Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[C:5]([CH3:10])=[CH:4]1)[CH3:2].[CH2:11]=[CH:12][CH:13]=C.[Cl-].[Cl-].[CH2:17]([Al+2])C>ClCCl>[CH2:1]([CH:3]1[CH:4]2[C:5]([CH3:17])([CH2:10][CH:11]=[CH:12][CH2:13]2)[C:6](=[O:9])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CC[Al+2]
Reactant: C=CC=C
Reactant: CCC1C=C(C)C(=O)CC1
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1CCC(=O)C2(C)CC=CCC12

Procedure:
Prepared according to the general procedure # I, with the following quantities: 4-Ethyl-2-methyl-2-cyclohexen-1-one (27.6 g, 0.20 mol), Butadiene (21.6 g, 0.040 mol), Ethyl aluminium dichloride (1 molar solution in hexane, 100 ml, 0.10 mol), Dichloromethane (300 ml)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>>[ClH:1].[CH3:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][CH2:21][CH2:19][OH:20])=[CH:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Reactant: NCCO
Product: Cc1ccc2c(NCCO)cc(-c3ccccc3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 234-236° C., and MS: m/e=278 (M+), was prepared from 4-chloro-7-methyl-2-phenyl-quinoline and ethanolamine.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]([NH2:28])([CH2:26][CH3:27])[CH3:25]>>[CH:24]([NH:28][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: CCC(C)N
Product: CCC(C)Nc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12

Procedure:
The title compound was prepared following procedure and work up described for example 85 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and sec-butylamine (53.50 mg; 0.73 mmol; 5.0 eq.) as a white solid (4 mg, 7%). HPLC, Rt: 3.44 min. (purity 89.4%). LC/MS, M+(ESI): 379.1, M−(ESI): 377.0.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][C:17]([O:19]CC)=[O:18])[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].O.[OH-].[Li+]>O1CCCC1.CO.O.O>[CH2:1]([N:4]([CH2:16][C:17]([OH:19])=[O:18])[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)OCC)NC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCN(CC(=O)O)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To the solution of ethyl 2-(1-allyl-2-(benzylcarbamoyl)hydrazinyl)acetate (Compound V-1) 1.31 g (4.5 mmol) in tetrahydrofuran/methanol/water (2:3:1) 24 ml, lithium hydroxide monohydrate 377 mg (9.0 mmol) was added and stirred at room temperature for 5 hour. The reaction mixture was diluted with water 25 ml and washed with ether 25 ml. The aqueous phase was acidified with 10%-citric acid 25 ml and extracted with chloroform 30 ml. The organic phase was washed with brine 25 ml and dried with magnesium sulfate then filtered. The filtrate was concentrated in vacuo to obtain the title compound 982 mg (83%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:3]=1[C:4](O)=O.O.[CH:14]([NH2:16])=[O:15]>>[C:11]([C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:14](=[O:15])[N:16]=[CH:4]2)#[N:12]
Reactant: NC=O
Reactant: N#Cc1ccc(N)c(C(=O)O)c1
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)ncc2c1
Yield: 44 %

Procedure:
A stirred solution of 2-amino-5-cyanobenzoic acid (2.0 g, 12.3 mmol) in formamide (10 ml) was heated at 190° C. for 7 hours. The dark solution was allowed to cool and poured into water (50 ml). The resulting precipitate was collected by filtration and dried in vacuo at 60° C. to give 6-cyanoquinazolinone (0.93 g, 5.43 mmol, 44%); [2H6]DMSO 12.65 (1H, s), 8.50 (1H, s), 8.28 (1H, s), 8.18 (1H, dd), 7.81(1H, d).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:33]([N:32]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Cl)c1

