Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:22]([O:24]CC)=[O:23])[C:14](=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)[CH3:4].Cl>O1CCCC1.O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:22]([OH:24])=[O:23])[C:14](=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(OCC)cc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Lithium hydroxide (108 mg, 4.37 mmol) was added to a solution of ethyl (2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (320 mg, 0.728 mmol) in tetrahydrofuran:water (1:1, 20 mL) and the reaction was allowed to stir at rt until complete. The reaction mixture was acidified with 4 M aq HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as a solid (220 mg, 73%). MS (LCMS) m/z 412.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.40 (m, 3H) 1.54 (s, 3H) 2.07-2.26 (m, 1H) 2.43 (d, J=6.24 Hz, 1H) 3.14 (s, 3H) 3.83-4.15 (m, 4H) 6.42 (d, J=7.81 Hz, 1H) 6.93-7.07 (m, 2H) 7.50 (dd, J=8.68, 1.85 Hz, 2H) 7.97 (d, J=6.83 Hz, 1H).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3ccc(C)cc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(Oc3ccc(C)cc3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.176 ml, 1.48 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 139 (460 mg, 1.48 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (420 mg of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 9:1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1.[H-].[Na+].O>CN(C=O)C>[CH:10]1[C:11]2[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:16]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(Cl)n1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(-n2c3ccccc3c3ccccc32)nc(-n2c3ccccc3c3ccccc32)c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of carbazole (97.0 g, 0.58 mol) and 2,6-dichloropyridine (41.0 g, 0.28 mol) in dry DMF (200.0 ml) was slowly added NaH (20.0 g, 0.83 mol) at room temperature under nitrogen atmosphere and stirring. The addition of NaH was taken over 60 minutes. After the addition of NaH, the mixture was heated to 160° C. and kept at this temperature for 12 hours. After cooling, water (300.0 ml) was added into the reaction mixture. The product as a brown solid was collected by filtration. The crude product was purified with recrystallization from acetone/water to give 92.2 g (81.3 g) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:27]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:35]/[C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:26][N:27]=3)=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
A solution of 4-(4-formyl-3-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 3.0 mmol) obtained in Step 1 in methanol (10 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.99 g, 3.0 mmol) and potassium carbonate (0.82 g, 5.9 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain (E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-3-nitrophenyl}piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 16%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH2:16]([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=1[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]OS(C)(=O)=O)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=1[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])[CH3:17]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCCOc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)OCC)c1
Product: CCCc1c(OCCCCCOc2ccc(OCCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Yield: 83.6 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.7 g (1.4 mmol) of 2-[5-(methylsulfonyl)oxypentyloxy]-5-(3-ethoxycarbonylpropoxy)benzenepropanoic acid ethyl ester (from example 46), 5-(3-ethoxycarbonylpropoxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid ethyl ester was obtained in 83.6% yield (0.7 g) as a solid. This diester (1.17 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 25 mL of tetrahydrofuran, at room temperature, for 37 hr. Work-up as in example 4 gave a light-brown oily acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.39 g (61.5%) of pure 5-(3-carboxypropoxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy] pentyloxy]benzenepropanoic acid. Recrystallization from hexane-ethyl acetate gave a colorless solid, mp 119°-124° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:14][C:3]1[CH:4]=[N:5][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:7][C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:36])=[O:20]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)C(=O)Nc1cnc(N2CCOCC2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1NC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 3.50 g (9.0 mmol) N-(4-iodo-6-morpholin-4-yl-pyridin-3-yl)-2,2-dimethyl-propionamide, 35 ml toluene, 18 ml 2 N sodium carbonate solution, 312 mg (0.27 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.34 g (9.9 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and evaporated. Purification by flash-chromatography gave 3.23 g (quantitative) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:53][CH2:52]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:54]=[O:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:56]=[O:57].[OH-].[Na+].[BH4-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:52][CH2:53]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:56][OH:57])[CH2:54][OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 23.7 %

