Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][CH2:31][OH:32]>>[CH3:28][N:29]([CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:30][CH2:31][OH:32]
Reactant: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNCCO
Product: CN(CCO)CCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester and 2-Methylaminoethanol were converted to yield 2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanol as light brown oil, MS: 395 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:32]=[CH:31][CH:30]=[CH:29]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[N:10]=1)=[O:5])C.[NH2:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][NH:34][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:29]=[CH:30][CH:31]=[CH:32]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[N:10]=1)=[O:5]
Reactant: CCOC(=O)c1nc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cs1
Reactant: NCCO
Product: O=C1CC(c2cccc(-c3csc(C(=O)NCCO)n3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
A sample of 4-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-thiazole-2-carboxylic acid ethyl ester (Example 28) (0.26 g) was reacted with 2-amino-ethanol in an analogous manner to the procedure described in Example 34 to give the title compound (0.07 g) as a light-yellow solid.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH3:15])[C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:16]2[CH2:18][CH2:17]2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:34])[NH:26][C@H:27]([C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:28])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.N1CCCC1>O.CS(C)=O>[C:20]([O:24][C:25](=[O:34])[NH:26][C@@H:27]([C@H:29]1[CH2:33][CH2:32][N:31]([C:7]2[C:6]([CH3:15])=[C:5]3[C:10]([C:11](=[O:12])[N:2]([NH2:1])[C:3](=[O:19])[N:4]3[CH:16]3[CH2:18][CH2:17]3)=[CH:9][C:8]=2[F:13])[CH2:30]1)[CH3:28])([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: Cc1c(F)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Solvent: C1CCNC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(N2CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Temperature: 120 °C
Yield: 45.6 %

Procedure:
A solution of 0.5 g (1.9 mmol) of 3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione (Example 24e), 0.64 g (3.0 mmol) of ((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester, 0.81 g (8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide is heated at 110° C. for 24 hours. After thin layer chromatography showed incomplete reaction, an additional 0.43 g (2.0 mmol) of pyrrolidine derivative and 0.81 g (8.0 mmol) of triethylamine are added and the reaction is heated at 120° C. for 18 hours. The reaction mixture is cooled to room temperature, poured into 200 mL of ice and water and extracted with ethyl acetate (2×125 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 1.1 g of crude product. Chromatography on flash grade silica gel (230–400 mesh) eluting with ethyl acetate provided 0.4 g of the title compound, mp 86–88° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:12][CH2:11]1)([O-])=O>CO.[Pd]>[O:18]1[CH2:19][CH2:20][CH:16]([N:13]2[CH2:14][CH2:15][N:10]([C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[NH2:1])[CH2:11][CH2:12]2)[CH2:17]1
Reactant: O=[N+]([O-])c1cnccc1N1CCN(C2CCOC2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1N1CCN(C2CCOC2)CC1
Yield: 82 %

Procedure:
A solution of 1-(3-nitropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine (316 mg, 1.13 mmol) in MeOH (15 mL), Pd on C (10%, wet, Degussa) (120 mg) was stirred overnight at RT under an hydrogen atmosphere (balloon). The mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude was redissolved in MeOH and loaded into a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to give 4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-amine as a solid which was used in next step without further purification. (300 mg, purity 77%, yield 82%). MS (ES+) 249.2.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cc2ccc(Cl)o2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Cc2ccc(Cl)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a mixture of (4-(5-chloro-furan-2-ylmethyl)-phenyl)-methanol (650 mg, 2.9 mmol) described in Manufacturing Example 62-1-3 and dichloromethane (20 mL) was added manganese dioxide (6.5 g, 75 mmol) at room temperature, which was stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad. The filtrate was evaporated under a reduced pressure to obtain the title compound (530 mg, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[F:34])[O:6][CH2:7][CH3:8])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:34])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Yield: 86.2 %

Procedure:
(RS)-[4-(tert-Butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester (6.85 g) was dissolved in THF (135 ml) and a 1 M TBAF sol. in THF (15.1 ml) was added. After 3 h the reaction mixture was poured on AcOEt (300 ml) and H2O (300 ml). The aqueous layer was extracted with two more portions of AcOEt (100 ml). The combined organic layers were washed with brine and dried (MgSO4) and the solvent was evaporated. Crystallization from ice cold CH2Cl2 afforded 3.08 g (86%) of (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester. White crystals. MS 258.9 ([M−H]+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>>[NH2:1][C@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:33][C:32]([C:30]([OH:36])=[O:31])([F:35])[F:34]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 0.5 h

