Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17](Cl)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:48][C:49]1[CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:52]=[CH:51][N:50]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:53]2[CH:52]=[CH:51][N:50]=[C:49]([Cl:48])[CH:54]=2)[N:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1nc(Cl)nc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(Cl)c2)nc2ccccc12
Temperature: 80 °C

Procedure:
A solution of 5-(2-chloro-quinazolin-4-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.145 g, 0.4 mmol) in DME (2 mL) under nitrogen were added palladium acetate (0.0045 g, 0.02 mmol), tri-o-tolylphosphine (0.015 g, 0.048 mmol), and 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (0.19 g, 0.8 mmol), followed by 2M Na2CO3 (0.6 mL, 1.2 mmol). The resulting mixture was heated at 80° C. for 20 h. The reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate and brine and dried (MgSO4). Flash chromatography of the crude product mixture with 25:10:65, 35:10:55, and 50:10:40 EtOAc-CH2Cl2-Hexane gave the title compound. MS (ES+): 438.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3(O)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCOCC3)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
Add to a solution of 4-[3-(4-hydroxy-tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acid methyl ester (20.0 g, 48.19 mmol) in anhydrous methylene chloride (500 mL) at room temperature, triethylsilane (20.0 mL, 125.19 mmol) and trifluoroacetic acid (61.5 mL, 798.2 mmol). Stir the resulting solution for 1 h, concentrate, and obtain the oil and partition between ethyl acetate (500 mL) and saturated sodium bicarbonate (500 mL). Dry the organic layer over sodium sulfate, filter through a silica gel pad, and back-wash with ethyl acetate (400 mL). Concentrate the filtrate to low volume, add hexanes, and a separate the solid. Filter the solid and hold aside, 14 g. Concentrate the filtrate to low volume and add MTBE to provide a second crop of crystals, filter and found identical by TLC (3:2 hexanes/ethyl acetate) to the original lot, 2.8 g. Combine the two lots and dry (20 mmg Hg, 40° C.) to provide one lot of highly pure title compound for subsequent hydrolysis (16.8 g, 87%); 1H NMR (DMSO-d6) δ 8.10 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.28 (t, J=7.1 Hz, 1H), 3.94 (m, 2H), 3.85 (s, 3H), 3.50 (t, J=11.5 Hz, 2H), 3.03 (m, 1H), 1.86 (m, 2H), 1.70 (m, 2H); MS (ESI) m/z 400 (m+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:18][O:17][N:16]([CH3:15])[C:9](=[O:10])[C:8]1[C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(trifluoromethyl)nicotinic acid (2.11 g, 11.04 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.077 g, 11.04 mmol) in DCM (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.78 mL, 22.08 mmol), and HATU (4.20 g, 11.04 mmol). The reaction was stirred at rt under N2 for 5 h. The reaction was then diluted with H2O (50 mL) and extracted with DCM (2×50 mL). The organic layers were combined, dried (MgSO4), and concentrated to give the amide. Purification by ISCO (80 g SiO2, 10-50% EtOAc/hexanes) gives N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide as a yellow oil.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1>ClCCl.CO>[Br:1][CH2:15][C:14]([C:10]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: CC(=O)C1(c2cccc(Cl)c2)CCC1
Reactant: BrBr
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)C1(c2cccc(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (9.9 ml) in dichloromethane (50 ml) was added dropwise at 10°-15° C. over 3 hours to a stirred solution of 1-[1-(3-chlorophenyl)cyclobutyl]-ethanone (38 g) in a mixture of methanol (75 ml) and dichloromethane (15 ml). When the addition was complete, the mixture was stirred at ambient temperature for 2.5 hours, then poured onto an excess of ice-water. The aqueous layer was separated and the product extracted into dichloromethane (3×90 ml). The combined organic solutions were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried over calcium chloride and the solvent removed in vacuo to leave 2-bromo-1-[1-(3-chlorophenyl)cyclobutyl]ethanone as an oil (47 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[NH:17][C:16](=O)[N:15]3[CH:19]=[CH:20][N:21]=[C:14]3[CH:13]=2)[CH:9]=[N:8]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:35]>C(Cl)Cl>[Cl:35][C:16]1[N:15]2[CH:19]=[CH:20][N:21]=[C:14]2[CH:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:23])([CH3:22])[CH3:1])[CH:11]=2)[N:17]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(=O)[nH]2)cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of 7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one (Step B, 772 mg, 2.33 mmol) in dry DCM (15 mL) was added DIEA (1.22 mL, 6.99 mmol) and the mixture was stirred at ambient temperature for 5 minutes. The mixture was cooled to 0° C. and POCl3 (855 μL, 9.32 mmol) was added. The mixture was stirred for 1 hour at 0° C. then at ambient temperature for 18 hours. The reaction mixture was concentrated and the residual syrup was dissolved in EtOAc (15 mL). The solution was added dropwise to stirred 1M K2CO3 (20 mL) cooled to 0° C. and stirred for 30 minutes. The mixture was allowed to reach ambient temperature and the EtOAc layer was removed. The remaining aqueous layer was extracted with EtOAc (2×) and the combined EtOAc fractions were washed with saturated NaCl. The EtOAc solution was dried over MgSO4/activated carbon, filtered through a packed Celite plug (EtOAc elution) and concentrated. The residual dark syrup was dissolved in Et2O, treated with activated carbon and filtered through a packed Celite pug (Et2O elution). The Et2O solution was concentrated to give a brittle tan foam that was pulverized to a flowing solid and dried in vacuum. This afforded the title compound (416 mg, 51.0% yield) as a light tan solid. MS (apci) m/z=350.1 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.BrC1C=C(O)C=CC=1.