Procedure:
Crude (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1e (1.3 g, 1.7 mmol) was dissolved in 15 mL 1,4-dioxane, followed by addition of 37% formaldehyde solution (2.6 mL, 34 mmol) and a solution of sodium hydroxide (204 mg, 5.1 mmol) in 5.1 mL water into the reaction mixture. The reaction mixture was stirred for 4 hours at 70° C., then cooled to 50° C. and stirred for 16 hours. The reaction mixture was extracted with ethyl acetate (20 mL×3) after 20 mL saturated sodium chloride solution were added. The organic extract was washed with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. Then 20 mL of mixed solution (THF and MeOH, v:v=1:1) were added into the residue, before sodium borohydride (130 mg, 3.4 mmol) was added. The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and partitioned. The organic extract was washed with saturated sodium chloride solution (10 mL×2), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, then the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 1f (320 mg, colorless oil), yield: 23.7%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH:19]1([CH:22]2[NH:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:21][CH2:20]1>N1C=CC=CC=1>[CH:19]1([CH:22]2[NH:27][CH2:26][CH2:25][N:24]([C:10]3[CH:11]=[C:12]4[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:14])[CH2:23]2)[CH2:21][CH2:20]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CNC(C2CC2)CN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C4CC4)C3)cc21
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 1.265 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.86 g of 3-cyclopropylpiperazine and 15 ml of pyridine was heated at 100° C. in a pressure bottle for 3 hours, then cooled and evaporated. The residue was purified by silica gel flash chromatography, eluting with chloroform:methanol:water:triethylamine (9:0.5:0.02:0.02), giving 180 mg of the desired product, mp 250° C. (dec.).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[S:12])[NH2:11])[CH3:9])(C)(C)C.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[N:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[S:12][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(NC(=O)OC(C)(C)C)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(C(C)N)n1
Yield: 14.6 %

Procedure:
(1-Thiocarbamoyl-ethyl)-carbamic acid tert-butyl ester (8.7 g, 42.5 mmol) and ethyl bromopyruvate (90% Tech., 9.21 g, 42.5 mmol) were heated at reflux in ethanol (200 mL) for 12 hours. The ethanol was removed in vacuo and the residue was purified by flash chromatography (5:95 MeOH:CH2Cl2) to afford the title compound (1.24 g, 15% over two steps): 1H NMR (400 MHz, d6-DMSO): 8.37 (s, 1H), 4.28 (qd, 2H), 4.24 (q, 1H), 2.60 (br s, 2H), 1.37 (d, 3H), 1.29 (t, 3H); MS (ESI-LCMS) for C8H13N2O2S: 201 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16][C@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[C:22]#[N:23])=[CH:11][CH:10]=1>O1CCCC1.C(OCC)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16][C@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[CH2:22][NH2:23])=[CH:11][CH:10]=1
Reactant: COc1ccc(CS[C@H]2COC[C@H]2C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2COC[C@H]2CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A room temperature solution, under argon, of 4.22 ml of 1.0M lithium aluminum hydride in tetrahydrofuran is treated, dropwise, with 0.876 g of product from Example 199 in 3 ml of diethyl ether; during which time the reaction refluxes gently. After complete addition, the reaction is stirred at room temperature for 2 hour. The reaction mixture is quenched with 1 ml of water, 10.5 ml of 1.0N sodium hydroxide and 2.0 ml of water. The solid white precipitate formed is collected and washed with large volumes of diethyl ether. The diethyl ether layer is concentrated in vacuo to give 0.889 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1.F[B-](F)(F)F.[C:20]([Si](C)(C)C)#[CH:21].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1)#[CH:21]
Reactant: COC(=O)C1(c2ccccc2Br)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccccc1C1(C(=O)OC)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A solution of methyl 1-(2-bromophenyl)cyclopropanecarboxylate (I4) (658 mg, 2.58 mmol), PdCl2(PPh3)2 (91 mg, 0.13 mmol) t-Bu3PH.BF4 (37 mg, 0.13 mmol), CuI (25 mg, 0.13 mmol) and ethynyltrimethylsilane (0.44 mL, 3.1 mmol) in dry DMF (5.0 mL) was degassed with nitrogen for 10 minutes before the addition of Et3N (2.0 mL). After stirring at 65° C. under nitrogen for 16 hours the resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound I5 as an orange oil (569 mg, 81%); 1H NMR (400 MHz, d6-DMSO) δ 7.67-7.12 (m, 4H), 3.57-3.47 (m, 3H), 1.64-1.49 (m, 2H), 1.26-1.16 (m, 2H), 0.22-0.13 (m, 9H). LCMS-A: rt 6.977 min; m/z 273 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[C@@H:12]([C:18]([F:21])([F:20])[F:19])[O:11][C:10]([NH2:22])=[N:9]2.[N+:23]([O-])([OH:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:23]([O-:25])=[O:24])=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[C@@H:12]([C:18]([F:19])([F:20])[F:21])[O:11][C:10]([NH2:22])=[N:9]2
Reactant: C[C@H]1OC[C@]2(c3ccccc3F)N=C(N)O[C@H](C(F)(F)F)[C@H]12
