Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:34])[C:17]2[O:23][C:22]3[C:24]([Cl:30])=[CH:25][C:26]([CH2:28][NH2:29])=[CH:27][C:21]=3[CH2:20][S:19](=[O:32])(=[O:31])[C:18]=2[CH:33]=1)=[O:13].Cl.ClC1C=CN=CC=1>O1CCOCC1>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:34])[C:17]2[O:23][C:22]3[C:24]([Cl:30])=[CH:25][C:26]([CH2:28][N:29]4[CH:3]=[CH:7][CH:6]=[CH:5]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:31])(=[O:32])[C:18]=2[CH:33]=1)=[O:13]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(CN)cc(Cl)c1O2
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(Cn3cccc3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
2,5-Dimethoxytetrahydrofuran (0.090 mL, 0.655 mmol) was added with stirring to a solution of Example 198k (0.2 g, 0.52 mmol) in dry dioxane (10 mL) followed by the addition of 4-chloropyridine hydrochloride (0.008 g, 0.05 mmol). The reaction mixture was allowed to stir at 110° C. for 2 h under nitrogen atmosphere. It was concentrated, treated with cold water and the solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, chloroform/pet ether) to obtain the title compound as a white solid. Yield: 0.086 g, (41.54%); 1H NMR (DMSO-d6): δ 2.69 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 4.67 (s, 2H, CH2), 5.02 (s, 2H, CH2), 6.22 (s, 2H, Ar), 6.68 (s, 2H, Ar), 7.04 (s, 1H, Ar), 7.38 (s, 1H, Ar), 8.09 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (ES+) 432 (M+1).
Reaction SMILES: Cl.C(OCC)(=O)C.[CH:8]([NH:11][C:12](=[O:31])[CH:13]([OH:30])[C@@H:14]([NH:22]C(OC(C)(C)C)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:10])[CH3:9]>>[CH:8]([NH:11][C:12](=[O:31])[CH:13]([OH:30])[C@@H:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:10])[CH3:9]
Reactant: CC(C)NC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)C(O)[C@@H](N)Cc1ccccc1
Reaction time: 5 h

Procedure:
A 4 M hydrogen chloride/ethyl acetate solution (2 ml) is added to N1-isopropyl-(2RS,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyramide (300 mg, Reference compound No. 20-1), and the mixture is stirred for five hours. The reaction mixture is concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution is added to the resulting residue, and the whole is extracted with ethyl acetate. The extract is washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (212 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[O:11][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[CH:9][CH:8]=1.[H-].[Na+].Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[O:11][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[N:13]=2)=[CH:9][CH:8]=1
Reactant: c1ccc2c(-c3ccc(C4OCCCO4)o3)n[nH]c2c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c(-c1ccc(C3OCCCO3)o1)nn2Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 g (7.41 mmol) of 3-(5-(1,3-dioxan-2-yl)furan-2-yl)indazole in 10 ml of DMF is added to a suspension of 355 mg of NaH (60 per cent in paraffin) in 10 ml of DMF under argon, and the mixture is stirred at room temperature for 1 hour. 1.46 g of 4-picolyl chloride hydrochloride are then added, followed by 355 mg of NaH (60 percent in paraffin). The mixture is stirred at room temperature for 1 hour and then at 100° C. for 1 hour, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent. 1 g (37% of theory) of an oil is obtained. Rf (SiO2, ethyl acetate): 0.25
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[N:8][C:7]([O:10]C)=[C:6]2[NH:12][CH:13]=[CH:14][C:5]=12.CN1CCCC1=O>O>[OH:10][C:7]1[N:8]=[CH:9][C:4]([O:3][CH3:2])=[C:5]2[C:6]=1[NH:12][CH:13]=[CH:14]2
Reactant: COc1cnc(OC)c2[nH]ccc12
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cnc(O)c2[nH]ccc12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridine hydrochloride (50 g) taken in 2 L 3-necked round bottom flask, 250 ml N-methyl-2-pyrrolidinone was added followed by 8 ml of water, and was heated to 90° C. for about 4 hrs. The reaction mixture was cooled to room temperature, diluted with water (1 L) and the whole mixture was kept in cold room for about one hour. The resulting solid was collected by filtration, washed with cold water and dried in vacuum oven at 50° C. for 4 hrs to afford 7-hydroxyl-4-methoxy-6-azaindole as white solid.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:8]([O:10]CC)=[O:9])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>C(O)C>[CH3:1][C:2]([CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:3]([OH:5])=[O:4])[C:8]([OH:10])=[O:9]
Reactant: C#CCCCC(C)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#CCCCC(C)(C(=O)O)C(=O)O
Reaction time: 15 h

Procedure:
A mixture of diethyl 2-methyl-2-(pent-4-ynyl)malonate (11 g) and potassium hydroxide (15 g) in 95% ethanol (150 ml) was heated to reflux for 4 hours and then stood at room temperature for 15 hours. The bulk of the solvent was removed in vacuo and the residue was taken up in water. The resulting aqueous phase was washed with dichloromethane before acidification to pH 1 with concentrated hydrochloric acid and further extraction with fresh dichloromethane. These organic extracts were washed with brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. 2-Methyl-2-(pent-4-ynyl)malonic acid was obtained as a pale yellow solid (6.7 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=3)[C:31](OC)=[O:32])=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.[CH3:38][NH2:39]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]3[CH:37]=[CH:36][CH:35]=[C:30]([C:31](=[O:32])[NH:39][CH3:38])[CH:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(C(=O)OC)c3)cnc2c1
Reactant: CN
Product: CNC(=O)c1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCOC)ccn45)cccc32)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a vial was added methyl 3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate (Example 93; 0.026 g, 0.0521 mmol) followed by methylamine (0.972 mL, 7.81 mmol, 33% in EtOH) and the mixture was sealed and heated to 50° C. with stirring for 8 hours. Additional methyl amine (0.972 mL, 7.81 mmol) was added and the mixture was stirred at 50° C. overnight. The mixture was cooled to ambient temperature and purified directly by preparative TLC (10% MeOH/CH2Cl2), providing 0.014 g (54%) of the product as a tan powder. MS (ES+APCI) m/z=499 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[O:34][CH:33]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:31][C:32]1[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[O:42])[O:34][CH:33]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1occ(CBr)c2ccccc12
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2coc(=O)c3ccccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-isochromen-1-one following the procedure of Example 478: MS (ESI) m/z 552; HRMS: calcd for C33H20F3NO4+H+, 552.14172; found (ESI, [M+H]+), 552.1434.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:9][C:10]1NN=N[N:11]=1.[C-]#N.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][C:10]#[N:11])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(Cc2nnn[nH]2)cc1OCc1c(C)cccc1C
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC#N)cc1OCc1c(C)cccc1C

Procedure:
The solution of 2-((5-(bromomethyl)-2-methoxyphenoxy)methyl)-1,3-dimethylbenzene (Step D, 3.28 g, 9.7 mmol) and NaCN (0.624 g, 12.7 mmol) in dry DMF (20 ml) was heated at 120° C. for 2.5 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO2, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][NH:24][CH2:23][CH2:22]4)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].I[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC#N.CCOC(C)=O>[N:1]1([C:7]2[O:8][C:9]([C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][N:24]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:23][CH2:22]4)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CI
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1oc(N2CCCCC2)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCc2cc(NC(=O)c3oc(N4CCCCC4)nc3C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 54 %

Procedure:
To a suspension of compound 154 (0.098 g, 0.25 mmol) and K2CO3 (0.5 g) in CH3CN (5 mL) was added ethyl iodoacetate (0.036 mL). After 19 h of stirring at RT, the reaction mixture was diluted in EtOAc (50 mL) and filtered. The fitrate was washed with sat NaHCO3 (2×50 mL), dried over Na2SO4, filtered, and concentrated. The crude materials were purified by prep-TLC using 25% CH3CN in CH2Cl2 as eluents to yield compound 155 as a white solid (0.064 g, 54% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.47 (d, 1H, J=2.2 Hz), 7.41 (dd, 1H, J=8.0, 2.2 Hz), 7.02 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J=7.3 Hz), 3.66 (s, 2H), 3.61 (m, 4H), 3.41 (s, 2H), 2.80 (s, 4H), 1.61 (m, 6H), 1.21 (t, 3H, J=7.3 Hz); LCMS (ESI) Rt=3.21 min, [M+1]+ 481.3.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][N:11]2[C:14](=[O:16])[CH3:15])=[CH:7][CH:6]=1.CCOCC>CN1C(=O)CCC1>[C:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:1]#[N:2])[CH:13]=2)[C:9]([CH3:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CC(C)(c2ccccc2)c2ccc(Br)cc21
Reactant: N#C[Cu]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CC(=O)N1CC(C)(c2ccccc2)c2ccc(C#N)cc21
Temperature: 175 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
