Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].C(NC(C)C)(C)C.[Li+].CCC[CH2-].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25].Cl>C(OCC)(=O)C.O.O1CCCC1>[F:22][C:23]([F:30])([F:29])[C:24]([C:21]1[C:16]([F:15])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:25]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1ccccn1
Agent: Cl
Agent: [CH2-]CCC
Agent: [Cl-]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cccnc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
Lithium chloride (0.500 g, 11.79 mmol) and diisopropylamine (1.8 mL, 12.84 mmol) were combined under nitrogen with dry tetrahydrofuran (10 mL) and cooled in a dry ice bath. N-Butyllithium (2.5 M solution in hexane, 5.0 mL, 12.50 mmol) was added and the mixture stirred for 10 minutes. 2-Fluoropyridine (0.800 mL, 9.30 mmol) was added dropwise and the reaction stirred. After 10 minutes, additional dry tetrahydrofuran (5 mL) was added to help with stirring. The mixture was stirred for 90 minutes then ethyl trifluoroacetate (1.7 mL, 14.30 mmol) was added dropwise. After 60 minutes the reaction was quenched by addition of hydrochloric acid (5N in 2-propanol, 5 mL, 10 mmol). The mixture was warmed to room temperature and water (150 mL) and ethyl acetate (200 ml) were added. The phases were mixed and separated and the organic dried with magnesium sulfate. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 2,2,2-trifluoro-1-(2-fluoropyridin-3-yl)ethanone (0.812 g, 4.21 mmol, 45.2% yield).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[C:41]([NH:40][C:38]1[N:39]=[C:34]2[CH:33]=[CH:32][C:31]([O:30][C:29]3[CH:28]=[C:27]([NH:26][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=4)[CH:46]=[CH:45][CH:44]=3)=[N:36][N:35]2[CH:37]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)ccc2n1
Yield: 68.2 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (160 mg, 0.85 mmol), oxalyl chloride (90 μL, 1.1 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (4.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (200 mg, 0.71 mmol) and N-methylpyrrolidone (5.0 mL) as starting materials and in the same manner as in Example 335, the title compound (220 mg, 69%) was obtained as a white powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:14]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH:16]1[O:18][CH2:17]1
Reactant: BrCC1CO1
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc(-c2cccc(OCC3CO3)c2)cc1
Reaction time: 15 h

Procedure:
4.7 g of m-phenylphenol, 15.1 g of epibromohydrin, 13.6 g of potassium carbonate and 33.3 g of 2-butanone were introduced into a three-necked flask with reflux condenser and stirrer. In addition, air was slowly passed through and the temperature was held at 70° C., and the mixture was stirred for 15 hours. After filtration, the filtrate was freed from low-boiling components in a rotary evaporator. m-Phenylphenol glycidyl ether was obtained as a clear, liquid product: 1H-NMR (CDCl3, 400 MHz): 2.78 (dd, 1H), 2.90 (t, 1H), 3.36 (m, 1H), 4.02 (dd, 1H), 4.24 (dd, 1H), 6.90 (dd, 1H), 7.15 (d, 1H), 7.20 (d, 1H), 7.35 (m, 2H), 7.40 (t, 2H), 7.55 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1I.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][C:24]=4[Cl:26])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Cl)c2nc3n(c12)CCCCN3
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
A mixture of 10-chloro-7-nitro-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (Reference Example 106; 1.74 g, 6.50 mmol), 2,4-dichloro-1-iodobenzene (8.87 g, 32.5 mmol), copper(I) iodide (1.24 g, 6.50 mmol), 2,2′-bipyridyl (2.02 g, 13.0 mmol) and cesium carbonate (4.24 g, 13.0 mmol) in N,N-dimethylformamide (100 mL) was stirred at 150° C. for 12 hr. The mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (1.20 g, 2.91 mmol, 45%) as a light yellow amorphous.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#[C:10][OH:11])[CH:5]=[CH:4][CH:3]=1>CO.O=[Pt]=O>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CC#CO)n1
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1cccc(CCCO)n1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3-(6-methyl -2-pyridyl)propyn-1-ol was dissolved in MeOH (100 mL) and PtO2 (0.09 g) was added. The reaction mixture was hydrogenated at 4 atm for 30 min. The catalyst was filtered off and methanol evaporated in vacuo. The orange oily residue (2 g) was purified by column chromatography (silica gel, ethyl acetate) yielding a yellow oil (77%). MS (DCI) (M+H)+ at m/z 152.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.C([O-])(=O)C.[Na+]>CCOCC.[Pd]>[F:9][C:7]1[CH:8]=[C:3]([CH3:2])[CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(F)cc(F)c1
Reaction time: 24 h

