Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([CH:16]([CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])C1C=CC=CC=1.[OH:34]O.O.[OH-].[Li+]>O1CCCC1.O>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH:16]([CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([OH:15])=[O:34])([CH3:24])([CH3:23])[CH3:22]
Reactant: OO
Reactant: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)O
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of tert-butyl 3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-cyclohexylhexanoate (64.0 g, 139.9 mmol) in tetrahydrofuran:water (3:1, 800 ml) was cooled to 5° C. then treated sequentially with hydrogen peroxide (30%w/v water, 87 ml, 769 mmol) then lithium hydroxide hydrate (10.0 g, 238 mmol). The reaction was stirred for 1 hour then quenched by dropwise addition of an aqueous solution of sodium thiosulphate (500 ml) keeping the temperature below 20° C. The mixture was extracted with ethyl acetate (discarded) and the aqueous phase was acidifed to pH 2 with solid citric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (2:1) gradually changing to hexane:ethyl acetate (1:1) to afford the title compound (40.7 g)
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13](Br)[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[ClH:21]>CN1CCCC1=O.O>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:21])[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)CCc1c(Br)cccc1C2=O
Reactant: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc2c(c1)CCc1c(Cl)cccc1C2=O

Procedure:
0.81 G. of 2-carboxy-9-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene and 0.32 g. of cuprous chloride were refluxed for 8 hours in 10 ml of N-methylpyrrolidinone. The solution was cooled and added to a solution of 4.4 g. of ferric chloride hexahydrate in 6 ml of water and 3 ml of concentrated hydrochloric acid. The mixture was heated to 90° for 1 hour, then was poured into water and filtered. The residue was recrystallized from aqueous dimethylformamide to afford 2-carboxy-9-chloro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, m.p. 258.5°-260°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21]C)=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51 mL) were dissolved in methylene chloride (26 mL), and ethyl chlorooxoacetate (1.10 mL) was added thereto under ice cooling, followed by stirring at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture to partition the mixture, and the organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1). The resultant pale-yellow solid was dissolved in methanol (20 mL), and the solution was stirred at 50° C. for 11 hours. The reaction mixture was concentrated under reduced pressure. The precipitated crystals were collected by filtration, and were dried, to thereby give the title compound (0.43 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>CCOCC.CCCCCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([B:23]([OH:24])[OH:22])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccccc1-c1ccccc1
Temperature: -67 °C
Yield: 64.6 %

Procedure:
Under an atmosphere of argon, 2-bromobiphenyl (20 g, 86 mmole) was dissolved into anhydrous ether (200 ml) and the resultant solution was cooled at −35° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 63 ml, 95 mmole) was added dropwise and the resultant mixture was stirred at −20° C. for 1 hour. After the reaction mixture was cooled at −67° C., a solution (50 ml) of triisopropoxyborane (50 ml, 0.22 mole, 2.5 eq) in anhydrous ether was added and the resultant mixture was stirred at −65° C. for 1 hour and at the room temperature for 2 hours and left standing for one night. To the obtained reaction mixture, a 10% hydrochloric acid (200 ml) was added. After the resultant mixture was stirred at the room temperature for 1 hour, the formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. The solid obtained after removing the solvent by distillation was washed with hexane and a white solid (11 g, 62%) was obtained.
Reaction SMILES: C([Si](C)(C)[C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])(C)(C)C.[OH-].[Na+]>CO.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[C:7]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])#[CH:6]
Reactant: Cc1ccc(C#C[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc(C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl-dimethyl-(4-methyl-2-nitro-phenylethynyl)-silane (3.5 g, 15 mmol) in MeOH (20 mL) was added NaOH (1.8 g, 45 mmol, in 5 mL of H2O). After stirring for 1 hour, the reaction was diluted with EtOAc (150 mL) and 10% Na2CO3 (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1 by 75 mL) The organic layers were combined, dried over MgSO4, filtered, and dried under reduced pressure to yield 1.40 g (58% over two steps) of a brown solid.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[F:44].[C:45]([Si:49]([CH3:52])([CH3:51])Cl)([CH3:48])([CH3:47])[CH3:46]>ClCCl>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:43][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:52])[CH3:51])([C:35]([F:36])([F:37])[F:38])[C:39]([F:41])([F:42])[F:40])=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:15][C:14]=1[F:44]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.559 mmol, 0.233 mL, 237 mg) was added to a cooled (ice/slurry) solution of (4-amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (1.199 mmol, 575 mg) and tert-butyldimethylchlorosilane (1.559 mmol, 235 mg) in dichloromethane (20 mL) under nitrogen. The resulting solution was stirred for 15 minutes prior to the removal of the external cooling bath. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 0.5M hydrochloric acid (100 ml), 0.5M sodium hydroxide (100 ml) and brine (100 ml). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give a crude oil. This oil was purified by SCX chromatography to afford the title compound (534 mg). MS (ESI) m/z 594.3 [M+H]+
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9]1[C:10]([F:30])=[C:11]([N:15]([CH2:27][O:28][CH3:29])[S:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)=O>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9]2[C:10]([F:30])=[C:11]([N:15]([CH2:27][O:28][CH3:29])[S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:4]=1
Reactant: COCN(c1cccc(C(=O)CBr)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: NC(N)=S
Solvent: CCO
Product: COCN(c1cccc(-c2csc(N)n2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 60 °C
Yield: 79.3 %