CuCN (179 mg, 2 mmol) was added to a solution of 1-(6-bromo-3-methyl-3-phenyl-2,3-dihydro-indol-1-yl)-ethanone (330 mg, 1 mmol) in NMP (5 mL). The reaction was stirred at 175° C. for 16 h. Et2O was added to the mixture and the solid was filtered off. The filtrate was washed with 2 M aqueous HCl and saturated aqueous NaHCO3. The solvent was removed in vacuo to give the title compound (250 mg) as a brown solid. MS: [M+H]+=277.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]>[C:13]1([N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(-c2ncc[nH]2)nc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccnc2-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
2-(1H-imidazol-2-yl)pyridine (6.91 g), iodobenzene (11.47 g), Cs2CO3 (25 g), and copper powder (15 g) were combined in 60 mL anhydrous DMF in a 250 mL round bottom flask equipped with a magnetic stirrer and a reflux condenser. The mixture was degassed with N2 for 15 minutes at room temperature and then refluxed under N2 in an oil bath for 24 hours. The resulting mixture was cooled to room temperature and suction-filtered to remove the solid byproduct. The filtrate was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (2×100 mL), then with saturated NaCl (2×150 mL), and subsequently dried with anhydrous Na2SO4. Evaporation of the solvent gave crude 2-(1-phenyl-1H-imidazol-2-yl)pyridine. The crude product is generally pure enough to use in making redox mediators, although the crude product may be further purified using a silica gel column and eluting with MeOH/CHCl3.
Reaction SMILES: [Mg].II.[CH2:4]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13]Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br[C:26]1[CH:30]=[CH:29][S:28][CH:27]=1.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(CBr)CCCCCCCC
Reactant: Brc1ccsc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CCCCCCCC)Cc1ccsc1
Temperature: 25 °C

Procedure:
1.3 g (54 mmol) of magnesium turnings, a catalytic amount of iodine, and 50 mL of dry THF was mixed in a flask and heated to slight reflux under nitrogen. A solution of 2-octyldodecyl bromide (18.1 g, 50 mmol) and 25 mL of dry THF was added drop-wise into the mixture. The mixture was then allowed to reflux for 3 h. After resulting grey solution was cooled to room temperature, transferred into a dry droping funnel, and added drop-wise into a dry THF solution of 3-bromothiophene (6.5 g, 40 mmol) and Ni(dppp)Cl2 (160 mg, 1.2 mmol) at 0° C. The mixture was heated to reflux overnight under nitrogen atmosphere. The mixture was then cooled and a dilute hydrochloric acid aqueous solution was added to quench excess Grignard reagent. The crude product was extracted from the mixture with hexane, washed with water, and purified by silica gel chromatography eluting with hexane. The final product was 7.2 g of colorless oil (49%). The product was characterized by 1H NMR: (CDCl3, 400 MHz, ppm) δ 7.23-7.21 (m, 1H), 6.90-6.88 (m, 2H), 2.56-2.55 (d, 2H, J=6.8 Hz), 1.61-1.59 (m, 1H), 1.25 (br, 32H), 0.90-0.87 (t, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18]([OH:20])=O)=[N:10]2)[CH:4]=1)#[N:2].[NH2:21][C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][CH2:23][C@@H:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Reactant: CC(C)[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CO)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (50 mg, 0.188 mmol), (S)-2-amino-3-methylbutan-1-ol (19.37 mg, 0.188 mmol), and triethylamine (0.052 mL, 0.376 mmol) in DMF (2 mL) was added HATU (71.4 mg, 0.188 mmol). The mixture was stirred at 23° C. for 30 min and purified by HPLC to give the title compound (53 mg) as a white solid. LCMS m/z=352.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 1.26 (td, J=8.0, 4.9 Hz, 1H), 2.05 (oct, J=6.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.52 (t, J=5.6 Hz, 1H), 2.78-2.82 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.7, 6.4 Hz, 1H), 3.75-3.92 (m, 3H), 7.00 (d, J=7.8 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC(OC)=CC=1B(O)O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([NH:30][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: COc1ccc(I)c(B(O)O)c1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NCc1ccccc1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Into a 25 mL round bottom flask equipped with a stir bar was added phenyl acetic acid (0.075 g, 0.55 mmol, 1.1 equiv), (2-iodo-5-methoxyphenyl)boronic acid (13.9 mg, 0.05 mmol, 10 mol %) and 1 g of activated 4 Å Molecular Sieves. Dichloromethane (7 mL) was added and the mixture was stirred for 10 min. Then, benzylamine (55 pit, 0.5 mmol, 1 equiv) was added (in order to get reproducible results, it is necessary to use a gas tight 100 μL syringe). The resulting mixture was stirred for 2 h at room temperature (24-25° C.). The reaction mixture was filtered through a pad of Celite® 545, the filtrate was washed with aqueous acidic solution (pH=4), aqueous basic solution (pH=10-11) and brine. The organic layer was collected, dried over anhydrous Na2SO4 and evaporated to yield the title compound (71% using 1, 98% using 2) as a pure product. The catalyst can be recuperated in up to 80% yield by acidification of the aqueous basic solution to pH 7 and extraction with EtOAc.