Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](=[O:21])[CH:8]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:10][C:11]=2[C:12](Cl)=[CH:13][CH:14]=1)=[O:4].CCN(CC)CC>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](=[O:21])[CH:8]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: CCOC(=O)c1cc(=O)c2c(C(=O)OC)ccc(Cl)c2[nH]1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)c2c(C(=O)OC)cccc2[nH]1
Temperature: 50 °C

Procedure:
To a suspension of 24 (4.50 g, 14.5 mmol) in EtOAc (100 mL) was added Et3N (50 mL). The reaction mixture was heated to 50° C. to generate a clear solution. 10% Pd/C (0.500 g) was added carefully. The reaction mixture was hydrogenated (50 psi) on a Parr hydrogenation apparatus at room temperature for 4 h. Then the catalyst was filtered off on a pad of celite and the filtrate washed with water (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was washed with Et2O (100 mL) to give an off-white solid (29, 3.46 g, 99.1%). 1H NMR (DMSO-d6, 300 MHz) δ ?8.05 (d, J=8.6 Hz, 1H), 7.75 (t, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.63 (s, 1H), 4.44 (q, J=7.3 Hz, 2H), 3.80 (s, 3H), 1.37 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.[NH2:25][NH2:26]>CS(C)=O>[F:8][C:7]1[C:2]([NH:25][NH2:26])=[N:3][C:4]([CH3:10])=[N:5][C:6]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: NN
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NN)c(F)c(N2CCCC2)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (100 mg, 0.55 mmol) was dissolved in 2 mL of DMSO and stirred at room temperature. Pyrrolidine (50 μL, 0.61 mmol) was added, followed by DIPEA (210 μL, 1.21 mmol). The resulting reaction mixture was stirred for 2 h, and then hydrazine was added (1.0 mL) and the contents were heated to 80° C. for 1 h. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to provide 5-fluoro-4-hydrazino-2-methyl-6-(1-pyrrolidinyl)pyrimidine (69 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([OH:27])=[O:26])[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[C:34](O)=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]>CCOC(C)=O>[F:28][C:29]1[C:34]([O:26][C:25](=[O:27])[C@@H:15]2[CH2:14][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][N:16]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)Oc2c(F)c(F)c(F)c(F)c2F)N(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 95 %

Procedure:
trans-4-(N-tert-Butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline (1.96 g, 5.06 mmol) was dissolved in EtOAc (40 mL) and pentafluorophenol (PFP) (1.03 g, 5.6 mmol) was added in one portion. (1,3-)dicyclohexylcarbodiimide (DCC 1.15 g, 5.6 mmol) was pre-dissolved in EtOAc (10 mL) and added dropwise over 1 minute. A white precipitate immediately formed which, upon stirring for 1 hour, 1:5 was filtered and the filtrate was concentrated to dryness to reveal the title compound in 95% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]3([CH2:31]C#N)[CH2:29][O:28]C(=O)[NH:26]3)=[C:18]([Cl:34])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:35].[Na+].Cl.[CH2:38]([OH:40])C>>[ClH:34].[NH2:26][C:25]([CH2:29][OH:28])([CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[CH:17][C:18]=1[Cl:34])[CH2:31][C:38]([OH:40])=[O:35]
Reactant: N#CCC1(CCCc2ccc(Sc3cccc(OCc4ccccc4)c3)cc2Cl)COC(=O)N1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: NC(CO)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)CC(=O)O

Procedure:
To the compound of Example 146 (196 mg), a 3 mol/L aqueous solution of sodium hydroxide (5 mL) and ethanol (0.5 mL) were added and the mixture was refluxed for 8 hours. While the mixture was stirred in an ice bath, 4 mol/L hydrochloric acid was added to adjust the pH of the mixture to 2 to 1. Using ethyl acetate and water, the mixture was separated into an organic phase and an aqueous phase. The organic layer was dried over anhydrous sodium sulfate, was concentrated, and was dried in a vacuum pump to give the desired product as a pale white solid (201 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=NN)[C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#N.[OH-:22].[Na+].C(O)C[O:26]CCO>O>[C:1]([C:3]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:26])=[O:22]
Reactant: COc1ccc2c(c1)C(=NN)Cc1c(C#N)cccc1S2
Reactant: OCCOCCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)CCc1c(cccc1C(=O)O)S2
Reaction time: 5 h