[CH3:20][O:21][C:22]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]2[C:23]=1[C:24](=[O:44])[C:25](=[O:43])[N:26]2[CH2:33][C:34]1[O:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:44][C:24]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:23]2[C:27](=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:22]=2[O:21][CH3:20])[N:26]([CH2:33][C:34]2[O:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=2)[C:25]1=[O:43]
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: COc1ccc2c(c1OC)C(=O)C(=O)N2Cc1ccc(C(F)(F)F)o1
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COc1ccc2c(c1OC)C(O)(c1cc3c(cc1O)OCCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (67%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.59 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.71-6.65 (m, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 6.33-6.25 (m, 2H), 4.89-4.71 (m, 2H), 4.25-4.02 (m, 4H), 3.99 (s, 1H), 3.83 (s, 6H).
Reaction SMILES: [C:1]([N:9]([CH3:11])[OH:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24](Cl)(=[O:26])=[O:25])=[CH:16][CH:15]=1)=[CH2:13].C(N(CC)CC)C.O>O1CCCC1>[CH:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:1]([N:9]([CH3:11])[OH:10])=[O:8])(=[O:26])=[O:25])=[CH:16][CH:15]=1)=[CH2:13]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: CN(O)C(=O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=Cc1ccc(S(=O)(=O)c2ccccc2C(=O)N(C)O)c2ccccc12
Reaction time: 2 h
Yield: 69.9 %

Procedure:
10.0 g of N-methylhydroxylamine hydrochloride was added to 100 ml of tetrahydrofuran. 19.8 g of pyridine was added to the mixture. A solution of 16.8 g of benzoyl chloride in 100 ml of tetrahydrofuran was dropwise added to the mixture under stirring at room temperature over 1 hr. The stirring was continued at room temperature for additional 8 hr. to conduct the reaction. 50 ml of dilute hydrochloric acid was added thereto and then tetrahydrofuran was removed under reduced pressure. After extraction with ethyl acetate, the extract was dehydrated over anhydrous magnesium sulfate. Ethyl acetate was removed under reduced pressure. The resultant crude product was purified according to column chromatography (packing: silica gel, developer: ethyl acetate/hexane) to obtain 8.5 g of N-benzoyl-N-methylhydroxylamine as an oil having a melting point of 20° C. or below. 130 ml of tetrahydrofuran was added to 7.6 g of N-benzoyl-N-methylhydroxylamine and 12.6 g of 4-vinyl-1-naphthalenesulfonyl chloride. A solution of 5.1 g of triethylamine in 20 ml of tetrahydrofuran was dropwise added thereto under stirring over 2 hr. while the mixture was cooled so that the temperature of the solution was below 25° C. After conducting the reaction at 15° to 25° C. for additional 2 hr., the reaction solution was poured into 700 ml of water and the precipitate thus formed was collected by filtration. After recrystallization from acetonitrile, 12.8 g of o-(4-vinyl-1-naphthalenesulfonyl)-N-benzoyl-N-methylhydroxylamine was obtained.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1)=[O:14].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:33][C:2]([F:1])([F:32])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1)=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Cc1ccc(O)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(1-(2-(2,2,2-trifluoro-ethoxy)-4-hydroxyphenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.54 g, 1.2 mmol) from Example 32 in DMF (10 mL) was added tert-butyl bromoacetate (0.51 mL, 3.6 mmol) and Cs2CO3 (0.48 g, 1.5 mmol). The mixture was stirred at ambient temperature for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (10 mL) and water (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 1-(1-(2-(2,2,2-trifluoro-ethoxy)-4-(tert-butyloxycarbonylmethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one as a pale yellow oil (HPLC retention time=27.3 min (method D)).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[N:25]1([CH:30]([C:32]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[CH2:40]O)=[CH:34][CH:33]=2)[CH3:31])[CH:29]=[CH:28][N:27]=[CH:26]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:40]/[CH:39]=[CH:38]/[C:35]1[CH:34]=[CH:33][C:32]([CH:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH3:31])=[CH:37][CH:36]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(c1ccc(/C=C/CO)cc1)n1ccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(C(C)n3ccnc3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-3-[4{-1-(1-imidazolyl)ethyl)phenyl]-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 519 mg (95.7%).