Procedure:
To 2.00 g of BOC-Thr(Bzl)-Pro-NH2, under cooling at -5° C., was added 6 ml of TFA and the mixture was stirred for 30 minutes, followed by concentration under reduced pressure. The residue was treated with diethyl ether and the product precipitated was collected by filtration and dried over sodium hydroxide under vacuo overnight to obtain H-Thr(Bzl)-Pro-NH2.TFA.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:20])([CH3:19])[CH2:15][C:16](N)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[K+]>C(O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:20])([CH3:19])[CH2:15][C:16]([OH:21])=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(O)(CC(N)=O)c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Product: CC(O)(CC(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
g. of 3-p-phenoxyphenyl-3-hydroxybutyric acid amide (obtainable from 4-phenoxyacetophenone and bromoacetamide/zinc) and 5 g. of KOH in 100 ml. of ethanol are boiled for 3 hours under nitrogen. The mixture is evaporated and worked up to give 3-p-phenoxyphenyl-3-hydroxybutyric acid, m.p. 137°-138°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]([O:15]CC)=[O:14])[CH:3]=1>[OH-].[Na+].C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)oc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Saponification of 0.5 g of the ester was accomplished by refluxing 12 hours in 10 ml of 25% aqueous sodium hydroxide and 5 ml of ethanol. Acidification precipitated the crude acid, which was recrystallized from water-ethanol to give 5-methyl-2-phenyl-3-furoic acid, mp 146°-147.5° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:19])([O:20][Si:2]([CH3:1])([CH3:8])[CH3:9])[CH3:18])=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CC(C)(O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O[Si](C)(C)C)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
N-trimethylsilylimidazole (80.6 mL, 0.552 mol) was added to a solution of the crude 2-(4-bromo-phenyl)-propan-2-ol in tetrahydrofuran (500 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography (n-hexane:ethyl acetate=40:1) to give the title compound as a colorless oil (125.6 g, 87% in two steps).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1C=CC=C[CH:3]=1.[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH:10]1[CH2:19][OH:20]>>[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH:10]1[CH2:19][O:20][CH2:3][CH:2]1[O:8][CH2:1]1
Reactant: OCc1ccccc1
Reactant: OCC1COc2ccccc2O1
Product: c1ccc2c(c1)OCC(COCC1CO1)O2

Procedure:
In a similar manner to Example (1a), with benzyl alcohol replaced by (1,4-benzodioxan-2-yl)methanol, 1-[(1,4-benzodioxan-2-yl)methoxy]-2,3-epoxypropane is obtained. The latter derivative, when condensed according to Example (1b) with 2-aminoethyl hydrogen sulfate, leads to the derivative of formula: ##STR26## Empirical formula: C18H23NO8Molecular mass: 381.38
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[NH:9])[O:15][CH2:13][CH3:14])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl 4-nitrobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 4-nitrobenzonitrile (26.5 g, 0.179 mol) was reacted with hydrogen chloride in ethanol (250 mL) to give 35.7 g (86%) of the target compound as colorless crystals.
Reaction SMILES: [ClH:1].Cl.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(N4CCNCC4)=CC=3)SC=12.[F:45][C:46]1[CH:76]=[C:75]([NH:77][C:78]([NH:80][C:81](=[O:89])[CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[S:79])[CH:74]=[CH:73][C:47]=1[O:48][C:49]1[C:50]2[S:57][C:56]([C:58]([N:60]3[CH2:64][CH2:63][CH:62]([NH:65]C(=O)OC(C)(C)C)[CH2:61]3)=[O:59])=[CH:55][C:51]=2[N:52]=[CH:53][N:54]=1>>[ClH:1].[NH2:65][CH:62]1[CH2:63][CH2:64][N:60]([C:58]([C:56]2[S:57][C:50]3[C:49]([O:48][C:47]4[CH:73]=[CH:74][C:75]([NH:77][C:78]([NH:80][C:81](=[O:89])[CH2:82][C:83]5[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=5)=[S:79])=[CH:76][C:46]=4[F:45])=[N:54][CH:53]=[N:52][C:51]=3[CH:55]=2)=[O:59])[CH2:61]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3ncnc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)C1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(N5CCNCC5)cc4)sc23)c(F)c1
Product: NC1CCN(C(=O)c2cc3ncnc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)C1
Yield: 40 %

