Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CN(C)CC(O)=O>O1CCOCC1.CCOC(C)=O.O>[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(O)cc1
Reactant: Brc1ccc(-c2cnco2)cc1
Agent: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ncc(-c2ccc(Oc3ccc(OC[C@@H]4CCCN4)cc3)cc2)o1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-bromophenyl)-1,3-oxazole (224 mg, 1.0 mmol) in dioxane (2 mL) was added (S)-2-(4-Hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (440 mg, 1.5 mmol) in dioxane (2 mL) and cesium carbonate (651 mg, 2.0 mmol). The vessel was purged with nitrogen for 15 min before N,N-dimethylglycine hydrochloride (12.5 mg, 0.09 mmol) in dioxane (1 mL) and Cu(I) iodide (6 mg, 0.03 mmol) were added. The resulted mixture was stirred it 85° C. for 16 h. It was then diluted with EtOAc and water, organic layer was separated, washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo to dark brownish oil. The crude mixture was purified by silica gel flash chromatography (10% EtOAc/Hexane) before treating it with 4M HCl in dioxane (5 mL) at rt for 1 h. Solvent was removed in residue was triturated with ether and dried under vacuum to give the product, as white solid (336 mg, 90%): MS; m/z 337.4 M+H), 1H NMR (400 MHz, DMSO-d6); δ 1.71-2.15 (m, 4H), 3.18-3.25 (m, 2H), 3.88-3.91 (m, 1H), 4.12-4.17 (m, 1H), 4.23-4.27 (m, 1H), 7.00-7.10 (m, 6H), 7.59 (s, 1H), 7.71 (dd, 2H, J1=6.8 Hz, J2=2.4 Hz, 8.41 (s, 1H), 9.04 (br, 1H), 9.6 (br, 1H); HPLC (UV); 99%
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:8]
Reactant: Cc1cc(F)ccc1NC1CN(c2ncc(F)cc2C(=O)O)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cnc3N3CC(Nc4ccc(F)cc4C)C3)CC2)cc1
Yield: 24.1 %

Procedure:
The title compound (D190) (26 mg) was prepared according to the experimental procedure described in Description 169 starting from 5-fluoro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinic acid (D135) (70 mg, 0.219 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (50 mg, 0.219 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C1COCC1.CN(C=O)C.[CH3:37][C:38]([OH:42])([C:40]#[CH:41])[CH3:39]>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.[Cu]I>[NH2:20][C:17]1[O:18][CH2:19][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:41]#[C:40][C:38]([CH3:39])([OH:42])[CH3:37])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:11][CH:10]=3)[N:16]=1
Reactant: C#CC(C)(C)O
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 110 °C

Procedure:
Combined (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (99 mg, 0.242 mmol), tetrakis(triphenylphosphine)palladium (28.0 mg, 0.024 mmol), copper(i) iodide (4.61 mg, 0.024 mmol) and THF (969 μL, 0.242 mmol) and DMF (969 μL, 0.242 mmol). Added DIPA (679 μL, 4.85 mmol) then 2-methylbut-3-yn-2-ol (118 μL, 1.211 mmol) and flushed the reaction tube with argon. Sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH to give (S)-4-(2′-amino-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol as a white solid after evaporation from DCM/hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:17][CH:18]1[NH:22][C:21](=O)[CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]1([CH3:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]([C:21]2[CH2:20][CH2:19][CH:18]([CH3:17])[N:22]=2)[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC1CCC(=O)N1
Reactant: CC1(C)c2ccccc2Nc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3C(C)(C)c3ccccc32)=N1
Yield: 11 %