Procedure:
21 mg (0.27 mmol) of thiourea were added to a solution of 122 mg (0.27 mmol) of N-[3-(bromoacetyl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in 5 mL of ethanol. The mixture was heated at 60° C. for 20 min in a microwave apparatus. The solvent was then removed, the residue taken up with DCM and washed with water. The organic layer was separated, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography eluted with DCM-CH3OH 95/5, giving 92 mg (80%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].[C:22]([O-:25])(=[O:24])[CH3:23].[K+].[I-].[Na+].CN(C=O)C>O>[C:22]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19])(=[O:24])[CH3:23]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCOC(C)=O
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 1.3 %

Procedure:
1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (3.8 g, 12.5 mmol, prepared as described in Example 19) was combined with potassium acetate (3.68 g, 37.5 mmol), sodium iodide (470 mg, 3.12 mmol), and DMF (21 mL). The mixture was heated at 90° C. for 2 hours, allowed to cool to ambient temperature, diluted with water (100 mL), stirred for 20 minutes, and then filtered to remove a black solid. The filtrate was allowed to stand for 1 week at which time crystals had formed. The crystals were isolated by filtration, purified by chromatography on a HORIZON HPFC system (25+M cartridge eluting with chloroform/CMA in a gradient from 100:0 to 70:30), and then recrystallized from acetonitrile to provide 55 mg of 4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl acetate as a tan crystalline solid, mp 128-129° C. MS (APCI) m/z 327 (M+H)+;
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.F[C:21]1[CH:33]=[CH:32][C:24]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=1.[H-].[Na+].O>CS(C)=O>[C:4]1(=[O:14])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][N:12]([C:21]3[CH:33]=[CH:32][C:24]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=3)[CH:13]=2)[C:1](=[O:19])[C:2]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:3]12
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(-n2cnc(CCCN3C(=O)c4ccccc4C3=O)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5.10 g (20 mmol) of 4-(3-phthalimidopropyl)-imidazole followed by 3.92 g (20 mmol) of 3-(4-fluorobenzoyl)-propionic acid are added portionwise to a suspension of 1.20 g (40 mmol) of sodium hydride (80% on paraffin oil) in 50 ml of dimethyl sulphoxide. The reaction mixture is initially stirred at room temperature until gas evolution ceases and then at 100° C. for 17 hours. After cooling, the mixture is poured out on 50 ml of water and extracted with 3×50 ml dichloromethane. The aqueous phase is then adjusted to pH 5 with 2N hydrochloric acid and the precipitated solid is suction filtered and recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:13])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([O:13][C:10]1[C:11]([F:12])=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(O)c(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(OCc3ccccc3)c(F)c(F)cc2c1O
Reaction time: 11 h

Procedure:
To a stirred solution of ethyl 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethylformamide (6 ml), was added anhydrous potassium carbonate (308 mg) and then benzyl chloride (145 μl). The mixture was stirred at 55°-65° C. for 11 hours. The reaction mixture was diluted with water (30 ml) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (7 g) using acetone/chloroform (1:20) as an eluent to give 113 mg of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate, mp 200°-201° C.; MS m/z 359 (M+), after recrystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[Li]CCCC.[I:20]I>C1COCC1>[F:1][C:2]1[C:7]([I:20])=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[O:11][CH2:12][CH2:13][O:14]1
Reactant: COc1ccc(C2OCCO2)c(F)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2OCCO2)c(F)c1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane (4.27 g, 21.54 mmol) in anhydrous THF (30 mL) was added, at −78° C. under argon, n-BuLi (1.6 M in hexane, 13.5, 21.54 mmol). The resulting orange solution was stirred at −78° C. for 2 hours then iodine (6.015 g, 23.70 mmol) in THF (30 mL) was added. At the end of the addition the reaction mixture was warmed to room temperature and stirred for 1 hr. The solution was extracted with ethyl acetate. The organic phase was washed successively with 10% aqueous sodium thiosulfate (2×50 mL), water, brine and dried (MgSO4), filtered and evaporated to give 5.794 g of crude 2-(2-fluoro-3-iodo-4-methoxy-phenyl)-[1,3] dioxolane. use as this in the next step.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:44][O:45][NH2:46]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:46][O:45][CH3:44])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of the carboxylic acid (6b, 965 mg, 3.49 mmol) of Example 9 or 16 in tetrahydrofuran (20 mL) were added triethylamine (1.95 mL), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (802 mg), 1-hydroxybenzotriazole.monohydrate (658 mg), and O-methylhydroxylamine hydrochloride (363 mg), followed by agitating to room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/10) to afford 773 mg of the title compound (yield 72%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:14][CH2:15][CH2:16][SiH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>CCOCC>[C:1]([C:5]1[CH:11]=[C:10]([O:12][CH2:14][CH2:15][CH2:16][SiH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: CC(C)=C[SiH2]CCCCl
Solvent: CCOCC
Product: CC(C)=C[SiH2]CCCOc1ccc(O)c(C(C)(C)C)c1