Procedure:
Following the procedure described above for the synthesis of compound 159 (scheme 30, example 121) but substituting Boc-protected amino compound 158 for the Boc-protected amino compound 26l, title compound 191 was obtained in 40% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 8.12 (s, 0.5H), 8.06 (s, 0.5H), 7.92(dd, J=2.4 and 12.0 Hz, 1H), 7.54(t, J=8.4 Hz, 1H), 7.48(dd, J=2.4 and 8.4 Hz, 1H), 7.36-7.31 (m, 4H), 7.30-7.25 (m, 1H), 4.2-3.80 (m, 1H), 3.08 (s, 2H), 3.80-3.50 (m, 4H), 2.10-1.98 (m, 1H), 1.82-1.64(m, 1H). LRMS (M+1) 550.6 (100%).
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)/C(/N)=N/[N+]([O-])=O.[S:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>O.CCOCC>[CH3:3][O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([S:13](=[O:15])(=[O:16])[NH2:14])=[CH:25][CH:24]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of KOH (108 mg, 2.0 mmol) in water (1 mL) was added Et2O and cooled to 0° C. MNNG (292 mg, 1.99 mmol) was added and the resulting yellow solution was added to a suspension of 4-Sulfamoyl-benzoic acid in Et2O at room temperature and stirred overnight. The reaction was quenched with acetic acid and the resulting mixture was diluted with water. The mixture was then extracted with ethyl acetate and the combined organic extracts was washed with bine and dried over Na2SO4. Removal of solvent gave the crude product which was used in the next reaction without further purification. 1H NMR (400 MHz, MeOD) δ8.17 (d, 2H), 8.00 (d, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[CH3:36][O:37][C:38](OC)(OC)OC>C(O)(=O)C>[CH3:36][O:37][C:38]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COC(OC)(OC)OC
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Solvent: CC(=O)O
Product: COc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 179, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol, tetramethylorthocarbonate and acetic acid were reacted to give 166. LCMS: M+H+=521.3. 1H-NMR (400 MHz, DMSO-d6): δ 7.83 (m, 1H), 7.48 (m, 1H), 7.18 (m, 2H), 4.23 (s, br, 4H), 4.15 (s, 3H), 4.02 (s, 1H), 3.80 (s, 3H), 3.76 (m, 4H), 3.72 (s, 2H), 2.87 (m, 2H), 1.99 (m, 2H), 1.65 (m, 2H), 1.20 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[C:24]([CH3:34])=[N:23]1>>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])[C:5]4[N:17]([CH3:20])[CH:18]=[N:19][C:4]=4[CH:3]=3)=[CH:28][CH:29]=2)[C:24]([CH3:34])=[N:23]1
Reactant: Cc1nn(C)c2ccc(B(O)O)cc12
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: Cc1nn(C)c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc12

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (45 mg, 0.153 mmol) and 1,3-dimethyl-1H-indazol-5-ylboronic acid (35 mg, 0.183 mmol), (R)-4-((R)-1-(6-(1,3-dimethyl-1H-indazol-5-yl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.31 was isolated, following column chromatography.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH:40]([CH2:45][CH2:46]O)[CH2:39][CH2:38]3)=[CH:29][CH:28]=1>C1COCC1.O>[C:27]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH:40]([CH2:45][CH2:46][I:25])[CH2:39][CH2:38]3)=[CH:29][CH:28]=1
Reactant: II
Reactant: OCCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: ICCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a solution of triphenylphosphine (12.5 g) in THF (200 ml) were successively added imidazole (3.25 g) and iodine (12.1 g). A solution of 6-(4-biphenylyl)methoxy-2-(2-hydroxyethyl)tetralin (13.15 g) in THF (100 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 5 min, diluted with water, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent; toluene) to obtain the titled compound (13.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH2:12][CH2:13][N:14]4[C:19]([C:10]=3[NH:9][C:6]2=[CH:7][CH:8]=1)=[CH:18][CH2:17][CH2:16][C:15]4=[O:20]>C1COCC1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH2:12][CH2:13][N:14]4[C:19]([C:10]=3[NH:9][C:6]2=[CH:7][CH:8]=1)=[CH:18][CH:17]=[CH:16][C:15]4=[O:20]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)CCC=C31
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c3c(c2c1)CCn1c-3cccc1=O
Yield: 55 %