Procedure:
A mixture of 1-(bromomethyl)-3,5-difluorobenzene (50 g, 0.24 mol), 10% Pd/C (3 g) and sodium acetate (140 g, 1.7 mol) in anhydrous ether (250 mL) was stirred under hydrogen at atmospheric pressure for 24 hr. The mixture was filtered and the filtrate was dried over anhydrous Na2SO4, filtered, and then used directly in the next step. 1H NMR (500 MHz, CDCl3): δ 6.56 (d, 2H, J=6.0 Hz), 6.47 (t, 1H, J=9.0 Hz), 2.22 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]2[C:3](=[O:20])[N:4]([CH3:19])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8]2)=[O:24])=[CH:31][CH:32]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1ccc(F)cc1
Product: CC(C(=O)NCc1ccc(F)cc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=473.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(4-fluoro-benzyl)-malonamic acid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.BrC1C=NC2C(C=1)=CC=CC=2N1CCN(C)CC1.[Na+].[C:38]1([S:44]([O-:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.[Cu]I.CO.ClCCl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[N:4]=[CH:3][C:2]([S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])=[CH:11]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3cc(I)cnc23)CC1
Reactant: O=S([O-])c1ccccc1
Agent: [Cu]I
Agent: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Temperature: 120 °C
Reaction time: 40 h
Yield: 7 %

Procedure:
A 4:1 mixture of 3-iodo-8-(4-methyl-piperazin-1-yl)-quinoline (D2) and 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1) (1.5 g), phenylsulfinic acid sodium salt, dihydrate (2.52 g, 12.6 mmol) and copper (I) iodide (2.4 g, 12.6 mmol) in N,N-dimethylformamide (25 ml) was stirred in an oil bath at 120° C. for 40 h under argon. To the reaction mixture, cooled to ambient temperature, was added 5% sodium hydrogen carbonate solution (100 ml) and dichloromethane (100 ml) with vigorous shaking. The insoluble material was filtered, washed with dichloromethane (3×20ml) and discarded. The filtrate and washings were transferred to a separating funnel and the layers separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic extracts were washed with water (100 ml), dried (MgSO4) and concentrated in vacuo to an oil (0.9 g). The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford an orange oil (0.28 g, Rf 0.11, methanol/dichloromethane 1:19). This material was further purified by passage through a strong cation exchange (SCX) column eluting firstly with methanol (fractions discarded) and then with methanol/aqueous ammonia-880 (10:1) to give the title compound (E1) as an orange oil (0.152 g, 0.41 mmol, 7% over two steps);
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7][C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(Cl)Cl.B(Br)(Br)Br>CO>[CH:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:14][C:15]=2[CH:16]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc2c(c1)Oc1ccccc1S2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)Oc1ccccc1S2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A stirred 3-methoxyphenoxathiin (3.00, 13.03 mmol) 25 ml CH2Cl2 was cooled to -70° C. under N2 and BBr3 (45.6 ml, 45.6 mmol, 1.0 M in CH2Cl2) was added dropwise over 1 h. The resulting bright, blue, heterogeneous mixture was allowed to warm to room temperature and stirred overnight. After 21 h the yellow homogeneous reaction is cooled to -60° C. and poured onto 300 mL MeOH at -60° C. After warming to room temperature the solution was concentrated in vacuo to a dark yellow oil which was purified by column chromatography (CH2Cl2 /hexane, gradient elution, 50:50 to 100:00) to give 2.59 g (91%) 3-phenoxathiinol as a white solid. TLC (CH2Cl2 /hexane 50:50) Rf =0.14; HPLC (Tr =14.2), 1H-NMR (CDCl3) δ 4.78 (s, 1H, --OH), δ 6.52 (d, J=8 Hz, 1H, C2 --H), δ 6.56 (s, 1H, C4 --H), δ 6.92-7.14 (m, 5H); MS m/z (relative intensity) 217 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([NH:15]C(=O)OC(C)(C)C)=[CH:10][C:9]=2[CH3:23])=[CH:5][C:4]=1[CH:26]([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH:26]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[C:9]([CH3:23])=[CH:10][C:11]([NH2:15])=[CH:12][C:13]=1[CH3:14])([CH3:28])[CH3:27]
Reactant: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2c(C)cc(N)cc2C)cc1C(C)C
Reaction time: 4 h