Reactant: O=[N+]([O-])O
Product: C[C@H]1OC[C@]2(c3cc([N+](=O)[O-])ccc3F)N=C(N)O[C@H](C(F)(F)F)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
(4S,4aS,5R,7aS)-7a-(2-fluorophenyl)-5-methyl-4-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]oxazin-2-amine (Preparation Example 30-(7)) (226 mg, 0.71 mmol) was dissolved in nitric acid (4.80 g, 76.20 mmol). The reaction was then stirred at RT for 90 min. LCMS (Agilent Method A) retention time 3.25 min, ES+: 364 [MH]+. The reaction was concentrated and purified by flash chromatography (Hexane/EtOAc 20-100%). 218 mg (84% yield) of the title compound (85%) and its isomer (15%) were isolated as a mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23].N1C=CC=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:18][C:17]=1[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ncc(N)cc1C
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ncc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1C
Yield: 76.3 %

Procedure:
The title compound (2.69 g, 8.32 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (2.41 g, 10.9 mmol), 6-methoxy-5-methylpyridin-3-amine (1.66 g, 12.0 mmol) and pyridine (2.64 mL, 32.7 mmol) in 1,4-dioxane (25 mL) at rt using the methods of (IntA1), step 1.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([OH:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1C=CN=C1.O[C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][C:35]#[N:36])[CH2:30][CH2:29]1>C(#N)C>[C:35]([CH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([O:19][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:30]1)#[N:36]
Reactant: O=C(O)c1ccccc1
Reactant: N#CC[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: CC#N
Product: N#CC[C@H]1CC[C@H](OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of p-toluenesulfonyl chloride (4.71 g), benzoic acid (2.52 g), N-methylimidazole (4.9 mL), and acetonitrile (50 mL), an acetonitrile (50 mL) solution of trans-(4-hydroxy-cyclohexyl)-acetonitrile (2.87 g) obtained in Example (41a) was added at 0° C. The reaction mixture was warmed to room temperature, then stirred overnight, and then concentrated. The residue was diluted with ethyl acetate, then washed with water and saturated brine, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (4.42 g, 88%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[CH3:17])=[CH:6]/[C@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])[CH3:2]>C(OCC)(=O)C.[Pt]>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH3:17])[CH2:6][C@H:7]([NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH3:8])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)C[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
Next, a solution of (E)-(R)-4-tert-butoxycarbonylamino-2-methyl-pent-2-enoic acid ethyl ester (1.83 g, 7.11 mmol) in ethyl acetate (75 mL) is hydrogenated over 10% Pt/C (183 mg) at 1 atm for 18 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by chiral HPLC to afford (2R,4R)-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid ethyl ester, 1H-NMR (400 MHz, CDCl3); 6 ppm 1.13 (t, 3H), 1.18 (m, 3H), 1.26 (t, 3H), 1.43 (s, 9H), 1.81 (s, 1H), 2.50 (m, 1H), 3.72 (m broad, 1H), 4.14 (m, 2H), 4.33 (m broad, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (70 mg, 76%), MS (ISP) m/z=370.4 [(M+H)+], mp 274° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([Cl:8])([Cl:7])=[CH2:6].Cl[C:10]([CH3:15])([CH:12]([CH3:14])[CH3:13])[CH3:11]>C(O)(=O)C>[Cl:7][C:5]([Cl:8])=[CH:6][C:10]([CH3:15])([CH3:11])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(C)(C)Cl
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CC(C)C(C)(C)C=C(Cl)Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
20 g of anhydrous, powdered aluminum chloride are added in portions to 2,040 g (21 mols) of vinylidene chloride at -10° C., in a dry apparatus equipped with a drying tube. 837 g (7 mols) of 2-chloro-2,3-dimethylbutane are then added dropwise in the temperature range from 0° to 10° C. The mixture is allowed to warm up to 20° C., and further aluminum chloride portions (a maximum of 20 g) are added, while cooling, until the reaction is no longer exothermic. The mixture is stirred for a further 4 hours at room temperature, the catalyst is deactivated by dropwise addition of 70 ml of acetic acid, and the mixture is filtered over sodium sulphate. The volatile constituents are separated from the sparingly volatile constituents by continuous-feed distillation under 1 mbar. The distillate is fractionated in a column. 824 g (65% of theory) of 1,1-dichloro-3,3,4-trimethyl-pent-1-ene of boiling point 60°-75° C./20 mbar are obtained. ##STR19##
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([OH:16])=[C:9]3[C:8]2=[O:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([O:16][C:15]1[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=3)[C:8](=[O:22])[C:9]=12)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (8.2 g, 24.6 mmol) in DMF (200 mL), cesium carbonate (10.4 g, 32.0 mmol) and benzyl bromide (3.2 mL, 27.1 mmol) were added. The reaction mixture was stirred at room temperature over night. The mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between ethyl acetate and brine. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with hexanes and ethyl acetate gradient to give titled material.