Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][C:15]3[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=3)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH2:3]1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][C:15]3[N:16]([CH3:29])[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=3)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)[nH]3)C21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)n3C)C21

Procedure:
To a stirred solution of 77 mg (0.2 mmol) 2-methyl-butyric acid 3,7-dimethyl-8-[2-(6-oxo-1,6-dihydro-pyridin-2-yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml DMF are added 0.1 g (0.8 mmol) potassium carbonate and 0.1 g (0.8 mmol) methyl iodide. After 2 hours at room temperature the mixture is poured on water. The aqueous phase is separated and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated in vacuo. The residue is chromatographed over silica gel eluting with hexane/acetone 1/1 to afford the title compound as white powder.
Reaction SMILES: [C:1]([CH:3]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[C:6](=[O:24])[NH:5][C:4]1=[O:25])#[N:2].C(OCC)(=O)C>[Pd].CO>[C:1]([CH:3]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]([C:14]([OH:16])=[O:15])[C:6](=[O:24])[NH:5][C:4]1=[O:25])#[N:2]
Reactant: N#CC1C(=O)NC(=O)C(C(=O)OCc2ccccc2)C12CCCCC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC1C(=O)NC(=O)C(C(=O)O)C12CCCCC2
Temperature: 12 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
1.8 g of benzyl 5-cyano-2,4-dioxo-3-azaspiro[5,5]undecane-1-carboxylate, 25 ml of ethyl acetate and 0.09 g of 5% Pd/C are placed in a 100 ml flask equipped with a magnetic stirrer, thermometer and condenser. The mixture is stirred for 4 hours at 12° C. under a hydrogen atmosphere. 10 ml methanol are added and the mixture is filtered through celite. The solvent is evaporated at 20° C. under reduced pressure to obtain 1.32 g of 5-cyano-2,4-dioxo-3-azaspiro[5,5]undecane-1-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[NH:3]1.C([Li])CCC.[Br:16][CH:17]([CH3:21])[C:18](Br)=[O:19].P([O-])([O-])([O-])=O>O1CCCC1.CCCCCC>[Br:16][CH:17]([CH3:21])[C:18]([N:3]1[C:2]([CH3:10])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][C:4]1=[O:9])=[O:19]
Reactant: CC(Br)C(=O)Br
Reactant: CC1(C)NC(=O)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Br)C(=O)N1C(=O)OC(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,5,5-tetramethyloxazolidin -2-one (0.30 g; 2.01 mmol) in tetrahydrofuran (2.5 ml), a hexane solution of 1.57 N n-butyl lithium (1.50 ml; 2.3 mmol) was added at 0° C., and after 5 minutes, 2-bromopropionyl bromide (0.54 g; 2.5 mmol) was added thereto and followed by stirring at the same temperature for 10 minutes. A phosphate buffer (pH 7) (1.1 ml) was added thereto to decompose the excess reaction agent, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate and then brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a residue, which was purified by silica gel column chromatography (benzene→benzene:ethyl acetate=95:5) to give 3-(2'-bromopropionyl)-4,4,5,5-tetramethyloxazolidin-2-one as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[CH3:25])=[CH:9][CH:8]=1)C.[OH-].[K+]>C(O)C.O1CCCC1>[C:21]([C:19]1[CH:18]=[CH:17][C:16]([CH3:25])=[C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:26])=[O:3])=[CH:8][CH:9]=2)[CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C(C)(C)C)ccc2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C(C)(C)C)cc1C#Cc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A solution of 3-[4-(5-tert-butyl-2-methyl-phenylethynyl)-phenyl]-acrylic acid ethyl ester (Intermediate 111, 0.09 g, 0.26 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with 3M potassium hydroxide solution (1 mL, 3 mmol) and the resulting reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo slightly, the residue was neutralized with dilute hydrochloric acid, and the solid that was formed was filtered and washed with water and acetonitrile and dried to afford title product (0.064 g, 77%).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-])C.[K+].[C:12]([CH2:15][CH2:16][CH:17]([CH:19]1[C:35]2([CH3:36])[CH:22]([CH:23]3[CH:32]([CH2:33][CH:34]2[OH:37])[C:31]2([CH3:38])[CH:26]([CH2:27][CH:28]([O:39][CH2:40][CH2:41][NH:42][C:43]4[C:48]([F:49])=[CH:47][C:46]([CH:50]=[C:51]([CH3:57])[C:52](OCC)=[O:53])=[CH:45][C:44]=4[F:58])[CH2:29][CH2:30]2)[CH2:25][CH:24]3[OH:59])[CH2:21][CH2:20]1)[CH3:18])([OH:14])=[O:13].Cl>CN(C=O)C.CO.C(O)(=O)C.O.O>[F:49][C:48]1[CH:47]=[C:46]([CH:50]=[C:51]([CH3:57])[C:52]([NH:4][C:3]([NH2:5])=[NH:2])=[O:53])[CH:45]=[C:44]([F:58])[C:43]=1[NH:42][CH2:41][CH2:40][O:39][CH:28]1[CH2:27][CH:26]2[C:31]([CH3:38])([CH:32]3[CH:23]([CH:24]([OH:59])[CH2:25]2)[CH:22]2[C:35]([CH3:36])([CH:19]([CH:17]([CH3:18])[CH2:16][CH2:15][C:12]([OH:14])=[O:13])[CH2:20][CH2:21]2)[CH:34]([OH:37])[CH2:33]3)[CH2:30][CH2:29]1
