Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]=[C:31]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:30]=[CH:29]1>>[NH:28]1[CH:32]=[C:31]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:39][CH:40]=2)[N:30]=[CH:29]1
Reactant: Nc1ccc(Cc2c[nH]cn2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cc2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(imidazol-4-yl-methyl)-aniline Rf value: 0.2 (silica gel, methylene chloride/methanol=5:1) C27H22N4O3
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide (Intermediate 13, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:20]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([Br:20])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(CC(=O)OC)cc(OCOC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(CC(=O)OC)c(Br)c(OCOC)c1
Temperature: 4 °C
Reaction time: 3 h

Procedure:
Methyl 3,5-bis(methoxymethoxy)phenylacetate (43 g, 0.16 mol) obtained in Example 1, Step 1 was dissolved in N,N-dimethylformamide (0.68 L). After the solution was cooled to 4° C., N-bromosuccinimide (28 g, 0.16 mol) was added thereto, followed by stirring for 3 hours, while the temperature of the reaction mixture was raised to room temperature. To the reaction mixture was added water (0.50 L), and the mixture was extracted with a mixed solvent of hexane and ethyl acetate (hexane/ethyl acetate=1/2, 0.40 L×4). The organic layer was washed with a saturated aqueous solution of sodium chloride (50 mL) and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/2) to obtain a quantitative yield of methyl 3,5-bis(methoxymethoxy)-2-bromophenyl-acetate.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Yield: 95.8 %

Procedure:
1-Benzenesulfonyl-4-methoxy-benzene (5.92 g, 23.8 mmol) was dissolved in methylene chloride and stirred. A solution of BBr3 (6.77 g, 71.68 mg) in 120 mL of methylene chloride was added dropwise to the reaction mixture, after which the mixture was stirred for 4 hours at room temperature. Water (150 mL) was then added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted three times with 45 mL methylene chloride, and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (30-50% EtOAc in hexanes) to afford 5.348 g of 4-benzenesulfonyl-phenol (22.8 mmol, 99%) as an oil. MS: 235 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([Br:19])=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=O)(C)(C)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[Br:19][C:15]1[C:14]([CH3:20])=[CH:13][C:12]2[N:11]3[C@H:21]([CH3:23])[CH2:22][NH:8][CH2:9][C:10]3=[CH:18][C:17]=2[CH:16]=1
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1Br)cc1n2[C@H](C)CNC1

Procedure:
A solution of 0.12 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 3 mL of a 2M solution of hydrochloric acid in ethyl acetate was stirred at room temperature under argon for 2 h. The precipitate was collected by filtration and dried to constant weight to yield the title compound (0.065 g) as off-white crystals. m.p.: 241° C. (dec.); MS: M+H=279.1; HNMR: (250 MHz, DMSO-d6, δ [ppm]) 1.50 (d, J=6.5 Hz, 3H); 2.45 (s, 3H); 3.48-3.74 (m, 2H); 4.36-4.58 (m, 2H); 4.74-4.89 (m, 1H); 6.35 (s, 1H); 7.54 (s, 1H); 7.78 (s, 1H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:22])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetic acid (9) (170 mg, 638 μmol) in CH2Ch (5 mL) was added DMF (1 drop) by a Pasteur pipette at room temperature. To this was added oxalyl dichloride (110 μL, 1.30 mmol) at 0° C. and the mixture was stirred for 30 minutes while elevating to room temperature. The mixture was concentrated under reduced pressure to give crude 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) as a colorless oil, which was used in the following reaction without further purification.
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:50])=[CH:30][C:29]=1[NH:51][C:52]([C:54]1([C:57](O)=[O:58])[CH2:56][CH2:55]1)=[O:53].[F:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:50])=[CH:30][C:29]=1[NH:51][C:52]([C:54]1([C:57]([NH:65][C:64]2[CH:66]=[CH:67][C:61]([F:60])=[CH:62][CH:63]=2)=[O:58])[CH2:56][CH2:55]1)=[O:53]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Reaction time: 68 h
Yield: 73 %

