Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O1CCCC1.[Cl:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[NH2:14].Cl[S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27]C)=[O:26])(=[O:19])=[O:18]>CCCCCC>[Cl:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[NH:14][S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([OH:27])=[O:26])(=[O:18])=[O:19]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a mixture of sodium hydride (60%, 2.1 g, 52 mmol) and tetrahydrofuran (20 mL) was added a mixture of 4-chloro-3-methyl-1,2-oxazol-5-amine (3.0 g, 23 mmol) and tetrahydrofuran (20 mL) at 0° C., followed by stirring at that temperature for 30 minutes. Methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (5.3 g, 22 mmol) was added at that temperature to the reaction mixture, which was then stirred for 1 hour at 0° C., and then stirred for 4 hours at room temperature. Hexane (100 ml) was added at room temperature to the reaction mixture, and the precipitated solid was collected by filtration. Methanol (20 mL) was added to the solid, followed by a 2N aqueous solution of sodium hydroxide (20 mL), and the reaction mixture was stirred for 5 hours at room temperature. The solvent was distilled away under reduced pressure, and ice water (20 mL) was added to the residue, followed by a 2 N aqueous solution of hydrochloric acid (20 mL). The precipitated solid was collected by filtration to give the title compound (2.5 g, 35% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1C2C(=CC=CC=2)C=N1.N([O-])=O.[Na+]>[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([CH:13]=[N:22][N:17]2[CH2:18][CH:19]([OH:21])[CH3:20])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CC(O)CNc1cc(OCc2ccccc2)ccc1C=O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Product: CC(O)Cn1ncc2ccc(OCc3ccccc3)cc21
Yield: 60 %

Procedure:
The product of Step C (202.7 g, 0.71 mol) was treated as described for Steps C and D of Preparation 3. After the nitrosamine intermediate had been converted to a mixture of the desired indazole product and unreacted starting material (5:1), sodium nitrite (29.5 g, 0.43 mol) was added to renitrosate the starting material. Zinc dust (84 g, 1.28 mol) was then added in portions with cooling as described. When the starting material was consumed, the reaction mixture was worked up as described and combined with the product from another batch that started with 176 g of the product of Step C. The combined crude products were purified by chromatography (Biotage Kiloprep-250) to give a solid (226 g, 60%): 99% purity by HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:23]4[C@@H:19]([O:20]C(C)(C)[O:22]4)[C@H:18]([O:26]C)[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.FC(F)(F)C(O)=O>O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:23]([OH:22])[C@@H:19]([OH:20])[CH:18]([OH:26])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: CO[C@@H]1O[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)[C@H]2OC(C)(C)O[C@@H]12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3OC(O)[C@H](O)[C@@H]3O)c21
Temperature: 80 °C

Procedure:
To a suspension of 4-Amino-5-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (Example 212b) (15 mg, 0.038 mmol) in water (1 mL) was added trifluoroacetic acid (0.2 mL) and the mixture was heated overnight at 80° C. The reaction mixture was evaporated to dryness to furnish the title compound as a white solid in quantitative yield (mixture of diastereomers˜10/1). 1H NMR (400 MHz, DMSO-d6): δ 3.71 (m, 4H), 4.12 (m, 3H), 4.35 (m, 1H), 5.02 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 8.03 (br s, 1H), 8.31 (br s, 1H), 10.96 (br s, 1H), [11.00 (br s, 0.1H)].
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(O)(=O)C.[CH3:34][NH2:35].C1COCC1>ClCCCl>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH:35][CH3:34])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CN
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CNC)C1=O
Reaction time: 48 h

Procedure:
To a solution of 1.67 g (3.88 mmol) of (S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal (Example 126, Step C) and acetic acid (6.60 mL, 116 mmol) in DCE (40 mL) was added 2 M methylamine in THF (19.40 mL, 38.8 mmol) and sodium triacetoxy hydroborate (3.29 g, 15.52 mmol) at room temperature. The reaction was stirred for 2 days. The reaction was quenched with sat aq. NaHCO3, extracted with EtOAc, and the combined organic layers were washed with 1N NaOH and sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as a pale yellow oil, which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[C:12]([NH2:20])(=[NH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na]>C(O)C>[C:13]1([C:12]2[NH:20][C:3](=[O:5])[CH2:2][C:1](=[O:9])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)NC(c2ccccc2)=N1