Reactant: CCOC(=O)C(C)=Cc1cc(F)c(NCCOC2CCC3(C)C(C2)CC(O)C2C3CC(O)C3(C)C(C(C)CCC(=O)O)CCC23)c(F)c1
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=Cc1cc(F)c(NCCOC2CCC3(C)C(C2)CC(O)C2C3CC(O)C3(C)C(C(C)CCC(=O)O)CCC23)c(F)c1)C(=O)NC(=N)N
Temperature: 112.5 °C
Reaction time: 6 h

Procedure:
130 mg of guanidine hydrochloride and 125 mg of potassium t-butoxide are stirred at RT for 30 minutes in 1 ml of anhydrous DMF. A solution of 150 mg of ethyl 3-(4-{2-[17-(3-carboxy-1-methylpropyl)-7,12-dihydroxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-3-yloxy]ethylamino}-3,5 -difluorophenyl)-2-methylacrylate in 1 ml of anhydrous DMF is then added and the mixture is stirred at 110-115° C. for 6 hours. The reaction mixture is then poured onto 100 ml of water, adjusted to pH=6 using aqueous HCl solution and the product is filtered off. It is dried in a fine vacuum and 8.0 mg of an amorphous solid are obtained. Rf (CH2C12 /MeOH/acetic acid/water 32:8:1:1)=0.21 MS (ES): 689 (M+H)+
Reaction SMILES: [Ru:1].[Ru].[Cl-:3].[NH4+].[C:5]1([C@H:11]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20](C)[CH:19]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:42](C1C=CC=CC=1)(=O)C.C1([C@@H](O)C)C=CC=CC=1>C(N(CC)CC)C.C(O)=O>[Ru:1].[Cl-:3].[NH4+:13].[C:5]1([C@H:11]([NH:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:33])=[O:34])[C@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:42])=[CH:22][CH:23]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](NCCCCc2cccc(C)c2)c2ccccc2)cc1
Agent: [Ru]
Agent: C[C@H](O)c1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: Cc1ccc(CCCCN[C@@H](c2ccccc2)[C@@H](NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Reaction time: 5 h

Procedure:
In a 25-ml Schlenk tube, 4.9 mg (0.00339 mmol, S/C=1000) of the ruthenium dimer complex produced in Example 5, acetophenone (0.82 g, 6.86 mmol), and 3.4 ml of a formic acid-triethylamine (5:2) azeotrope were mixed with each other, and the reaction was allowed to proceed at 60° C. for 5 hours. GC analysis of the reaction liquid showed that (S)-1-phenylethanol was formed with a conversion of 98.9% and 96.6% ee.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8]CC)=O)C.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH2:14]([O:13][C:11]([C:5]1[CH:4]=[N:21][C:20]2[C:22]([C:6]=1[OH:8])=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:12])[CH3:15]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1O
Yield: 98.1 %

Procedure:
From a mixture of 216 g of diethyl ethoxymethylenemalonate, 126.6 g of p-chloroaniline, and 800 ml of diphenyl heated first at 150°-160° for 15 min and then at 245° for 20 min there was obtained on cooling the above-named compound as a precipitate. This precipitate was collected, and washed with water and with hexane to give 245 g of crude damp solid, which was used directly in the hydrolysis reaction described below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:13][CH:14]=1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
A solution of 3.02 g (10.44 mmol) of [4-(5-Hydroxy-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester in 70 ml CH2Cl2 was treated at 0° C. with 0.89 ml (11.48 mmol) methanesulfonylchloride, 1.26 ml (15.66 mmol) pyridine and 1.28 g (10.44 mmol) DMAP. The reaction mixture was warmed up over night to room temperature, water (10 ml) was added and the reaction mixture was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×) the organic phases were washed with aqueous KHCO3 (2×), aqueous 10% NaCl, dried (Na2SO4) and evaporated to yield 3.74 g (97%) of Methanesulfonic acid 5-[4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-pent-4-ynyl ester, mp: 85-87° C.; MS: 367 (M).