Procedure:
To a stirred solution of 3-chlorosulfonylbenzoyl chloride (25.0 g, 1.1406 mol) in 250 ml of THF at 0° C. was added in one portion a cold suspension of dioctadecylamine (59.3 g, 0.1137 mol) and N,N-diisopropylethylamine (13.5 g, 0.1406 mol) in 500 ml of THF. The addition was exothermic to ≃10° C. The reaction was stirred without cooling overnight. The white insolubles were filtered and the filtrate poured into dilute hydrochloric acid. The aqueous mixture was extracted with ethyl acetate and the organic layer washed with water, dried over anhydrous magnesium sulfate and concentrated to dryness under aspirator pressure at 35° C. The resulting 68 g (90 percent) of yellow oil slowly crystallized. NMR was consistent for the product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C(O)=O)=[CH:3][CH:2]=1.[C:14]([N:21]1[CH:25]=[CH:24]N=C1)(N1C=CN=C1)=[O:15].Cl.[CH3:27][C@H:28]1[CH2:33]C[C@H](N)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:27][C@H:28]1[CH2:33][CH2:24][C@H:25]([NH:21][C:14]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:15])[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2cccc3cccnc23)CC1
Temperature: 50 °C

Procedure:
A solution of quinoline-4-carboxylic acid (173 mg, 1 mmol), and 1,1′-carbonyldiimidazole (162 mg, 1 mmol) in dimethylformamide (2 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (150 mg, 1 mmol), and N,N-diisopropylethylamine (0.262 mL, 1.5 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with chloroform (10 mL). The organic solution was washed with water (3×10 mL), 1 N NaOH (10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 224 mg (84%) of 404:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[C:28]([CH:40]=O)[NH:27][C:26]=1[CH3:42])=[O:24])[CH3:21].N1CCCCC1.Cl>C(O)C>[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)=[C:28]([CH:40]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:11]3[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=3)[C:16]([OH:18])=[O:17])[NH:3][C:2]2=[O:1])[NH:27][C:26]=1[CH3:42])=[O:24])[CH3:21]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c1CCCN1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (51 mg, 0.2 mmol), 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64 mg, 0.2 mmol) and piperidine (0.2 mL) in ethanol (1 mL) was heated in a sealed tube at 60° C. for 5 hours. The reaction was acidified with 1N HCl and the resulted precipitate was collected by vacuum filtration, washed with water and dried to give the title compound.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][CH:5]=1.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][CH:5]=[C:4]2[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1
Reactant: Oc1cccc(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2nccc(Oc3cccc(O)c3)c2cc1OC
Temperature: 140 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Potassium hydroxide (14 mg, 0.25 mmol) and 4-chloro-6,7-dimethoxyquinoline (50 mg, 0.22 mmol), (prepared as described for the starting material in Example 2), were added to 1,3-dihydroxybenzene (1 g, 9 mmol) melted at 140° C. under argon. After stirring for 1 hour at 140° C., the mixture was partitioned between ethyl acetate and water and 2M hydrochloric acid was added to adjust the aqueous phase to pH4. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloridelethyl acetate (6/4 increasing to 3/7). The purified product was triturated with ether, collected by filtration and dried under vacuum to give 6,7-dimethoxy-4-(3-hydroxyphenoxy)quinoline (51 mg 78%).
