Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:54]=[C:53]([CH3:55])[C:52]([OH:56])=[C:51]([CH3:57])[CH:50]=1>CN(C=O)C.C(O)=O>[OH:56][C:52]1[C:51]([CH3:57])=[CH:50][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[CH:54][C:53]=1[CH3:55]
Reactant: Cc1cc(CN)cc(C)c1O
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (67 mg, 0.30 mmol), TBTU (106 mg, 0.33 mmol) and ethyl-diisopropylamine (169 μL, 0.99 mmol) in DMF (2 mL) is allowed to stand at rt for 10 min. A solution of 4-aminomethyl-2,6-dimethyl-phenol (45 mg, 0.30 mmol) in DMF (0.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL) the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (100 mg) as a colourless oil. LC-MS: tR=1.03 min, [M+1]+=356.23.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(-c2cccnc2N2CCNCC2)nc1
Reactant: COc1cccc(OCCCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OCCN2CCN(c3ncccc3-c3ccccn3)CC2)c1
Yield: 77 %

Procedure:
A stirred mixture of 1-(2-chloroethoxy)-3-methoxybenzene (0.65 g, 3.5 mmol), 1-[3-(2-pyridyl)-2-pyridyl]piperazine (0.7 g, 2.9 mmol) and K2CO3 (3.5 mmol) in DMF was refluxed overnight. After cooling, the mixture was evaporated to dryness and H2O (20 mL) was added to the residue. The aqueous phase was extracted with AcOEt (2×30 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 9:1, as eluent) to afford pure compound in 77% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1I.[F:12][C:13]1[CH:14]=[CH:15][C:16]2=[C:17]([CH:33]=1)[O:18][CH2:19][C:20]1[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[CH:27][C:21]=1/[C:22]/2=[C:23](/[CH3:26])\[C:24]#[N:25]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[CH:31]([OH:32])[C:29]1[CH:28]=[CH:27][C:21]2/[C:22](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:33][C:17]=3[O:18][CH2:19][C:20]=2[CH:30]=1
Reactant: Clc1nc2ccccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(Cl)nc4ccccn34)cc2COc2cc(F)ccc21
Yield: 44.6 %

Procedure:
[step 2] Using 2-chloro-3-iodoimidazo[1,2-a]pyridine (500 mg, 1.80 mmol) obtained in step 1 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (263 mg, 0.90 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-{8-[(2-chloroimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (179 mg, 45%) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:55]12[CH2:62][CH2:61][CH:58]([CH2:59][CH2:60]1)[C@@H:57](O)[CH2:56]2>C1COCC1>[N:55]12[CH2:62][CH2:61][CH:58]([CH2:59][CH2:60]1)[C@@H:57]([O:12][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:56]2
Reactant: COc1ccc(C(Nc2ccccc2)C(=O)O)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
(4-Methoxy-phenyl)-phenylamino-acetic acid hydrochloride (I92) (300 mg, 1.02 mmol), DCC (253 mg, 1.23 mmol), and HOBT (188 mg, 1.23 mmol) are dissolved in THF (10 mL). DIPEA (0.36 mL, 2.04 mmol) and (R)-quinuclidin-3-ol (130 mg, 1.02 mmol) are added. The mixture is stirred ad RT for 16 hours. Then DCC (25.3 mg, 0.12 mmol), HOBT (18.8 mg, 0.12 mmol), DIPEA (36 uL, 0.204 mmol) and (R)-quinuclidin-3-ol (13.0 mg, 0.10 mmol) are added again and reaction is stirred for additional 32 hours. THF is evaporated and the residue is dissolved in EtOAc and washed with sat. NaHCO3, H2O and brine. The organic layer is dried (Na2SO4), filtered and evaporated. The crude residue is purified by flash chromatography (DCM/MeOH=97/3 to 92/8) to obtain the title compound as a yellow solid (90 mg, 24% yield, mixture of diastereoisomers).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[C:12](=[CH:15]O)[CH:13]=[O:14].C([O-])(=O)C.[Na+]>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:12]([CH:13]=[O:14])=[CH:15][N:10]=1
Reactant: O=CC(Br)=CO
Reactant: NC(=S)Nc1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=Cc1cnc(Nc2ccccn2)s1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 51.9 %