Procedure:
4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (388 mg) was added to a mixture of 1-[({2,5-difluoro-4-[(2-{[((R)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylic acid triethylamine salt (185.3 mg), 4-fluoroaniline (0.0623 ml) and tetrahydrofuran (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 68 hours. A saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the reaction mixture and stirred, and the mixture was partitioned after the addition of ethyl acetate and tetrahydrofuran (1:1) (40 ml) and water (30 ml). The organic layer was washed with brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (132.8 mg, 73%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:24][OH:25])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[OH:23])[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[Cl-].[NH4+]>[CH:1]([C:4]1[C:5]([CH2:24][OH:25])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1OCc1ccccc1
Yield: 99.8 %

Procedure:
A mixture of the racemic compound prepared in Example 241 (293 mg, 851 μmol), benzyl bromide (110 μL, 925 μmol), and potassium carbonate (303 mg, 2.19 mmol) in acetone (29 mL) was heated to reflux for 3 h. The mixture was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with Et2O (3×50 mL). Silica gel chromatography (90:10 hexane/ethyl acetate) provided a colorless oil (0.369 g, 100%). 1H NMR (CDCl3, 300 MHz): δ 7.34 (s, 1H), 7.23 (m, 3H), 7.12 (m, 1H), 7.03 (m, 2H), 6.84-6.75 (m, 2H), 5.04 (d, 12.1 Hz, 1H), 4.94 (d, 12.1 Hz, 1H), 4.38 (dd, 11.4 Hz, 8.5 Hz, 1H), 4.25 (dd, 11.4 Hz, 3.3 Hz, 1H), 3.39 (sept, 6.9 Hz, 1H), 3.18 (sept, 6.9 Hz, 1H), 2.30-2.40 (m, 1H), 2.09-2.20 (m, 1H), 1.65 (dd, 8.5 Hz, 3.3 Hz, 1H), 1.26-1.34 (m, 14H), 0.72 (t, 7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[P:5]([CH2:10][CH:11]([F:17])[C:12](OCC)=[O:13])([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[NH4+:21]>C(O)C>[NH2:21][C:12](=[O:13])[CH:11]([F:17])[CH2:10][P:5]([CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])(=[O:6])[O:7][CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCOC(=O)C(F)CP(=O)(OCC)C(OCC)OCC
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(F)C(N)=O)OCC
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-2-fluoropropanoate (16.0 g, 51.1 mmol) in ethanol (22 mL) was added concentrated ammonium hydroxyde (14.8 N, 3.5 mL, 51.1 mmol). The solution was stirred for 16 h and evaporated. The residue was purified by chromatography on a wet-packed silica gel column (7×37 cm) eluting with 96.5:3.5 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 3.43 g (27%) of ethyl (3-amino-2-fluoro-3-oxopropyl)(diethoxymethyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 5.70 (s, 1H), 5.21-5.49 (dm, 1H), 4.7 (dd, 1H), 4.18-4.31 (m, 2H), 3.65-3.91 (m, 4H), 2.21-2.81 (m, 2H), 1.30-1.40 (m, 3H), 1.20-1.28 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(O)CC1CCNCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCC(CC(=O)O)CC3)nc(N)c2cc1OC
Yield: 74.3 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (17.3 g), piperidine-4-acetic acid hydrochloride (12.0 g) and triethylamine (20 ml) in n-butanol (500 ml) were stirred under reflux for 20 hours. The mixture was then cooled to 0°-4° and the separated product collected. The solid was slurried with acetone (100 ml), filtered, slurried with chloroform (100 ml), filtered and washed with ether to give 4-amino-2-(4-carboxymethylpiperidino)-6,7-dimethoxyquinazoline hydrochloride (19.0 g). A sample was recrystallised from acetic acid and had an m.p. of 250°-252°.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2].[NH2:24][C:25]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:36])[NH:30]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:17])([F:16])[F:18])[CH:13]=[N:24][C:25]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29](=[O:36])[NH:30]3)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2]
Reactant: CCc1c(F)ccc(C(CC)C[C@@](O)(C=O)C(F)(F)F)c1OC
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CCc1c(F)ccc(C(CC)C[C@@](O)(C=Nc2cc(F)cc3[nH]c(=O)ccc23)C(F)(F)F)c1OC