Procedure:
600 mg of 9-cyano-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin hydrazone and 600 mg of sodium hydroxide were added to 10 ml of diethylene glycol and the resulting mixture was heated with stirring at 190°-200° C. for 5 hours. After cooling, water was added to the mixture, which was extracted with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was chromatographed over silica gel and eluted with chloroform-ether (10:1). There was obtained 9-carboxy-2-methoxy-10,11-dihydrodibenzo[b,f]thiepin. Recrystallization from benzene afforded 140 mg of the desired product as colorless needles having a melting point of 185°-187° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl.O1CCOCC1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38]C)[N:33]=2)[C:22]=1[CH3:40]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[NH:33][C:34](=[O:38])[CH:35]=[CH:36][CH:37]=4)[C:22]=3[CH3:40])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: COc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2cccc(=O)[nH]2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (108 mg, 0.48 mmol) (described herein), 4.0M hydrochloric acid in 1,4-dioxane (100 μL, 0.40 mmol), 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (120 mg, 0.40 mmol) (described herein), and NMP (660 μL). The reaction mixture was stirred and heated in a microwave at 150° C. for 180 min. Purification afforded 6-(4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methylquinolin-2-yl)pyridin-2(1H)-one as a yellow solid. Mass Spectrum (ESI) m/e=479 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([C:25](O)(O)[C:26]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:27])[CH2:23][CH3:24].O>C(#N)C>[Br-:20].[Br-:20].[CH2:22]([CH2:25][C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH3:27])[CH2:23][CH3:24]
Reactant: CCCC(O)(O)C(C)(C1CCCCC1)C1CCCCC1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCCCC(C)(C1CCCCC1)C1CCCCC1
Product: [Br-]
Temperature: 10 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Triphenylphosphine (0.4 mol) is suspended in acetonitrile and cooled to 10° C., and bromine (0.39 mol) is added at this temperature. The suspension is stirred for a further 1 hour, and propyldicyclohexylpropane-diol B3.7 (0.2 mol) is then added. The mixture is stirred overnight at room temperature and subsequently refluxed for 4 hours. After cooling to room temperature, water is added, and the mixture is extracted with petroleum ether. The organic phase is dried and evaporated, and the residue is filtered through silica gel. Evaporation gives propyldicyclohexylpropane dibromide B3.8. Yield: 94%.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[CH3:11][Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:11][O:4][C:3](=[O:5])[C:2]([CH3:10])([CH3:1])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C)(C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCC(C)(C)C(=O)OC
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of 2,2-Dimethyl-hexanoic acid (10.15 g, 0.07 mol) in ether (150 mL) was added (trimethylsilyl)diazomethane (46 ml, 2M in hexanes, 0.092 mol) drop wise. The mixture was stirred for 3 h, and ether was evaporated without applying reduced pressure. Fractional distillation of the residue provided the title ester 11.12 g (b.p. 90-95° C./1 mmHg). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 3H), 1.1-1.2 (m, 2H), 1.13 (s, 6H), 1.21-1.31 (m, 2H), 1.44-1.51 (m, 2H), 3.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)[C@@H](N)CO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 100 °C

Procedure:
7.2 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g (R)-(−)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100° C. until no further reaction takes place, then cooled and evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[C:12]([O:15][CH2:16][CH2:17][C:18]#[N:19])(=O)[CH3:13].C([OH:23])(C)C>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]=[C:17]([C:18]#[N:19])[C:16]([O:15][CH2:12][CH3:13])=[O:23])[CH:9]=1
Reactant: CC(C)O
Reactant: CC(=O)OCCC#N
Reactant: COc1ccc(Cl)cc1C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(C#N)=Cc1cc(Cl)ccc1OC
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 5-chloro-2-methoxybenzaldehyde (32.2 g), cyanoethyl acetate and triethylbenzyl ammonium chloride (8.6 g) was stirred at 80° C. for 7 hours. To the reaction solution, isopropyl alcohol (97 ml) was added, then the mixture was stirred under ice cooling for 1 hour. The precipitated crystals were collected by filtration and dried in vacuo to obtain the title compound in an amount of 42.7 g as crystals.
Reaction SMILES: [CH:1]([CH:4]([C:7]1[CH:15]=[CH:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]=1)[C:5]#N)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:17].C(O)(=O)C.[OH2:25]>>[CH:1]([CH:4]([C:7]1[CH:15]=[CH:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]=1)[C:5]([OH:17])=[O:25])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)C(C#N)c1ccc2sccc2c1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)C(C(=O)O)c1ccc2sccc2c1
Yield: 28.9 %