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:23])[CH2:11][N:10]2[C@H:5]([CH2:6][CH:7]([NH:14][C@H](C3C=CC=CC=3)C)[CH2:8][C:9]2([CH3:13])[CH3:12])[CH2:4]1.[H][H]>CO>[ClH:1].[F:23][C:3]1([F:2])[CH2:11][N:10]2[C@H:5]([CH2:6][CH:7]([NH2:14])[CH2:8][C:9]2([CH3:13])[CH3:12])[CH2:4]1
Reactant: C[C@H](NC1C[C@@H]2CC(F)(F)CN2C(C)(C)C1)c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: CC1(C)CC(N)C[C@@H]2CC(F)(F)CN21
Reaction time: 39 h

Procedure:
A MeOH (20 ml) solution of (8aR)-2,2-difluoro-octahydro-5,5-dimethyl-N—((S)-1-phenylethyl)indolizin-7-amine hydrogen chloride and Pd(OH)2—C (20% on activated carbon, 50% wet, 0.2 g) was hydrogenated in a Parr flask under 45 psi of hydrogen. Additional Pd(OH)2—C was added (˜0.2 g) was added at 16 hours and 24 hours, and the reaction went to completion at 39 hours monitored by LC-MS. Solid was removed by filtration through a short Celite column, washing with MeOH. Filtrate was collected, solvent was removed in vacuo. Compound (8aR)-2,2-difluoro-octahydro-5,5-dimethylindolizin-7-amine hydrogen chloride was obtained as an off-white solid and was used directly in next reaction: 0.56 g; LRMS] (M+H) ink 204.99.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[C:36][CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(C#CC2CCCC2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#CC5CCCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyclopentylethynyl-pyridine.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][S:6][CH2:7][CH3:8])=[O:4])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(OC[C:34]1[N:38]([S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:37]=[N:36][CH:35]=1)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([S:3]([CH:5]([C:34]1[N:38]([S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:37]=[N:36][CH:35]=1)[S:6][CH2:7][CH3:8])=[O:4])[CH3:2]
Reactant: CCSCS(=O)CC
Reactant: CC(=O)OCc1cncn1S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCSC(c1cncn1S(=O)(=O)c1ccc(C)cc1)S(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 mmole of [[(ethylsulfinyl)methyl]thio]ethane in 20 ml of dry tetrahydrofuran is heated at 0° C. with 10 mmole of lithium diisopropylamide, prepared from a solution of diisopropylamine M in tetrahydrofuran and butyllithium 2 M in hexane. After 30 minutes at 0° C. a solution of 12 mmole of 5-acetyloxymethyl-1-tosylimidazole in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 25° C. overnight then is quenched with brine and extracted with ether. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give [[(ethylsulfinyl)-1-tosylimidazol-5-ylmethyl]thio]ethane. To a solution of 20 mmole of [[(ethylsulfinyl)-1-tosylimidazol-5-ylmethyl]thio]ethane in 20 ml of dry tetrahydrofuran is added at 0° C. and under nitrogen a solution of 20 mmole of lithium diisopropylamide prepared from a solution of diisopropylamine M in tetrahydrofuran and butyl lithium 2 M in hexane. Stirring is continued for 30 minutes at 25° C. after which a stream of chlorodifluoromethane is bubbled into the reaction mixture for 1/2 hour. The reaction mixture is maintained at 40° C. for 3 hours then quenched with brine and extracted with ether. The organic phase is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford [[(ethylsulfinyl)((difluoromethyl)-1-tosylimidazol-5-ylmethyl)]thio]ethane. To a solution of 30 ml of [[(ethylsulfinyl)((difluoromethyl)-1-tosylimidazol-5-ylmethyl)]thio]ethane in 33 ml of acetonitrile is added at 0° C. a 70% aqueous solution of perchloric acid (1.1 ml). After stirring for 2 hours at 0° C. the reaction mixture is poured into 60 ml of water then extracted with difluoromethane. The organic phase is washed with sodium bicarbonate then water, dried over magnesium sulfate and concentrated under reduced pressure to afford difluoromethyl 5-imidazolylmethyl ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(Cl)cc1