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1>[CH:15]([N:12]1[CH2:13][CH2:14][N:9]([C:7]([C:6]2[CH:18]=[CH:19][C:3]([CH2:1][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:4][CH:5]=2)=[O:8])[CH2:10][CH2:11]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A THF solution of 1-(4-formylbenzoyl)-4-isopropylpiperazine (containing 945 g of 1-(4-formylbenzoyl)-4-isopropylpiperazine and 3879 g of THF) was charged to a reaction vessel followed by the addition of morpholine (576.3 g, 6.55 mol). After 20 min, the reaction was cooled to about 0-10° C. and sodium triacetoxyborohydride (1167.3 g, 5.23 mol) was added in portions. Upon reaction completion, 10% sodium hydroxide solution (3623.2 mL, 9.06 mol) was added slowly and the reaction mixture was stirred for 20 min. The layers were separated, and the aqueous layer was washed with THF. The combined organic layers were dried over magnesium sulfate. The dried THF solution of (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone was used without further manipulations.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:30])[C:28]=1[OH:29])[C:22]([NH:24]O)=[NH:23])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH:1]1([C:6]2[CH:7]=[C:8]([C:9]3[O:11][N:24]=[C:22]([C:21]4[CH:26]=[C:27]([CH3:30])[C:28]([OH:29])=[C:19]([CH2:17][CH3:18])[CH:20]=4)[N:23]=3)[CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (21.0 g, 102 mmol), 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine (20.0 g, 103 mmol) and HOBt (1.24 g, 9 mmol) in THF (200 mL) is cooled to 5° C. before a solution of DCC (20.0 g, 97 mmol) in THF (100 mL) is added dropwise. Upon complete addition, the mixture is stirred at rt for 18 h then at 75° C. for 48 h. The solvent is evaporated and the remaining residue is dissolved in TBME (200 mL). The precipitate that forms is removed, filtered off and washed with additional TBME (200 mL). The filtrate is washed with approximately 4% aq. NaHCO3 solution (100 mL) and water (100 mL) and concentrated. The crude product is recrystallised from hot acetonitrile (200 mL) to give 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (28.6 g) as a white solid; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.70-1.80 (m, 2H), 1.84-1.96 (m, 4H), 2.05-2.16 (m, 2H), 2.36 (s, 3H), 2.74 (q, J=7.3 Hz, 2H), 3.25 (quint, J=7.5 Hz, 1H), 4.02 (s, 3H), 5.01 (s), 7.31 (s, 1H), 7.51 (s, 1H), 7.85 (s, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[F:28][C:29]1[CH:30]=[C:31]([SH:37])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[F:28][C:29]1[CH:30]=[C:31]([S:37][C:2]2[CH:3]=[CH:4][N:5]3[C:10]=2[C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]3)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Reactant: COc1ccc(S)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Sc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)cc1F
Yield: 71 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (286 mg, 0.60 mmol) was treated with 3-fluoro-4-methoxybenzenethiol (141 mg, 0.89 mmol), potassium carbonate (123 mg, 0.89 mmol) and copper(I) iodide (170 mg, 0.89 mmol) according to the method described in Preparation 44. The crude was purified using SP1® Purification System (0%-25%, hexane-ethyl acetate) to give 226 mg (71% yield) to the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:5]2=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH:3]=4)[C:8]4([CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(Br)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure N using 6′-bromo-1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (30 mg, 0.059 mmol), Pd2dba3 (5.4 mg, 5.94 μmol), morpholine (5.69 μL, 0.065 mmol), sodium tert-butoxide (11.4 mg, 0.119 mmol) and XPhos (5.66 mg, 0.012 mmol) in toluene (1.5 mL) and heating in the microwave for 1 h at 120° C. After purification 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dd, J=3.3, 1.0 Hz), 7.83-7.97 (3H, m), 7.75 (1H, dd, J=9.2, 6.1 Hz), 7.62 (1H, d, J=2.3 Hz), 7.41 (1H, ddd, J=7.0, 5.1, 2.0 Hz), 7.28-7.34 (1H, m), 5.83 (1H, d, J=2.3 Hz), 4.09-4.23 (2H, m), 3.95-4.04 (2H, m), 3.71-3.80 (4H, m), 3.52-3.62 (2H, m), 3.01 (4H, q, J=4.4 Hz), 2.32-2.46 (5H, m), 1.74-1.91 (2H, m). Mass Spectrum (ESI) m/e=512 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:11]([CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]1=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)C1CCCC(C(C)(C)C)C1=O
Yield: 97 %

Procedure:
500.0 g of 2,6-di-tert-butyl-phenol are hydrogenated in 1200 ml of methanol under 100 bar at 60° C. using 50 g of rhodium on carbon (5%) for 12 hours. The catalyst is filtered off and washed with ethanol. The solvent is distilled off under reduced pressure and the residue is distilled under high vacuum to leave 494.3 g (97% of theory) of 2,6-di-tert-butyl-cyclohexanone as a mixture of colourless crystals with a colourless liquid. Boiling point of the isomers: 63° C. (0.1 mbar) and 67° C. (0.08 mbar). These products are converted into 2,6-di-tert-butyl-cyclohexanol as in Example A1.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13](F)[CH:12]=1.O>CS(C)=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]2[CH:15]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[S:3][C:13]=2[CH:12]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.73 g, 18.3 mmol) was suspended in DMSO (10 mL) and ethyl mercaptoacetate (1.111 mL, 10.1 mmol) was added potionwise using a water bath to moderate the exotherm. On complete addition, the water bath was removed and stirring continued for 15 minutes. A solution of 4-bromo-2-fluorobenzaldehyde (1.86 g, 9.16 mmol) in DMSO (2 mL) was added in one portion. The dark solution was stirred for 15 minutes before pouring into cold water (300 mL). The products were extracted into Et2O (2×200 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave 1.15 g of desired product (pale yellow solid, 44%). 1H NMR (DMSO-d6) δ 8.37 (d, J=1.8 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.60 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].Cl>CN(C)C=O>[Si:18]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NC[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1CNC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
(S)-5-(hydroxymethyl)oxazolidin-2-one (570 mg, 4.87 mmol, as described by Danielmeier, K.; Steckhan, E. Tet. Asymmetry, 6(5), 1995, 1181) and imidazole (331 mg, 4.87 mmol) were dissolved in dimethylformamide (5 mL) and cooled to 0° C. tert-Butylchlorodiphenylsilane (1.34 g, 4.87 mmol) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The mixture was was poured into 0.5 N HCl (50 ml), and the resultant mixture was extracted with ethyl acetate. The layers were separated, and the organic phase was washed with saturated sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate and the solvent removed to afford crude material that was purified on a silica gel column (50% ethyl acetate in hexanes) to give the title compound (1.28 g, 74.0%). 1H NMR (300 MHz, DMSO-d6) δ: 1.0 (s, 9 H) 3.3-3.6 (m, 2 H) 3.6-3.9 (m, 2 H) 4.6-4.8 (m, 1 H) 7.3-7.8 (m, 11 H). MS (ES) (M+23)+: 278 for the Na+ adduct of C20H25NO3Si.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1([CH3:20])[O:19][CH2:18][CH2:17][O:16]1.[CH3:21]I.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[C:7]([CH:8]([O:14][CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1([CH3:20])[O:16][CH2:17][CH2:18][O:19]1
Reactant: CCCCCC(O)c1cccc(C2(C)OCCO2)c1F
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCC(OC)c1cccc(C2(C)OCCO2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a DMF (35 mL) solution of 2-[2-fluoro-3-(1-hydroxyhexyl)phenyl]-2-methyl-1,3-dioxolane e (6.9 g) and methyl iodide (6.1 mL) was added sodium hydride (1.96 g) under ice-cooling. After the reaction mixture was stirred at room temperature for 1 h, a saturated ammonium chloride aqueous solution was added into the reaction mixture. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=20:1) to obtain the compound (17) 6.99 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.C([Li])CCC.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Cl)[N:17]=1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[N:17]=2)[CH2:4][CH2:3]1
Reactant: CNC1CCN(C)CC1
Reactant: Clc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(NCc2cccc(Cl)n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Dissolve 1-methyl-4-(methylamino)piperidine (10 mL, 68.8 mmol) in tetrahydrofuran (50 mL) and cool to −78° C. Slowly add n-butyllithium (1.6 N in hexane, 43 mL, 68.8 mmol) to the reaction mixture and stir at −78° C. for 30 min. Warm the reaction mixture to room temperature and stir for 30 min. Then cool the reaction mixture to −78° C. and add 2,6-dichloropyridine (11.2 g, 75.7 mmol) in tetrahydrofuran (50 mL). Stir the reaction mixture at −78° C. for 15 min, warm to room temperature, and then heat to 60° C. for 19 hr. Cool the reaction mixture to room temperature and partition between ethyl acetate and water. Separate the organic layer and extract the aqueous layer with dichloromethane (2×50 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify the residue by column chromatography on silica gel using a gradient of 2%–10% (2M NH3 in methanol) in CH2Cl2 to give of the title intermediate (11.91 g, 72%): mass spectrum (ion spray): m/z=240.1 (M+1); 1H NMR: 6 (CDCl3, ppm) 7.34 (t, J=7.6, 16.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 4.41 (m, 1H), 2.94 (m, 2H), 2.86 (s, 3H), 2.32 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.68 (m, 2H).