Procedure:
Reaction of 9,9-dimethylacridan, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 9,9-DIMETHYL-10-(5-METHYL-1-PYRROLIN-2-YL)ACRIDAN as a distillable oil, b.p. 160°-180° C. at 0.15 mm Hg. in 11% yield. Conversion of the free base to the hydrochloride salt affords 9,9-DIMETHYL-10-(5-METHYL-1-PYRROLIN-2-YL)ACRIDAN HYDROCHLORIDE, m.p. 232.5°-234.5° C. (dec.) (corr.), by trituration with hot benzene.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[NH:15][C:14](=O)[CH2:13][N:12]([CH3:17])[C:11]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>[CH2:1]([O:8][CH2:9][C@H:10]1[NH:15][CH2:14][CH2:13][N:12]([CH3:17])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(=O)N[C@H](COCc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN[C@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of (R)-3-Benzyloxymethyl-1-methyl-piperazine-2,5-dione (1.93 g, 7.78 mmol) in THF (30 mL), LiAlH4 1M in THF (15 mL, 15.5 mmol) was added dropwise over 30 min and the solution was refluxed under N2 atmosphere for 3 h. The reaction was cooled to 0° C. and diluted with water (100 mL). Then 4 mL of a 15% aqueous NaOH solution was added. After 1 h 100 mL of water was added and the reaction stirred overnight. The white precipitate was filtered out and washed with DCM. The solvent was removed under reduced pressure and the residue was diluted with Et2O and decanted. The crude was purified by flash chromatography (DCM/MeOH/7N NH3 in methanol, 90:9:1) to give the desired compound (1.43 g, 83.5% yield) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[Na].Cl.[C:15](#[N:17])[CH3:16]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:16][C:15]#[N:17])=[O:9])=[CH:11][CH:12]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxybenzoate (7.2 kg) in dimethyl sulfoxide (21.6 L) were added sodium methoide (3.046 kg) and acetonitrile (2.135 kg) and the mixture was stirred at 110° C. for 2 hours. Then, water (10.83 L) was added dropwise thereto at 15° C. or lower and further acetonitrile (14.4L) was added to the mixture. Then, 6 N HCl was added thereto to adjust to pH 7.9 and the mixture was extracted with ethyl acetate (72L). The aqueous layer was further extracted with ethyl acetate (36.32 L). The organic layers were combined and concentrated until the content became 17.39 kg. Methanol (17.84 L) was added thereto and water (17.84 L) was added dropwise. Then, the mixture was stirred at 5° C. for 1 hours and crystals deposited were filtered off and washed with methanol-water (1:1) to obtain the titled compound '6.40 kg, 82.7 g). 1H-NMR (CDCl3) δ:3.90 (3H, s), 4.03 (2H, s), 6.98 (2H, d, J=11.25 Hz), 7.50 (2H, d, J=11.25 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C.[CH3:54][C:55]1[O:56][C:57]([C:60]2[C:61]([N:69]3[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]3)=[C:62]3[CH:68]=[CH:67][NH:66][C:63]3=[N:64][CH:65]=2)=[N:58][N:59]=1>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([N:72]2[CH2:71][CH2:70][N:69]([C:61]3[C:60]([C:57]4[O:56][C:55]([CH3:54])=[N:59][N:58]=4)=[CH:65][N:64]=[C:63]4[NH:66][CH:67]=[CH:68][C:62]=34)[CH2:74][CH2:73]2)=[O:12])[CH2:9][N:8]([CH:21]([CH3:22])[CH3:23])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:15][CH:16]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Cc1nnc(-c2cnc3[nH]ccc3c2N2CCNCC2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nnc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
(S)-3-(tert-Butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (180 mg, 0.52 mmol, see Example H), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (134 mg, 0.70 mmol), HOBt-H2O (108 mg, 0.70 mmol) and triethylamine (106 mg, 1 mmol) were added to 2-methyl-5-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3,4-oxadiazole (100 mg, 0.36 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 18 hours. After dilution with DCM, the mixture was washed with 1N HCl, 10% K2CO3 and brine. The organic phase was dried over MgSO4 and purified by chromatography (SP4, 12+M, water/ACN 90/10→10/90, 20CV) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (60 mg) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][N:4]3[C:3]([CH3:8])=[C:2]([Br:1])[C:6]([CH3:7])=[N:5]3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: Cc1n[nH]c(C)c1Br
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C)c1Br