Procedure:
In the same way as in Example 137, 45 mg (0.13 mmol) of (2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 23 mg (0.13 mmol) of 5-amino-7-fluoroquinolin-2(1H)-one and 0.09 ml (0.27 mmol) of titanium tert-butoxide are reacted to give 5-{[(2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-7-fluoroquinolin-2(1H)-one. 80 mg of crude imine are cyclized in the same way as in Example 137 at −30° C. with 1.3 ml (1.3 mmol) of 1 M boron tribromide solution. Purification by column chromatography on silica gel (hexane/isopropanol 16%) and subsequent preparative thin-layer chromatography on an amine phase (Merck NH2F254, ethyl acetate/triethylamine, 2%) yield 7 mg of the title compound and 5 mg of the corresponding (8R)-diastereomer.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH3:20])[C:16](=O)[NH:17][N:18]=2)[CH:10]=[CH:11][CH:12]=1>>[Cl:3][C:16]1[N:17]=[N:18][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(-c2cccc(Cl)c2)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2cccc(Cl)c2)nnc1Cl

Procedure:
A mixture of 25 ml. of phosphorus oxychloride and 3.0 g. of 6-(m-chlorophenyl)-4-methyl-3(2H)-pyridazinone is refluxed for 6 hrs. The mixture is concentrated to dryness under vacuum and water added to the residue. Filtration gives 3.28 g. of crystals, m.p. 138°-140° C. Recrystallized from ethanol gives 2.80 g. of crystals, m.p. 138°-141° C.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[O:15]1[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH:16]1[CH2:17][OH:18].[OH-].[Na+]>O1CCCC1>[OH:18][CH2:17][CH2:16][C@@H:19]([OH:15])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCCCCC1OC1CO
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCC[C@H](O)CCO
Reaction time: 8 h
Yield: 89 %