Procedure:
Activated manganese dioxide (400 mg) is added to a solution of 9-methoxy-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizin-4-one (150 mg) in THF (5 ml). After refluxing for 2 h 30, the mixture is cooled and activated manganese dioxide (400 mg) is again added. The medium is refluxed for 2 h 30. After filtration and washing of the dioxide with an ethyl acetate/methanol mixture (98/2) and after separation on a preparative plate, 9-methoxy4,6,7,12-tetrahydroindolo[2,3-a]quinolizin-4-one is obtained (55% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10])=[O:4].[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]([C:5]2[N:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:9]=2[CH3:10])=[O:4])=[CH:26][CH:25]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Reactant: Oc1ccc(CCC2OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCC2OCCO2)cc1
Reaction time: 20 h
Yield: 57 %

Procedure:
A mixture of 4-bromoacetyl-5-methyl-2-phenyloxazole (2.60 g), 4-[2-(1,3-dioxolan-2-yl)ethyl]phenol (1.82 g), potassium carbonate (1.28 g) and 2-butanone (60 ml) was stirred for 20 hours at temperatures ranging from 70 to 80° C. The reaction mixture was poured into water. Resulting crystalline precipitate was collected by filtration, which was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:1, v/v), 4-[4-[2-(1,3-dioxolan-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyloxazole (2.08 g, 57%) was obtained. Recrystallization from dichloromethane-isopropyl ether gave colorless prisms, m.p.119-120° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]2[CH:17]=[CH:16][N:15]([C@H:18]3[C@H:34]([OH:35])[C@@H:21]4[O:22][CH:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[O:24][CH2:25][C@@H:20]4[CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1[CH:41]=[CH:40][C:39]([O:42][C:43](Cl)=[S:44])=[CH:38][CH:37]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:43](=[S:44])([O:42][C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)[O:35][C@@H:34]1[C@@H:21]2[O:22][CH:23]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[O:24][CH2:25][C@@H:20]2[CH2:19][C@H:18]1[N:15]1[C:11]2[N:12]=[CH:13][N:14]=[C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[CH:17]=[CH:16]1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(SCc6ccccc6)ncnc54)[C@H](O)[C@@H]3O2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(SCc6ccccc6)ncnc54)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 140 %

Procedure:
To a solution of (4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol (990. mg, 2.02 mmol) in DCM (57.0 mL) was added 4-(dimethylamino)-pyridine (748 mg, 6.07 mmol) and phenyl chlorothionocarbonate (0.565 mL, 4.04 mol) under an atmosphere of nitrogen and the yellow reaction was stirred at rt. After 12 h, the dark yellow solution was purified via silica gel chromatography eluting with 10% EtOAc in hexanes, and then 10% MeOH in DCM on a column pre-treated with 1% TEA in hexanes to afford the title compound as a yellow oil (1.77 g, 97%). LC/MS: Rt=2.47 min, ES+ 626 (FA standard).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.I[CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[F:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(OCCCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of ethyl 4-hydroxybenzoate (0.46 g, 2.80 mmol), 1-iodo-4,4,4-trifluorobutane (0.67 g, 2.80 mmol) and anhydrous K2CO3 (1.16 g, 8.40 mmol) in methyl ethyl ketone (5 ml) was heated under reflux for 4 h under an atmosphere of argon. On cooling to room temperature, the solvent was removed under reduced pressure and the residue was partitioned between water (15 ml) and Et2O (30 ml). The organic layer was separated, and the aqueous phase extracted with Et2O (2×20 ml). The combined organic extracts were washed with brine (15 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a solid which was purified by flash chromatography (3:1 Hexane/EtOAc) to give the title compound (0.67 g, 87%) as a colourless solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Mg]Br)[CH:31]=[CH:32][CH:33]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[CH:33]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1.5 mL THF and 0.49 mL 1M 3-methoxyphenylmagnesium bromide. Yield: 53 mg of a white solid. LC-MSD, m/z for C23H17BrN2O3 [M+H]+=449.0, 451.0; HPLC retention time: 2.3 min.