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[I-].[Na+]>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][S:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:26][CH:25]=1
Reactant: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Yield: 61.5 %

Procedure:
A mixture of (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine (see Preparations 13 and 14) (2.8 g), 4-methoxyphenethyl bromide (2.6 g), sodium carbonate (1.30 g) and sodium iodide (50 mg) in acetonitrile (75 ml) was heated under reflux for 16 hours, evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution using initially dichloromethane as eluant and changing to dichloromethane/saturated methanolic ammonia (98:2). The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (2.5 g, 62%).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:25])[C:16](=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[NH:13][C:12]1=[O:26])[CH3:10])(C(C)(C)C)(C)C.Cl.OP([O-])([O-])=O.[K+].[K+]>CO.C(OC(=O)C)C.O>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:25])[C:16](=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[NH:13][C:12]1=[O:26])[CH3:10]
Reactant: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
The keto ester 2 (1.047 g, 2.73 mmol) in methanol (12.3 ml) was treated with 6N HCl (1.37 ml, 8.22 mmol, 3 eg) and stirred 1 hour at room temperature. The solution was treated with 1M K2HPO4 (8.2 ml) and stirred a few minutes, then diluted with ethylacetate and water. The organic layer was separated, washed with 5% NaHCO3 and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to give the product 3 (0.653 g, 89%) as a clear oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:11]([CH:26]2[CH2:28][CH2:27]2)[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:26]1([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=2[CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:27][CH2:28]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)c(C2CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccc(O)cc1C1CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of benzyl (4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylphenyl)acetate (586 mg) in tetrahydrofuran (6.89 mL) was added a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2.23 mL) under ice-cooling, followed by stirring at room temperature overnight. To a reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-cyclopropyl-4-hydroxyphenyl)acetate (398 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([CH2:17][CH2:18]O)[N:13]=[CH:14]3)=[CH:9][CH:8]=2)[CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1>C(Cl)Cl.C(#N)C>[CH3:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[CH2:18][CH2:17][C:12]1[N:13]=[CH:14][C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:16]=2
Reactant: C[C@@H]1CCCN1
Reactant: OCCc1cc2ccc(-c3cccnc3)cc2cn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCCN1CCc1cc2ccc(-c3cccnc3)cc2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product from Example 63A (0.25 g, 1.0 mmol) and triethylamine (0.15 g, 1.5 mmol) in methylene chloride (10 mL) at −5° C. were treated with methanesulfonyl chloride (0.12 g, 1.2 mmol) and stirred at 0° C. for 2 hours and then stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure and the residue was treated with K2CO3 (0.21 g, 1.5 mmol) and (2R)-2-methylpyrrolidine (0.13 g, 1.5 mmol) in acetonitrile (15 mL), and then heated at 60° C. for 5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 30 mL methylene chloride, washed with 10 mL 15% NaCl, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90:1 MeOH:CHCl3:Et3N) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.27 (s, 1H), 8.95 (m, 1H), 8.64 (dd, J=2, 4 Hz, 1H), 8.12 (s, 1H), 7.98 (m, 1H), 1.90-1.86 (m, 2H), 7.56 (s, 1H), 7.44-7.40 (m, 1H), 3.37-3.28 (m, 2H), 3.26-3.18(m, 2H), 2.68-2.61(m, 2H), 2.51-2.46(m, 1H), 2.38-2.31 (m, 1H), 2.00-1.93(m, 1H), 1.88-1.82(m, 1H), 1.80-1.72(m, 1H), 1.55-1.46 (m, 1H), 1.14(d, 3H); 13C NMR (CDCl3, 400 MHz) δ 9.27 153.8, 151.9, 148.4, 147.9, 135.6, 135.5, 135.4, 134.1, 129.1, 127.0, 126.9, 125.2, 123.4, 118.2, 60.4, 54.1, 54.0, 37.2, 32.8, 21.9, 19.0.