Procedure:
Wherein R1, R2 and R3 are defined as above. The cyclization reaction between the commercially available diethyl malonate and an appropriate benzamidine is effected by refluxing a substantially equimolar mixture of these reactants in a reaction-inert solvent, such as ethanol, in the presence of sodium metal for a period of about two to about five hours. After the reaction is complete, the reaction mixture is filtered, the filter cake dissolved in water and precipitated by acidification to afford a 2-phenyl-4,6-(1H,5H)-pyrimidinedione (I).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH:13][C:14]([NH2:16])=[O:15])[CH2:10][CH2:11][CH3:12].I[C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[CH2:9]([NH:13][C:14]([NH:16][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:15])[CH2:10][CH2:11][CH3:12]
Reactant: COc1cccc(I)c1
Reactant: CCCCNC(N)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Nc1cccc(OC)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
A test tube was charged with CuI (10 mg, 0.05 mmol, 0.05 equiv), K3PO4 (425 mg, 2.0 mmol, 2.0 equiv), butylurea (232 mg, 2.0 mmol, 2.0 equiv), filled with argon. 3-Iodoanisole (119 μL, 1.0 mmol, 1.0 equiv), N,N′-dimethylethylendiamine (11 μL, 0.10 mmol, 0.10 equiv) and dry toluene (1.0 mL) were added under argon. The test tube was sealed and the reaction mixture was stirred at 110° C. for 24 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with diethyl ether. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane:diethyl ether 1:2) provided 188 mg (85% yield) of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cu][C:12]#[N:13].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:12]#[N:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N#C[Cu]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#CC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 74.3 %

Procedure:
17.5 g (0.1 mol) 2-chlorobenzoyl chloride, 11.65 g (0.13 mol) copper (I) cyanide, and 8 mL of acetonitrile in 15 mL of toluene was refluxed for 3 hours, and then cooled to room temperature. Insoluble material was filtered and the residue was washed with toluene. The solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to yield 12.3 g of 2-chlorophenyloxoacetonitrile (yield=75%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Si:16]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ncn2ccsc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ncn2ccsc12
Reaction time: 2 h