Reaction SMILES: [CH2:1]([C:5]1([C:13](Cl)=[O:14])[CH2:10][CH:9]2[CH2:11][C:6]1([CH3:12])[CH:7]=[CH:8]2)[C:2](=[CH2:4])[CH3:3].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)([CH3:25])[CH3:24])=[CH:19][CH:18]=1.C1C[O:36]CC1>N1C=CC=CC=1>[CH2:1]([C:5]1([C:13]([OH:14])=[O:16])[CH2:10][CH:9]2[CH2:11][C:6]1([CH3:12])[CH:7]=[CH:8]2)[C:2](=[CH2:4])[CH3:3].[CH2:1]([C:5]1([C:13]([OH:14])=[O:36])[CH2:10][CH:9]2[CH2:11][C:6]1([CH3:12])[CH:7]=[CH:8]2)[C:2](=[CH2:4])[CH3:3].[OH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)([CH3:25])[CH3:24])=[CH:21][CH:22]=1
Reactant: C=C(C)CC1(C(=O)Cl)CC2C=CC1(C)C2
Reactant: C1CCOC1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: C=C(C)CC1(C(=O)O)CC2C=CC1(C)C2
Temperature: 80 °C

Procedure:
175 g of methallyl-methyl-bicyclo[2.2.1]hept-5-ene2-carbonyl chloride are added dropwise at 20° C. within 30 minutes to a solution of 87 g of bisphenol A in 300 ml of pyridine. The mixture is then stirred for a further hour at 80° C. and then worked up as described in Example 2. This gives 205 g (89% of theory) of a brown, liquid resin with η120 =640 mPas. By gel permeation chromatography (THF), the molecular weight is found to be 616 (Mn) or 656 (Mw).
Reaction SMILES: [CH3:1][C:2]1[N:18]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH3:16])[C:8]=3[CH2:17]2)=[C:4]([C:19](OC)=[O:20])[C:3]=1[C:23](OC)=[O:24].[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[CH3:1][C:2]1[N:18]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH3:16])[C:8]=3[CH2:17]2)=[C:4]([CH2:19][OH:20])[C:3]=1[CH2:23][OH:24]
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1c(c3ccccc3n1C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(CO)c(CO)c2n1Cc1c(c3ccccc3n1C)C2
Reaction time: 0.25 h

Procedure:
A solution of dimethyl 3,6-dimethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (3.5 g, 10.0 mmol) in anhydrous dichloromethane (35 mL) was added dropwise into a stirred suspension of LiAlH4 (0.9 g, 25.0 mmol) in anhydrous diethyl ether (20 mL) at 0 to −5° C. The reaction mixture was further stirred for 15 min after the addition was completed. The excess hydride was destroyed by the sequential addition of water (1 mL), 15% aqueous NaOH (1 mL), and water (1 mL) at 0° C. The mixture was filtered through a pad of Celite, the solid residue was washed with dichloromethane. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was triturated with ether to give [3,6-dimethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-diyl]dimethanol (BO-1922), 2.3 g (79%); mp 200-201° C. 1H NMR (DMSO-d6) δ 2.29 (3H, s, Me), 3.73 (3H, s, Me), 3.99 (2H, s, CH2), 4.38 (4H, brs, CH2 and exchangeable, OH), 4.44 (2H, s, CH2), 5.13 (2H, s, CH2), 7.05 (1H, t, J=7.4 Hz, ArH), 7.16 (1H, t, J=7.4 Hz, ArH), 7.46 (1H, d, J=7.8 Hz, ArH), 7.53 (1H, d, J=7.8 Hz, ArH). Anal. Calcd for (C18H20N2O2.0.5H2O): C, 70.80; H, 6.93; N, 9.17. Found: C, 70.85; H, 6.65; N, 9.02.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH2:16][NH:17][CH3:18])=[CH:14][C:13]([C:19]3[CH:20]=[N:21][C:22]([N:25]4[CH2:30][CH2:29][C:28]([CH3:36])([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]4)=[N:23][CH:24]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1.CO>C(O)(C)C.C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH2:16][N:17]([CH3:18])[C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[CH:14][C:13]([C:19]3[CH:20]=[N:21][C:22]([N:25]4[CH2:30][CH2:29][C:28]([CH3:36])([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]4)=[N:23][CH:24]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CNC)c2s1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CN(C)c3ncccn3)c2s1