Procedure:
A mixture of α-isopropylbenzo(b)thiophene-5-acetonitrile (2.00 g, 0.0093 mol), concentrated sulphuric acid (6.4 cm3), water (6.4 cm3) and acetic acid (26 cm3) was refluxed for 18 hr. The cooled mixture was poured into water and extracted with ether. The ether extract was extracted with saturated sodium bicarbonate solution. The aqueous solution was acidified and extracted with ether. The organic extract was dried (Na2SO4), filtered and the solvent was removed to give α-isopropylbenzo(b)thiophene-5-acetic acid (0.63 g, 2.7 m mol, 28.9%) m.p. 150°-151° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=2)[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1.O.Cl>C(O)C.[Fe]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc(N)ccc21
Yield: 40.1 %

Procedure:
3-(1H-Benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-ylamine can be obtained in the following way: 485 mg of powdered iron are added, in small fractions, to a solution, brought to reflux, of 350 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole, of 15 ml of ethanol, of 200 μl of distilled water and of 320 μl 12N hydrochloric acid and the mixture is maintained at reflux for 16 hours. After returning to a temperature in the region of 20° C., the medium is diluted with 60 ml of ethanol, stirred, and then filtered through a bed of Celite® 535, which is then washed with ethanol. The filtrate is basified to a pH in the region of 9 with a saturated aqueous sodium hydrogencarbonate solution. The precipitate thus formed is removed by filtration, and washed with ethanol, and the filtrate is then concentrated to dryness under reduced pressure. The evaporation residue is dissolved in distilled water and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 130 mg of 3-(1H-benzimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-ylamine are thus obtained in the form of an orange lac (Rf=0.34, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (50/50 by volume); mass analysis: El: m/z 379 (M+.) (base peak), m/z 306).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.O1CCCC1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OCC1(CO)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCC1(COCc2ccccc2)CCC1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 8.0 g (69 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 120 ml of a 1:1 mixture of tetrahydrofuran:N,N-dimethylformamide was added 3.30 g (69 mmol) of a 60% dispersion of sodium hydride in oil and the contents stirred for 30 min. 8.6 mL (72.4 mmol) of benzyl bromide was then added and the contents stirred for 2 h. The reaction was quenched with aqueous ammonium chloride followed by the addition of diethyl ether. The organic phase was isolated, dried using magnesium sulfate, and concentrated under vacuum to afford the crude product which was purified by silica gel chromatography using ethyl acetate:hexane (3:7) as the eluent to afford 12.0 g (86%) of {1-[(benzyloxy)methyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.25 (m, 5H), 4.49 (s, 2H), 3.66 (d, J=6 Hz, 2H), 3.52 (s, 2H), 2.53 (t, J=6 Hz, 1H), 1.91-1.73 (m, 6H). GC-MS m/z 207 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][C:7]=2[CH:22]=1)#[N:2].O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:24]1([O:18][C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][C:7]=4[CH:8]=3)=[CH:14][CH:15]=2)=[O:19])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1
Reactant: On1nnc2ccccc21
Reactant: N#Cc1ccc2oc(CCc3ccc(C(=O)O)cc3)cc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#Cc1ccc2oc(CCc3ccc(C(=O)On4nnc5ccccc54)cc3)cc2c1
Reaction time: 3 h
Yield: 78.5 %