Procedure:
To a solution of 2.42 mg of 7-hydroxymethylimidazo[5,1-b]thiazole in 15 ml of DMF were added under ice-cooling 1.4 g of imidazole and 2.73 g of t-butyldimethylsilylchloride, and the mixture was stirred at the same temperature for 2 hours. DMF was removed under reduced pressure, and the residue was extracted two times with ethyl acetate. The organic layer was washed two times with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and removed under reduced pressure to give 7-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole in a yield of 4.02 g.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1ccccc1O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a mixture of 152 g (1.0 mole) of methyl salicylate and 500 ml of chloroform were added dropwise with stirring a solution of 172 g (1.08 mole) of bromine in 300 ml of chloroform at about 10° C. over a period of 6 hours. After the addition, the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and then with an aqueous solution of sodium bicarbonate. Removal of the solvent gave 230 g of substantially pure methyl 5-bromosalicylate in 99.6% yield, M.P. 59° to 61.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30].C(N(C(C)C)CC)(C)C.[CH2:41]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH:52]1[CH2:57][CH2:58][SH:59])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(OCC)(=O)C.O>[CH2:41]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH:52]1[CH2:57][CH2:58][S:59][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:29]([O-:31])=[O:30])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:50])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCS
Reactant: Cc1cc(C)cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)cc(-c2c(SCCC3CCCCN3C(=O)OCc3ccccc3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a solution of trifluoromethanesulfonic acid 7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl ester (524 mg in 4 mL dry N,N-dimethylformamide) at 0° C. was added 0.38 mL diisopropylethylamine followed by 2-(2-mercaptoethyl)-piperidine-1-carboxylic acid benzyl ester (455 mg in 1 mL N,N-dimethylformamide) and the reaction allowed to warm to room temperature. After 1 hour, the mixture was diluted with ethyl acetate and water, and the layers separated. The organic portion was washed sequentially with water and brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 7:3) gave the title compound (142 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 1 g, 2.53 mmol), pyrrolidine (0.544 g, 5.06 mmol), DIPEA (1.325 mL, 7.58 mmol) and iPrOH (2.53 mL) were added to a MW vial and subjected to MW irradiation at 140° C. for 1 h. The mixture was treated with aqueous HCl (40 mL of 0.5 M) was added and extracted with EtOAc The combined extracts were washed with 0.5 M HCl (40 mL) and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from cyclohexane/EtOAc to yield the title compound as an off-white solid. UPLC-MS (Condition 3) tR=1.34 min, m/z=430.1/432.1 [M+H]+, m/z=428.3/430.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76-2.01 (m, 4H) 3.60-3.80 (m, 4H) 7.33 (d, J=8.20 Hz, 2H) 7.72-7.91 (m, 2H) 8.32 (d, J=1.95 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: C([O:5][C:6]1[C:7]([CH:12](F)[N:13]2[CH2:18][CH2:17][CH:16]([C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH2:15][CH2:14]2)=[N:8][CH:9]=[CH:10][N:11]=1)(C)(C)C.[F:30]C(F)(F)C(O)=O>>[F:30][C:10]1[NH:11][C:6](=[O:5])[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH2:15][CH2:14]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)Oc1nccnc1C(F)N1CCC(C(=O)Cc2ccccc2F)CC1
Reactant: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1F)C1CCN(Cc2ncc(F)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
After dissolving 122 mg of 1-[1-(3-tert-butoxy-fluoro-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone in 3 ml of trifluoroacetic acid, the mixture was stirred for 1.5 hours at room temperature. The reaction solution was cooled on ice, the pH was adjusted to 7 with a 5% sodium hydroxide solution, and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (97 mg, 93% yield).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].C[O:10][CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[N:26]=C=O>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:22]1[C:21]([NH:26][C:11]([C:12]2([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]2)=[O:10])=[C:20]([CH3:19])[O:24][N:23]=1
Reactant: COCC1(S(N)(=O)=O)CC1
Reactant: Cc1noc(C)c1N=C=O
Agent: CC(C)(C)NC(=O)O
Product: Cc1noc(C)c1NC(=O)C1(S(N)(=O)=O)CC1
Yield: 100 %

Procedure:
This compound was obtained in a crude 100% yield according to the procedure described for the synthesis of 1-methoxymethylcyclopropylsulfonylamine tert-butylcarbamate (Step B.1.a) except that 1.20 equivalents of 3,5-dimethylisoxazole-4-isocyanate was used as the electrophile. The compound was taken directly into the next reaction without purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:30]=[CH:31][CH:32]=2)[C:23]([F:38])=[CH:22][N:21]=1.C(Cl)(Cl)Cl.CO>C(O)CCC>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:30]=[CH:31][CH:32]=3)[C:23]([F:38])=[CH:22][N:21]=2)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(N)cc1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCCCO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)ncc2F)c1
Yield: 11.6 %

Procedure:
A solution of 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)aniline (4.02 g) and N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)acrylamide (4.0 g) in 1-butanol (10 mL) was heated to 135° C. for 3 hr. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, butanol was removed under reduced pressure and water was added. The mixture was extracted with ethyl acetate. Organic layer was dried over sodium sulfate and solvent was removed under reduced pressure. Crude material was purified by Combiflash chromatography eluting with 2.5% methanol in CHCl3 to give 0.828 g of N-(3-((2-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)acrylamide. 1H NMR: DMSO-d6 (400 MHz) 0.036 (s, 6H), 0.844 (s, 9H), 3.859-3.895 (d, 4H), 5.737-5.767 (dd, 1H, J=1.6, 8.4), 6.245-6.292 (dd, 1H, J=2, 15.2), 6.437-6.505 (m, 1H), 6.737-6.760 (d, 2H, J=9.2), 7.252-7.293 (t, 1H, J=8), 7.415-7.542 (m, 4H), 7.944-7.956 (d, 1H, J=4.8), 8.065-8.074 (d, 1H, J=3.6), 8.896 (s, 1H), 8.896 (s, 1H), 9.379 (s, 1H), 10.1190 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1