Yield: 27.1 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-(methylaminomethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (130 mg, 0.25 mmol), N,N′-diisopropylethylamine (3.69 mmol, 477 mg, 324 ul) and 2-chloropyrimidine (1.75 mmol, 200 mg) were combined in isopropanol (2 mL) in a microwave tube equipped with a stirrer. The tube was purged with N2, sealed and irradiated to 110° C. for 1 hr in a CEM explorer microwave with stirring however LCMS indicated only starting material was present and the reaction was diluted with isopropanol (4 mL) and N,N′-diisopropylethylamine (4.19 mmol, 540 mg, 400 ul), then purged with N2, sealed then irradiated to 110° C. for 1 hr in the CEM explorer with stirring. LCMS indicated conversion to the desired product along with the corresponding isopropylester and starting material. The reaction was allowed to cool, the solvents removed under reduced pressure and the resulting residue partitioned between EtOAc and water and the layers separated. The aqueous portion was extracted with EtOAc and the combined organic portions dried (MgSO4) and concentrated to afford the crude product (160 mg). This material was purified by flash silica chromatography eluting with 0 to 50% EtOAc in petroleum-ether then 0 to 10% MeOH in DCM to afford the target material (40 mg, 27% yield).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3]1.S(=O)(=O)(O)O.[CH3:19]O>CCC(O)(C)C>[CH3:19][O:12][C:11]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[CH2:3]1)=[O:13]
Reactant: CO
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCC(C)(C)O
Product: COC(=O)C1CC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 10.0 g of 3-oxo-indan-1-carboxylic acid (56.8 mmol, 1.0 equivalent) and 0.25 mL of concentrated sulfuric acid in 20 mL of methanol was heated to a reflux for 4 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL of methyl-tert-butyl alcohol. The organic solution was washed twice with 60 mL of a saturated aqueous sodium bicarbonate solution, and once with 50 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The title compound crystallized as a white solid upon concentration, (10.4 g, 96%); mp: 46-47° C.; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 4.29 (dd, J=8.0, 3.4 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J=19.1, 3.4 Hz, 1H), 2.86 (dd, J=19.1, 8.0 Hz, 1H); 13C NMR (100 MHz, CD3OD): δ 204.4, 172.5, 151.3, 136.5, 135.2, 129.1, 126.7, 124.1, 52.9, 43.8, 39.7; IR (neat, cm−1): 2954, 1710, 1602, 1462, 1435, 1403, 1319, 1241, 1206, 1168, 1092, 1044, 1014, 986, 881, 837, 760, 686, 580, 538.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:21]([O:25][C:26](=[O:39])[CH:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[C:32]([F:38])[CH:31]=1)[CH3:28])([CH3:24])([CH3:23])[CH3:22].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:21]([O:25][C:26](=[O:39])[CH:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:19][CH:18]=[C:17]([F:20])[CH:16]=2)=[O:15])=[C:32]([F:38])[CH:31]=1)[CH3:28])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.26) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-nicotinic acid and (±)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][C:9]([CH3:21])([CH3:20])[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:17])([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][C:9]([CH3:21])([CH3:20])[O:8][C:5]3=[CH:6][CH:7]=2)[CH:26]=[N:27][CH:28]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(Br)ccc2O1
Product: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(-c3cncc(Cl)c3)ccc2O1
Yield: 78 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,2-dimethyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.5) with 5-chloropyridin-3-ylboronic acid yielded the title compound (78% yield) as a white powder. MS (ISP): m/z=394.1 [M+H]+.