Product: N#Cc1cc(Cl)ccn1
Yield: 92 %

Procedure:
The general procedure of Referential Example 15 was repeated through use of 4-chloropyridine-N-oxide (6.00 g) and trimethylsilyl cyanide (17.5 mL), to thereby give the title compound as a solid (5.89 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:28]([CH2:29][CH2:30][OH:31])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:24][CH2:23][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34]>O.C(#N)C>[CH3:27][CH2:28][CH2:2][CH:3]([CH3:25])[CH3:4].[Cl:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][C:8]3([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]4[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=4)=[O:15])[CH2:9]3)[CH2:23][CH2:24]2)=[CH:25][CH:26]=[CH:27][C:28]=1[CH2:29][CH2:30][O:31][CH2:34][CH2:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CCCC(C)C
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triton-B (40% in water, 0.94 mL) was added to a solution of (9-(2-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-ethylthiazol-4-yl)methanone [Example 26, step c] (3.2 g) and tert-butyl acrylate (1.5 mL) in acetonitrile (1 mL) and the resulting mixture stirred overnight at RT. The solvent was evaporated and the residue was purified by flash silica chromatography, elution gradient 1:1:0.05 ethyl acetate:isohexane:triethylamine to 95:5 ethyl acetate:triethylamine to give the subtitled compound as a clear oil. Yield 3.2 g.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C@@H:5]2[O:6][C:7](=[O:9])[CH2:8][C@@H:4]2[C@H:3]1[CH2:11][CH2:12][C@@H:13]([OH:26])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.[C:33]([O-:36])(O)=O.[Na+]>C(Cl)Cl>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]1[O:1][C@@H:2]1[CH2:10][C@@H:5]2[O:6][C:7](=[O:9])[CH2:8][C@@H:4]2[C@H:3]1[CH2:11][CH2:12][C@@H:13]([O:26][CH:4]1[CH2:3][CH2:2][CH2:10][CH2:33][O:36]1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=1
Reactant: O=C([O-])O
Reactant: O=C1C[C@@H]2[C@@H](CC[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](CC[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1.2 g (3.2 mmol) of diol 26 and 0.05 g of ptoluenesulfonic acid monohydrate in 100 mL of CH2Cl2 at 0° C. was treated with 3,4-dihydro-2H-pyran (1.1 ml, 12 mmol) and the solution was stirred for 2 h at 0° C. After pouring into saturated NaHCO3, phases were separated and the organic layer was dried over MgSO4, filtered, concentrated, and purified by chromatography on silica gel (1/1, hexanes/EtOAc) to afford 1.1 g of 27 as a clear, colorless oil. 1H NMR (CDCl3) δ 8.04 (dd, J=7.0, 1.6, 1 H), 7.44 (m, 2 H), 7.12 (m, 1 H), 4.95 (dt, 1 H), 4.8 (m, 1 H), 4.7 (m, 2 H), 4.15-3.80 (m, 4 H), 3.5 (m, 2 H), 2.82 (dd, J=10.8,1 H), 2.55 (m, 2 H), 2.3 (m, 1 H), 2.1-1.3 (m, 6 H).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([C:23]([CH3:25])=[CH2:24])[CH3:22])[CH:20]=3)[CH:13]=[C:12]([CH3:26])[CH:11]=2)[N:4]=1.C[N+]1([O-])CC[O:32]CC1.C1COCC1.[OH2:41]>[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[F:27][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH3:22])[C:23]([CH3:25])([OH:32])[CH2:24][OH:41])[CH:20]=3)[CH:13]=[C:12]([CH3:26])[CH:11]=2)[N:4]=1
Reactant: O
Reactant: C=C(C)C(C)n1cc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(C(C)C(C)(O)CO)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Osmium tetroxide (4% solution in water, 1.06 ml, 0.14 mmol) was added to a flask containing 4-(difluoromethyl)-N-(3-methyl-5-(1-(3-methylbut-3-en-2-yl)-1H-pyrazol-4-yl)phenyl)pyrimidin-2-amine (200 mg, 0.54 mmol), N-methylmorpholine N-oxide (127 mg, 1.08 mmol), THF (2.5 ml) and water (1.25 ml) was. The reaction mixture was allowed to stir at room temperature for 3 hrs. The reaction was diluted with brine and reaction product extracted with ethyl acetate (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (20-100% ethyl acetate/hexanes) to afford racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol. The racemic mixture was purified by chiral SFC (Phenomenex Lux-4, 21×250 mm, 70 mL/min, 20% Methanol/CO2) to afford 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol. (Example 22.1, Isomer 1, first eluting): MS ESI calcd. for C20H24F2N5O2 [M+H]+ 404. found 404. 