Procedure:
The 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid thus obtained is reacted with benzyl bromide in the presence of potassium hydroxide, to obtain 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([CH:13]([OH:17])[C:14]([CH3:16])=[CH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:18](Cl)[CH:19]=[CH:20][CH3:21]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([O:17][CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:14]([CH3:16])=[CH2:15])[CH:19]=[CH:20][CH3:21]
Reactant: CC=CCCl
Reactant: C=C(C)C(O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: C=C(C)C(OCC=CC)c1ccccc1
Temperature: 5 °C
Yield: 83 %

Procedure:
Solid potassium tert-butylate (26 g, 0.228 mol) was added portion-wise (ca 15 min) to a solution of 1-phenyl-2-methyl-2-propen-1-ol (90% pure from Alfa Aesar, 25 g, 0.152 mol) in dry THF (300 ml) at room temperature under nitrogen (exothermic to 30° C.). After 1 more hour at room temperature, the reaction was cooled to 5° C. and tetra butyl ammonium iodide (2.9 g, 0.08 mol) was added followed by crotyl chloride (41.3 g, 0.456 mol) drop-wise. The reaction was warmed up to room temperature overnight and poured onto water (500 ml). The reaction was extracted twice with ethyl acetate. Each organic phase was washed with water and brine. Combined extracts were dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. After column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1) the product was purified by bulb-to-bulb distillation (100° C./0.001 mbar). A 3:1 mixture of E/Z isomers was obtained (95% pure, 26.78 g, yield=83%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:20]1[CH2:22][CH2:21]1)[C:17]([OH:19])=[O:18].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:32]=[C:33]([C:34]([O:36][CH3:37])=[O:35])[C:26]=12)=O>C(Cl)Cl>[C:41]([O:40][C:38]([N:31]1[C:27]2=[N:28][CH:29]=[CH:30][C:25]([CH2:23][NH:15][C@H:16]([CH:20]3[CH2:22][CH2:21]3)[C:17]([OH:19])=[O:18])=[C:26]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: N[C@@H](C(=O)O)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), (R)-2-amino-2-cyclopropylacetic acid (37.8 mg, 0.329 mmol), and DCM (2 mL). The reaction mixture was stirred at room temperature in for 30 min, after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C20H25N3O6, 404; found, 404.3.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[C:13]([F:18])[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[C:13]([F:18])[CH:12]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: Cc1ccc(B(O)O)s1
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: COCCOC
Product: Cc1ccc(-c2ccc(Br)cc2F)s1
Temperature: 75 °C
Yield: 75 %

Procedure:
A mixture of 5-methyl-2-thiophene-boronic acid (1 g, 7.0 mmol), 1-bromo-3-fluoro-4-iodobenzene (1.77 g, 5.9 mmol), tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.3 mmol), 2M Na2CO3(10 mL) in DME (10 mL) was heated to 75° C. under N2 for 15 h. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound (1.2 g, 75%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]([C:9]([CH3:11])=O)[CH2:7][CH3:8].N1CCCC1>CO.CCOCC.O>[CH3:8][C:7]([CH2:6][CH2:9][CH3:11])=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1
Reactant: CCCC(C)=O
Reactant: C1=CCC=C1
Solvent: CCOCC
Solvent: C1CCNC1
Solvent: O
Product: CCCC(C)=C1C=CC=C1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a solution of 10.00 g (151.3 mmol) of cyclopentadiene in 40 ml of methanol, 18.6 ml (174.2 mmol) of methyl propyl ketone and 4.5 ml (54.7 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (70° C./1 mmHg) to obtain 12.30 g (91.64 mmol) of a yellow liquid (yield: 61%). The analyzed values are given below.