Procedure:
At room temperature, 1 g of 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoic acid and 578 mg of 1-hydroxybenzotriazole were dissolved in 100 ml of dichloromethane, followed by the addition of 780 mg of 1,3-dicyclohexylcarbodiimide and by subsequent stirring at the same temperature for 3 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a chloroform/ethanol mixture as an elution solvent, and the thus purified product was crystallized from a benzene/n-hexane mixture. In this way, 1.1 g of 2-[2-[4-[[(1-benzotriazolyl)oxy]carbonyl]phenyl]ethyl]-5-benzofurancarbonitrile was obtained in a powdery form.
Reaction SMILES: C1(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([S:46]([C:49]2[CH:50]=[C:51](Br)[CH:52]=[CH:53][CH:54]=2)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>O1CCOCC1>[C:40]1([S:46]([C:49]2[CH:50]=[C:51]([N:66]3[CH2:65][CH2:64][N:63]([C:61]([O:60][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:62])[CH2:68][CH2:67]3)[CH:52]=[CH:53][CH:54]=2)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=S(=O)(c1ccccc1)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2cccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(S(=O)(=O)c3ccccc3)c2)CC1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
A solution of 2 2,2′-bis(diphenylphosphino-1,1′-binaphthyl (BINAP) (62 mg, 0.1 mmol) and cesium carbonate (329 mg, 1.01 mmol) in dry dioxane (2 ml) were sonicated for 45 min, under argon. To this solution was added 3-phenylsulfonylbromobenzene (D2) (200 mg, 0.67 mmol) and 1-(tert-butyloxycarbonyl)piperazine (314 mg, 1.68 mmol) and the reaction heated at 100° C. for 18 h. The reaction mixture was evaporated in vacuo and the residue partitioned between water (50 ml) and dichbromethane (50 ml). The organic layer was washed with sat. sodium hydrogen carbonate (50 ml), 10% citric acid (50 ml), brine (50 ml) and then dried (MgSO4). Solvents evaporated in vacuo and the residue purified by column chromatography (silica gel; 0-60% ethyl acetate/petroleum ether) to give the product as a colourless oil (192 mg, 71%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:2].[CH3:23][Si](C)(C)N[Si](C)(C)C.[K].CI>C1COCC1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:6]1[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:23])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)Cc1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: [K]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cc2ccccc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
tert-Butyl 2-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (3.0 g, 9.9 mmol) was added to anhydrous THF (29 mL) and cooled to −78° C. A 0.5M solution of potassium hexamethyldisilazane (20 mL, 9.9 mmol) was added slowly such that the internal temperature stayed below −60° C. Stirring was continued for 1 h at −78° C. Methyl iodide (727 μL, 11.7 mmol) was added to the mixture. The mixture was stirred for 30 minutes at room temperature. The mixture was quenched with sat. aq. ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na7SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethylacetate/hexane=1/9) to give tert-butyl 2-(1-ethoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate (2.8 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:14]([O-])=O.[Na+].C[Si](OP(=O)=O)(C)C.O>CCOC(C)=O>[F:24][C:13]([F:12])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:14]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][CH:7]=2)[N:1]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a mixture of 2-amino-4-methylbenzamide (804 mg, 5.36 mmol) and sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (1.25 g, 5.89 mmol) was added trimethylsilyl polyphosphate (ca. 10 mL) and the mixture was heated at 130° C. in a sand bath overnight. The mixture was allowed to cool to rt, and then water (75 mL) and EtOAc (75 mL) were added and the mixture was stirred at rt for 1 h. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-60% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazolin-4-ol (1.09 g, 66%). LCMS (ESI) m/z 306 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)[OH:5])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.O>[CH3:21][S:22]([O:5][CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:9]=[CH:8][N:7]=1)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)C(OS(C)(=O)=O)c1ncnn1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol (0.368 g, 1.32 mmol) in pyridine (15 mL) at 0° C. was added methanesulfonyl chloride (0.61 mL, 7.9 mmol) and the solution was slowly warmed to room temperature. The mixture was diluted with H2O, extracted twice with EtOAc and dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])(=[O:12])=[O:11])=[C:5]([CH3:33])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])(=[O:12])=[O:11])=[C:5]([CH3:33])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-Butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinoline-2-yl)methoxy)acetate (1 g, 2.103 mmol) was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (3.24 ml, 42.05 mmol) was added slowly. After stirring at room temperature for 2 h, the solvent was removed in vacuo and the residue was co-evaporated twice more with 20 ml of toluene each time. Yield: 0.84 g (95%).