Procedure:
In the first reaction shown, t-butylhydroquinone is reacted with chloropropyldimethylvinylsilane in a conventional Williamson ether synthesis to form 2-t-butyl-4-(3'-dimethylvinylsilylpropoxy)phenol (I).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c3) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:19][C:12](=[O:13])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)NCC(OC)OC)cc1OC
Reaction time: 1 h

Procedure:
While cooling with ice, a solution of 3,4-dimethoxyphenylacetic acid chloride (485.2 g) in methylene chloride (1.1 liters) is added dropwise at 15°-20° C. to a solution of aminoacetaldehyde dimethylacetal (246.2 ml) and triethylamine (315 ml) in methylene chloride (2.2 liters) and the resulting mixture is stirred for 1 hour at 16°-18° C. It is then extracted several times with water, dried over magnesium sulphate and concentrated by evaporation. The resulting oil slowly crystallizes out.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1C=C(Cl)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2)CCC1
Temperature: 95 °C
Reaction time: 7 h

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-DCM complex (313 mg, 0.383 mmol) was added to a stirred mixture of 8a (500 mg, 3.83 mmol), pyridin-3-yl-boronic acid (565 mg, 4.60 mmol) and sodium carbonate (2.87 mL of a 2M aq. solution, 5.74 mmol) in dioxane (14.0 mL) and water (2.00 mL). The resulting mixture was degassed and heated to 95° C. After 7 h, the reaction mixture was cooled to rt, diluted with EtOAc, filtered through a short column of Celite®, eluting copiously with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (0-90% EtOAc/hexanes as eluent) to afford the title compound, 8b. m/z (ES) 174 (MH)+
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:18]=[C:17]2[C:8]([N:9]3[C:14]([CH2:15][O:16]2)=[N:13][NH:12][C:11](=[O:19])[C@H:10]3[CH3:20])=[CH:7][C:6]=1[C@H:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)[CH3:22])([CH3:4])[CH3:3].C=O.[BH3-][C:31]#N.[Na+]>CO.C(O)(=O)C>[CH3:31][N:25]1[CH2:24][C:23]([C@@H:21]([C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][C:5]=2[CH:2]([CH3:3])[CH3:4])[O:16][CH2:15][C:14]2[N:9]3[C@H:10]([CH3:20])[C:11](=[O:19])[NH:12][N:13]=2)[CH3:22])([CH3:27])[CH2:26]1
Reactant: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of (R)-7-isopropyl-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (Example #133, Step G, 0.0227 g, 0.064 mmol) in MeOH (2 mL) and acetic acid (0.2 mL) was added paraformaldehyde (0.765 mL, 0.255 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 h. NaBH3CN (0.008 g, 0.127 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by prep-TLC (eluting with 10% MeOH in dichloromethane) to give (R)-6-[(R)-1-(1,3-dimethyl-azetidin-3-yl)-ethyl]-7-isopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.0199 g, 84%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.00 (s, 1H), 6.79 (s, 1H), 4.83 (br. s., 1H), 4.60 (s, 2H), 3.96 (m, 1H), 3.91 (m, 1H), 3.76 (d, J=9.8 Hz, 1H), 3.67 (d, J=9.8 Hz, 1H), 3.38 (m, 1H), 3.18 (m, 1H), 2.71 (s, 3H), 1.48-1.43 (m, 6H), 1.38 (d, J=6.8 Hz, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.601 min.; MS m/z: 371 [M+H]+. SFC (Table 1, Method 24) Rt=7.354 min.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([F:21])=[CH:12][N:11]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CC=CN=1)C>[Si:1]([O:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]1[C:13]([F:21])=[CH:12][N:11]=[C:10]([Cl:9])[N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCNc1nc(Cl)ncc1F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of t-butyldimethylsilyl chloride (1.63 g, 10.70 mmol) in dichloromethane (48.63 mL) was added 3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-1-propanol (Example 80, 2.0 g, 9.73 mmol), followed by triethylamine (1.49 mL, 10.70 mmol) and dimethylaminopyridine (0.02 g, 0.19 mmol). The resulting cloudy mixture was stirred at rt for 18 h and then diluted with dichloromethane (80 mL). The mixture was washed with water (50 mL), dried over magnesium sulfate, and concentrated. The product was purified by column chromatography (67% hexanes in EtOAc) to give the title compound as a white solid (2.68 g, 86%). 1H NMR (300 MHz, CD2Cl2) δ 7.78 (d, 1H), 3.64-3.59 (m, 2H), 3.44-3.41(m, 2H), 1.82-1.73 (m, 2H), 0.84 (s, 9H), 0.001 (s, 6H).