Procedure:
2 ml of a 3.4 molar solution sodium bis-(2-methoxyethoxy)-aluminum hydride (Red-AlR) (6.8 mM) are slowly added to a solution of 0.61 g (3.91 mM) 2S, 3S-2-epoxy-1-hydroxynon-8-ene (III) in 100 ml tetrahydrofuran at 0° C. in an argon gas atmosphere with agitation. After the addition, the mixture is allowed to react 3 hours at 0° C. and the reaction solution is subsequently left overnight at 25° C. After a careful addition of 5 ml 1 molar sodium hydroxide solution, the mixture is allowed to react one more hour with agitation. The organic phase is separated off and the aqueous phase is washed with 30 ml ether. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and subsequently the solvent is evaporated in a vacuum. Bulb tube distillation at 130° C./0.5 mm pressure yields 0.54 g (3.42 mM) 1,3(S)-dihydroxynon-8-ene (IV) with a melting point of approximately 20° C. This corresponds to a yield of 89%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Ru].CC(O)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ru]
Solvent: CC(C)O
Product: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
The ruthenium salt [RuCl2(P-Cymene)]2 and (S,R)-cis-aminoindanol were added to IPA at RT and aged 0.5 h. The solution generally turned bright yellow-orange over the age period. 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one was added and the reaction was degassed under vacuum. Base was then added and the reaction was aged until >98% complete by HPLC (4-6h). The reaction was then quenched by pouring it into 1 N HCl and extracted with heptane (2×10.5 L) and washed with 15 L brine. 1,4-Diazabicyclo[2.2.2]octane (DABCO) was added and the solution was concentrated to a volume of ˜4 mL/g of alcohol. At this point the KF was less than 200 and less than 5% IPA remains. The reaction can be flushed with additional heptane if these criteria are not met. Optionally, the reaction was seeded with the DABCO complex at 40° C. and the reaction was allowed to slowly cool to RT. Crystallization began to occur immediately. The reaction was then cooled to 0° C. and filtered. The cake was washed with cold heptane. The DABCO complex was isolated in 75-80% yield with an enantiomeric excess of >99%.
Reaction SMILES: [CH3:1][CH:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH2:3][OH:4].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][CH:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH2:3][O:4][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
In 1 ml of pyridine was dissolved 81 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-dien-21 -ol and, then, under ice-cooling, 70 mg of p-toluenesulfonyl chloride was added. The mixture was stirred at that temperature for 3 hours. The reaction mixture was then poured into ice water and extracted with diethyl ether. The extract was serially washed with aqueous copper sulfate solution, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 79 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-p-toluenesulfonyloxypregna-5,7-diene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CSc1cc(C(C)=O)c(O)cc1C
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(SC)cc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
1-(2-Hydroxy-4-methyl-5-methylsulfanyl-phenyl)ethanone (29 mg), 4-chloro-6,7-dimethoxyquinoline (66 mg), and 4-dimethylaminopyridine (54 mg) were suspended in o-dichlorobenzene (2 ml) to prepare a suspension which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (17 mg, yield 30%).
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][N:33]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:38]5[CH2:39][CH2:40][C:35]6([CH2:34][N:33]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:32]6)[CH2:36][CH2:37]5)=[O:23])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC5(CC4)CN(C(=O)OC(C)(C)C)C5)cn3)nc2n1C1CCCCCC1
Yield: 18.4 %

Procedure:
Following general amide formation method 1, 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (80 mg, 0.19 mmol, 1.0 eq) was combined with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (47.1 mg, 0.208 mmol, 1.1 eq) to afford tert-butyl 7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate as a white solid (22 mg, 0.035 mmol) in 18.4% yield. 1H NMR (400 MHz, chloroform-d) δ ppm 8.67 (s, 1H) 8.60 (d, J=8.59 Hz, 1H) 8.31 (d, J=2.02 Hz, 1H) 8.16-8.28 (m, 1H) 7.74 (dd, J=8.59, 2.53 Hz, 1H) 6.39 (s, 1H) 5.23 (s, 1H) 4.38-4.51 (m, 1H) 3.63 (s, 4H) 3.52 (br s, 2H) 3.10 (s, 6H) 2.48-2.66 (m, 2H) 1.86-2.03 (m, 2H) 1.56-1.85 (m, 9H) 1.42-1.56 (m, 4H) 1.38 (s, 9H). MS (m/z, MH+): 631.7
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22](=[O:31])[CH:23]=[C:24]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25]1)[CH3:20].[N+:32]([CH3:35])([O-:34])=[O:33]>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1([CH2:35][N+:32]([O-:34])=[O:33])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25]1)[CH3:20]
Reactant: CCOC(=O)C=C1CCC(C)(C)C1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC(C)(C)C1
Temperature: 70 °C
Reaction time: 19 h
Yield: 40.8 %

Procedure:
Tetrabutylammonium fluoride (5.75 mL of a 1 M solution in THF, 5.75 mmol) was added to a solution of the ester 2 (697 mg, 3.83 mmol) and nitromethane (467 mg, 7.66 mmol) in THF (20 mL) and the mixture heated to 70° C. After 19 hours, nitromethane (233 mg, 1.9 mmol) and tetrabutylammonium fluoride (1.9 mL of a 1 M solution in TBF, 1.9 mmol) were added and reflux continued for 7 hours, whereupon the solution was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with 2N HCl (20 mL) then brine (20 mL). The organic phase was dried (MgSO4) and concentrated. The crude product was flash chromatographed (9:1 hexane/ethyl acetate) to give the nitro ester 3 (380 mg, 41%) as an oil.