Procedure:
Protocol T was followed using 4-Bromo-3,5-dimethyl-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.95–7.1 (m, 2H), 6.84–6.92 (dd, 2H), 4.90 (s, 2H), 3.62–3.82 (m, 4H), 3.02–3.12 (m, 4H), 2.24–2.34 (d, 6H). 13C NMR (400 MHz, CDCl3): 165, 158.4, 156.6, 150.6, 146.8, 141.4, 119, 115.6, 115.2, 52.6, 51.6, 50.4, 45.2, 42.2, 14.8, 12.6.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH2:24])[CH2:21]2.[C:25]([C:29]1[N:33]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[CH3:41])[N:32]=[CH:31][C:30]=1[C:42](O)=[O:43])([CH3:28])([CH3:27])[CH3:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOCC>[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:42]([C:30]1[CH:31]=[N:32][N:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=3[CH3:41])[C:29]=1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])[CH2:21]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: Cc1cc(Cl)ccc1-n1ncc(C(=O)O)c1C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)ccc1-n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (Intermediate #115) (515 mg, 2.68 mmol) was added in one portion to 2-Adamantanamine hydrochloride (420 mg, 2.24 mmol), 5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (655 mg, 2.24 mmol), 1-Hydroxybenzotriazole (363 mg, 2.68 mmol) and N-Ethyldiisopropylamine (1.149 mL, 6.71 mmol) in DMF (10 mL). The is resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was diluted with Et2O (100 mL), and washed sequentially with water (3×25 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford desired product N-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl-pyrazole-4-carboxamide (860 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:25][CH2:26][CH2:27][N:12]4[CH:11]=2)[CH:15]=[C:16]([C:21]#[C:22][CH2:23]O)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Pt].C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:25][CH2:26][CH2:27][N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][CH2:22][CH3:23])[CH:17]=3)=[O:9])=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(C#CCO)cc3c1=O)OCC2
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1cc2c3c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn3CCO2
Yield: 34 %

Procedure:
A mixture of 50 mg of N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide of Example 2 and 20 mg of 5% platinum on carbon in 2 mL of 1:1 THF-methanol is stirred vigorously under 1 atmosphere of hydrogen gas for 3 hours, then filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure, and the residue chromatographed on silica using 2-3% methanol in dichloromethane. Following concentration under reduced pressure, the upper eluting fractions provide 16.5 mg of N-(4-chlorobenzyl)-7-oxo-9-propyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide (3B); the lower eluting fractions similarly afford 27.5 mg of N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide (3A).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:29][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)([OH:27])[CH3:28])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC1(c2ccc(Cl)cc2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(n(CC(C)(O)c3ccc(Cl)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Chlorophenyl)-2-methyloxirane (214 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol) as the TFA salt.
Reaction SMILES: [CH3:1][C:2]([NH2:7])([CH3:6])[CH2:3][S:4][CH3:5].[C:8](Cl)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]([NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:6])[CH2:3][S:4][CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSCC(C)(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
In tetrahydrofuran (300 ml) was dissolved 23.86 g (200 mmol) of 1,1-dimethyl-2-(methylthio)ethylamine, and 103.4 g (200 mmol) of a 30% solution of carbobenzoxy chloride in toluene and then a solution of 24.29 g (240 mmol) of triethylamine in tetrahydrofuran were slowly dropped thereinto under ice-cooling. After the resulting mixture was stirred at room temperature for 3 hours, the triethylamine hydrochloride precipitated was filtered under reduced pressure and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 36.35 g (yield 72%) of benzyl 1,1-dimethyl-2-(methylthio)ethylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:4]4[C:5]([F:9])=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=4)[CH2:18]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc2c(c1)CNCC2
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)CN(c1nc(Cl)ncc1F)CC2