1H NMR (500 MHz, DMSOd-6) δ 9.87 (s, 1H), 8.68 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.35 (s, 1H), 7.04 (m, 2H), 6.86 (t, J=54.5 Hz, 1H), 4.65 (t, J=4.5 Hz, 1H), 4.62 (s, 1H), 4.43 (q, J=6.5 Hz, 1H), 3.08 (m, 2H), 2.28 (s, 3H), 1.43 (d, J=6.5 Hz, 3H), 1.03 (s, 3H); and 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol. (Example 22.2, Isomer 2, second eluting): MS ESI calcd. for C20H24F2N5O2 [M+H]+ 404. found 404. 1H NMR (500 MHz, DMSOd-6) δ 9.85 (s, 1H), 8.66 (d, J=4.0 Hz, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.06-7.02 (m, 2H), 6.84 (t, J=45.5 Hz, 1H), 4.62 (t, J=4.5 Hz, 1H), 4.53 (s, 1H), 4.39 (q, J=6.5 Hz, 1H), 3.10-3.06 (m, 2H), 2.26 (s, 3H), 1.41 (d, J=6.5 Hz, 3H), 1.00 (s, 3H).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].[Cl-].[NH4+]>O.O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)[OH:18]
Reactant: CN1CCC(Cl)CC1
Reactant: O=C(c1ccccc1)c1ccccc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(C(O)(c2ccccc2)c2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a stirred and refluxing Grignard complex previously prepared starting from 80.2 parts of 4-chloro-1-methylpiperidine, 14.6 parts of magnesium and 270 parts of tetrahydrofuran, was added dropwise a solution of 101 parts of (2-fluorophenyl)phenylmethanone in 450 parts of tetrahydrofuran. Upon completion, stirring was continued for 18 hours at reflux temperature. The reaction mixture was cooled in an ice-bath and decomposed with a solution of 32 parts of ammonium chloride in 160 parts of water. After stirring for 30 minutes, the product was filtered off and washed with tetrahydrofuran. The filtrate was evaporated, the residue was taken up in methylbenzene and the latter was evaporated again in a boiling water-bath. The residue was dissolved in 700 parts of 2,2'-oxybispropane. The turbid solution was filtered and gaseous hydrogen chloride was bubbled through the filtrate. The solid product was filtered off and suspended in 1000 parts of water. The suspension was treated with ammonium hydroxide and extracted twice with 280 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The oily residue was crystallized from 240 parts of acetonitrile. After cooling to 0° C., the product was filtered off and dried, yielding 66 parts (44%) of α-(2-fluorophenyl)-1-methyl-α-phenyl-4-piperidinemethanol (intermediate 33).
Reaction SMILES: [OH:1][C@@H:2]([CH3:23])[C:3]([NH:5][CH:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:4].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:26].[CH2:37]([N:39]([CH2:42]C)CC)[CH3:38].Cl.C(N)C>C1(C)C=CC=CC=1>[CH3:14][N:11]1[C:12](=[O:13])[CH:6]([NH:5][C:3]([C@@H:2]([O:1][C:42](=[O:26])[NH:39][CH2:37][CH3:38])[CH3:23])=[O:4])[C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]1=2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Reactant: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Agent: CCN
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)O[C@@H](C)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-2-hydroxy-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide (30 mg, 0.09 mmol), 4-nitrophenyl chloroformate (19 mg, 0.09 mmol), and triethylamine (20 microliter) in toluol (1 ml) were shaken overnight at r.t. Ethylamine hydrochloride (7.9 mg, 0.1 mmol) was added and the mixture was shaken again overnight at r.t. The solvent was evaporated and the residue was dissolved in DMF (0.5 ml). The title compound, MS: m/e=382.3 (M+H+), (11 mg, 30%) was isolated from this mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 30 ml/min).