C=CC=CC=1>[CH2:30]([O:19][CH2:18][NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCNc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: OCc1ccccc1
Product: Fc1ccc(COc2ncc(F)c(NCOCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamino]methanol (0.10 g, 3.7 mmol) in benzyl alcohol (1 mL) was added a catalytic amount of p-toluene sulfonic acid. After 30 min, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic portion was dried over anhydrous Na2SO4, filtered and evaporated to obtain the crude product. Purification by reverse phase chromatography afforded 0.094 g (70%) of the title compound as a white solid: mp 64-66° C.; 1H NMR (CDCl3) δ 7.93 (d, J=2.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.37-7.29 (m, 5H), 7.08-7.00 (m, 2H), 5.81-5.70 (bm, 1H), 5.29 (s, 2H), 5.12 (d, J=6.9 Hz, 2H), 4.63 (s, 2H); MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12]([CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10](F)[C:9]=2[CH3:20])[CH2:4][CH2:3]1.[F-].[K+].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:20])=[C:10]([C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:15])[C:13]=2[F:14])[NH:26][CH:23]2[CH2:25][CH2:24]2)[CH2:4][CH2:3]1
Reactant: NC1CC1
Reactant: Cc1c(F)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(NC2CC2)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 23 h

Procedure:
To 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-methyl-5-nitrotoluene (1.73 g) are added anhydrous dimethyl sulfoxide (18 ml), potassium fluoride (0.53 g) and cyclopropylamine (2.2 ml) and the mixture is stirred at 100° C. for 23 hours. After cooling, the mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane: methanol=40:1) to give 3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-nitro-N-cyclopropylaniline (1.65 g).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2C=C(CN3CCN(C(OC(C)(C)C)=O)CC3)SC=2N=1.Cl.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[C:39]3[CH:54]=[C:53]([CH2:55][N:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)[S:52][C:40]=3[N:41]=[C:42]([C:44]3[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[N:48][CH:49]=3)[N:43]=2)[CH2:34][CH2:33]1.[C:62](O)(=[O:66])[C@H:63]([CH3:65])[OH:64]>>[OH:64][C@@H:63]([CH3:65])[C:62]([N:59]1[CH2:60][CH2:61][N:56]([CH2:55][C:53]2[S:52][C:40]3[N:41]=[C:42]([C:44]4[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[N:48][CH:49]=4)[N:43]=[C:38]([N:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[C:39]=3[CH:54]=2)[CH2:57][CH2:58]1)=[O:66]
Reactant: C[C@H](O)C(=O)O
Reactant: N#Cc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCNCC4)sc3n2)cn1
Agent: CC(C)(C)OC(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: Cl
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(C#N)nc4)nc3s2)CC1

Procedure:
Tert-butyl 4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (75 mg) was reacted with 6-cyanopyridin-3-yl-3-boronic ester via General Procedure A. This crude intermediate was subjected to General Procedure D in which the crude HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)pyridine-2-carbonitrile was reacted with L-Lactic acid via General Procedure B to give 7 mg of 404 after reverse phase HPLC purification. MS (Q1) 494.2 (M)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:31]([OH:33])=[O:32])=[CH:26][N:25]=1.ClCCl>CC(C)=O.C(OCC)(=O)C>[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:31]([O:33][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([F:7])=[C:9]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[O:32])=[CH:26][N:25]=1
Reactant: Cc1ncc(C(C(=O)O)C(C)(C)C)cn1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1ncc(C(C(=O)OCc2ccc(F)c(Oc3ccccc3)c2)C(C)(C)C)cn1
Reaction time: 6 h
Yield: 56.8 %

Procedure:
Solid potassium carbonate (0.4 g) was added to a solution of 4-fluoro-3-phenoxybenzyl bromide (0.4 g) and (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoic acid (0.3 g) in acetone (20 cm3), and the mixture was stirred for a period of 6 hours. After standing for a further 2 days, the reaction mixture was filtered, the residue washed with acetone, and the combined filtrate and acetone washings concentrated by evaporation of the solvent under reduced pressure to give an orange oil. Column chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent gave 4-fluoro-3-phenoxybenzyl (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoate (0.33 g) as an orange oil, which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl.Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 70 °C
Yield: 85.5 %

Procedure:
A mixture of 2-chloro-4-nitro-phenol (202 mg, 1.16 mmol), 2-chloromethyl-quinoline hydrochloride (224 mg, 1.04 mmol), K2CO3 (354 mg, 2.55 mmol) in CH3CN (3.6 ml) was heated at 70° C. for 8 h. DMA (2 ml) was added, and the mixture was heated at 80° C. for 4 h. The mixture was cooled to rt, diluted with EtOAc (120 ml), washed with H2O (6×80 ml) and brine (1×80 ml), dried (MgSO4) and filtered. The filtrate was concentrated to give 12A (280 mg, 85%).