Procedure:
In a like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1,2,3,4-tetrahydroisoquinoline were reacted to provide 2-chloro-N4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.08 (d, 1H, J=3.0 Hz), 7.95 (d, 1H, J=6.0 Hz), 7.50–7.42 (m, 2H), 7.21 (d, 1H, J=8.4 Hz), 6.96–6.90 (m, 1H), 4.95 (s, 2H), 4.04 (t, 2H, J=5.7 Hz), 2.99 (t, 2H, J=5.7 Hz); 19F NMR (282 MHz, CDCl3): −42555, −44573; LCMS: purity: 98%; MS (m/e): 410(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.[C:14]([CH2:16]C(OCC)=O)#[N:15].C(N(CC)CC)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:10][C:9](=[O:11])[C:16]([C:14]#[N:15])=[C:7]2[OH:12]
Reactant: CCOC(=O)CC#N
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2cc(Cl)ccc2[nH]c1=O

Procedure:
A solution of 6-chloro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (2 g, 10.1 mmol, Eq: 1.00), ethyl cyanoacetate (1.15 g, 1.08 ml, 10.1 mmol, Eq: 1.00) and triethylamine (14.5 g, 20.0 ml, 143 mmol, Eq: 14.2) in DMF (1.00 ml) was stirred at RT for 65 h. Then 1N HCl was added and the reaction mixture was extracted with ethyl acetate (3×). The combined extracts were washed brine. An off-white solid precipitated and was filtered off (337 mg). MS (ESI): 219.1 (M−H)−.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:27].[K+]>O.C(O)(=O)C>[I:27][C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CC(C)C(=O)Nc1ccc(N)c(C(F)(F)F)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(=O)Nc1ccc(I)c(C(F)(F)F)c1

Procedure:
To a solution of 23.0 g. of 4'-amino-3'-trifluoromethylisobutyranilide in 150 ml. of glacial acetic acid and 100 ml. of water, while maintaining the mixture temperature at 10°-20° C., slowly add 17 ml. of concentrated sulfuric acid, cool the resulting mixture to about 0° C. and slowly add 8.5 g. of sodium nitrite in 15 ml. of water maintaining the temperature of the reaction at about 0° C. for 30 minutes. Add 50 g. of potassium iodide in 150 ml. of water and stir the resulting mixture for 1 hour. Filter, water-wash and dissolve the precipitate in 200 ml. of ether and remove the iodine by washing with a 10% sodium sulfite solution. Dry, remove the solvent, and recrystallize from carbon tetrachloride, obtaining the compound of this example, m.p. 143°-145° C.
Reaction SMILES: C(OC(=O)CC1C=CC([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22](C4CC4)[CH:23]=2)[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]3([CH3:30])[CH3:29])=CC=1F)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:13]([C:14]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3([CH2:27][CH2:28]3)[CH2:18][C:17]([CH3:29])([CH3:30])[C:16]=2[CH:15]=1)#[CH:12]
Reactant: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CC1(CC1)O2

Procedure:
Following general procedure E and using 3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1 ′-cyclopropane] (Intermediate 37, 0.4 g, 1.42 mmol), potassium carbonate (0.98 g, 7.1 mmol) and methanol, the title compound was obtained as a yellow oil (0.3 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2].FC(F)(F)C([O-])=O.[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:22][CH3:23])[C:41]([NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C)cnc1-c1cc(CC(=O)OCC)ccc1OC
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, trifluoroacetate (0.36 mmol) was reacted with benzyl isocyanate (0.05 mL, 0.44 mmol) and triethylamine (0.152 mL, 1.09 mmol) in CH2Cl2 to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[C:36]2[CH:37]=[CH:38][C:39](B(O)O)=[CH:40][C:35]=2[CH2:34][CH2:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)=[CH:40][C:35]=2[CH2:34][CH2:33]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCO2
Yield: 91.4 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 2,3-dihydrobenzofuran-5-ylboronic acid (0.246 g; 1.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.184 g (91%) of the title compound.