Procedure:
578 mg (1.36 mmol) of tert-butyl 4-(4-methoxy-3-isopropylbenzyl)-3,5-dimethylphenylcarbamate (Example VI) are dissolved in 10 ml of 5% trifluoroacetic acid in dichloromethane at 0° C. and stirred for 4 hours. The mixture is neutralized with sodium bicarbonate solution and dried over sodium sulphate. The product after removal of the solvent is reacted further without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH2:31]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:31][CH2:30][S:32]([CH3:35])(=[O:34])=[O:33])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(ncn2CCS(C)(=O)=O)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (1.55 g, 3.89 mmol) is dissolved in 15 mL DMF under N2. K2CO3 (0.70 g, 5.06 mmol) is added followed by methyl vinyl sulfone (0.41 mL, 4.67 mmol). After stirring 16 hours at room temperature, the reaction mixture is diluted with ethyl acetate and water. The layers are separated and the organic layer is washed with water (3×) and brine. The combined aqueous washes are extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced. Purification by dissolving the residue in methylene chloride and precipitating with diethyl ether, repeated several times, provides 1.16 g (59%) pure desired product as a yellow solid: MS APCI (+) m/z 506, 504 (M+Br pattern) and 400, 398 (M—methyl ethyl sulfone Br pattern).
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3].[CH3:17]I.[H-].[Na+].O>CN(C=O)C.CCOCC>[N:1]([C@H:4]1[C@H:8]([O:9][CH3:17])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (2.00 g, 8.76 mmol) and MeI (1.64 mL, 26.3 mmol) in DMF (20 mL) was added 60% NaH (0.701 g, 17.5 mmol) at 0° C. The mixture was warmed to ambient temperature and stirred at ambient temperature for 1 hour. Water (20 mL) and ether (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate) to give (3R,4R)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate (2.04 g, 96.1%) as thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:9]2=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1cc(Cl)ccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1N1C(=O)CN(C)C1=S
Yield: 58.9 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113°-115° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (El, M.+) m/z 254/256.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[N:10]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:17][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[C:27]2[C:23]=1[CH2:24][CH2:25][C@H:26]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: Cc1cc(-c2ccn(C)c(=O)n2)cc(C)c1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccn(C)c(=O)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 4-(4-iodo-3,5-dimethylphenyl)-1-methylpyrimidin-2(1H)-one and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.14 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=2)=[CH:11][C:10]=1[O:28][CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:11][C:10]=1[O:28][CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A suspension of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I18) (500 mg, 1.23 mmol) and 10% Pd/C (50 mg) in MeOH (30 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was filtered through celite, washing with ethyl acetate (70 mL) then the filtrate evaporated to dryness. The residue was chromatographed (SiO2, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I19) (411 mg, 82%) as a pale yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=7.4 Hz, 1H), 6.99 (s, 1H), 6.76 (d, J=8.3 Hz, 1H), 6.67 (s, 1H), 4.21 (s, 2H), 3.84 (s, 3H), 2.77 (t, J=12.2 Hz, 2H), 2.57 (ddd, J=12.1, 9.0, 3.3 Hz, 1H), 1.79 (d, J=12.6 Hz, 2H), 1.68-1.54 (m, 2H), 1.50 (s, 9H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)COc1ccc2c(c1)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCc2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of ethyl [(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy]acetate (1.14 g, 4.58 mmol) in ethanol (20 ml) and 2M sodium hydroxide aqueous solution (4 ml) was refluxed for 2 hours. After cooling to ambient temperature, the solvent was evaporated in vacuo and the aqueous solution was acidified to pH 2 with 2M hydrochloride aqueous solution with ice-cooling. The precipitate solid was collected and dried in vacuo to give 894 mg (89% yield) of the title compound as a pale gray solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCN=[N+]=[N-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCN=[N+]=[N-]
Reaction time: 1 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-hydroxypyrrolidine (20.0 g) and triethylamine (15.2 ml) in dichloromethane (300 ml) was added methanesulfonyl chloride (7.8 ml) under ice-cooling. After stirring for 1 hour, water was poured into the mixture. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with 1N hydrochloric acid, sat. sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-methanesulfonyloxypyrrolidine (15.3 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:16][CH:15]=1)[CH2:8]2.Cl>C(O)C>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OCCC2C3CC4CC(C3)CC2C4)cc1
Agent: Cl
Solvent: CCO
Product: NCCc1ccc(OCCC2C3CC4CC(C3)CC2C4)cc1

Procedure:
Obtained from Intermediate 75 (0.788 g, 1.97 mmol) and hydrogen chloride 1.25 M in ethanol (26 mL) by the same procedure described in Intermediate 17. The title compound was obtained as a yellow solid (0.5 g, 84%) and used in the next step without further purification. MS (M+): 300.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.[C:13]([NH:16][CH2:17][C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:17][C:18]1([CH3:19])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:20]1)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:15])[CH3:14]
Reactant: CC(=O)CNC(C)=O
Reactant: SCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tryptophol (3.86 g; II, R2, R3, R4, R5, R6 = H and X1 =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O.H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is addded and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only by melting. Rf values of the amide and tryptophol are equal.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:3]1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:3]1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1C(=O)CC[C@H]1C(=O)O
Yield: 106.9 %

Procedure:
Methyl 1-methyl-5-oxo-prolinate (0.308 g, 1.96 mmol) was dissolved in methanol (˜10 ml) and to this was added a solution of sodium hydroxide (0.157 g, 3.92 mmol) in water (˜10 ml). The mixture was heated at reflux for 3 hrs, then cooled and evaporated to leave a minimal amount of water. This was acidified to pH 1 using 2M aqueous hydrogen chloride. The aqueous layer was washed with dichloromethane and then separated and evaporated to give 1-methyl-5-oxo-proline as a white solid (0.300 g).