Procedure:
To a solution of 1-(2-pyridyl)-2-thiourea (765 mg, 5.0 mmol) in acetone (14 mL) was added slowly 2-bromo-3-hydroxypropenal (755 mg, 5.0 mmol, for preparation see J. Org. Chem. 28, 3243, 1963) in acetone (14 mL) over a period of 5 min. After stirring for 1.5 h, a precipitate formed. The solids were separated, washed with acetone (10 mL) and then taken into mixed solvent (ethanol/water=1/1, 9 mL). To this suspension was added sodium acetate (1.23 g, 15.0 mmol) and the resulting mixture was heated at 75° C. for 1 h. After cooling to RT, the mixture was filtered and the solids were washed with water (10 mL), and dried in vacuo to provide compound A, 2-(pyridin-2-ylamino)-thiazole-5-carbaldehyde (533 mg, 52%) as a solid. LC/MS; (M+H)+=206
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17](OS(C)(=O)=O)[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1.[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1
Reactant: COCOc1ccc(CC(OS(C)(=O)=O)C(=O)OC)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(CC(Sc2ccccc2)C(=O)OC)cc1

Procedure:
A solution of 15 ml of N,N-dimethylformamide containing 745 mg of methyl 3-(4-methoxymethoxyphenyl)-2-methanesulfonyloxypropionate, 310 mg of thiophenol and 390 mg of potassium carbonate was stirred at 50° C. for 0.5 hours, and ethyl acetate and water were added to the reaction mixture. Then, the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 698 mg of the desired compound as a syrup.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]C(C2C=C(NC(=O)OCC=C)C=CC=2)=O)[CH:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:34]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:26]=1[C:27]([O:29]C)=O.ClC1N=C(C)C=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:27]([C:26]2[C:25]([F:24])=[C:34]([NH:35][C:36](=[O:37])[O:38][CH2:39][CH:40]=[CH2:41])[CH:33]=[CH:32][C:31]=2[F:42])=[O:29])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1F
Agent: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Yield: 60.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 11 using methyl 2,6-difluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (80 g, 295 mmol) and 2-chloro-4-methylpyrimidine (41.6 g, 324 mmol) the title compound of Step E was obtained (65 g, 60.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.49-9.60 (m, 1H), 8.72-8.77 (m, 0.3H), 8.58-8.64 (m, 0.6H), 7.57-7.83 (m, 2H), 7.15-7.25 (m, 1H), 5.89-6.01 (m, 1H), 5.75-5.82 (m, 0.6H), 5.20-5.40 (m, 2H), 4.55-4.62 (m, 2H), m/z (ES+): 368 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)[CH2:9]2)[O:7][NH:30]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 99.2 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorophenyl)piperidine-1-carboxylate (59 mg, 0.15 mmol) (from example 60, step 1) was dissolved in MeOH (1 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.045 mL, 0.15 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 9.33 μL, 0.15 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (0.784 mL, 4.71 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated, the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorophenyl)piperidine-1-carboxylate (53 mg, quant.) as a slightly yellow oil. MS m/z 357 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:19]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])C)[CH3:2].[CH:22]([N:35]1[CH2:38][C:37](OS(C)(=O)=O)([CH3:39])[CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:17][C:37]3([CH3:39])[CH2:38][N:35]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36]3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])[CH3:19])[CH3:2]
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)C(C)(CC)N1C(=O)COc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3(C)CN(C(c4ccccc4)c4ccccc4)C3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A mixture of ethyl 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (Example #65, Step C, 0.200 g, 0.754 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (0.275 g, 0.829 mmol) and Cs2CO3 (0.491 g, 1.508 mmol) in DMF (8 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 2-[6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester as a white solid (0.300 g, 79%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.30 (m, 3H), 7.29 (m, 1H), 7.28 (m, 2H), 6.87 (d, J=8.8 Hz, 1H), 6.28 (d, J=8.8 Hz, 1H), 6.22 (s, 1H), 5.32 (q, J=7.2 Hz, 1H), 4.55 (d, J=17.6 Hz, 2H), 4.42 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.38 (m, 2H), 3.19 (m, 2H), 1.59 (m, 6H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][N:8]=[N:9][C:10]=2O)[CH:6]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[N:8][N:9]=1
Reactant: Oc1nncc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nncc2ccccc12

Procedure:
The process according to one embodiment of this invention comprises the steps of: a) reacting phthalazinone with an approximately equimolar equivalent of phosphorous oxychloride at a specific temperature to produce a 1-chlorophthalazine salt; b) isolating the 1-chlorophthalazine salt formed in step (a) by precipitating the 1-chlorophthalazine salt by adding a mineral acid in the presence of solvent and filtering and drying the solid 1-chlorophthalazine salt; c) reacting the isolated and dried 1-chlorophthalazine salt with hydrazine hydrate without any organic solvent and precipitating the hydralazine base by adding a solvent; d) purifying the hydralazine base in a non-aqueous medium; e) converting the purified hydralazine base to hydralazine hydrochloride in a non-aqueous medium and isolating therein; and f) purifying the isolated hydralazine hydrochloride in aqueous medium
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1.[C:22](=S)([S:25][CH3:26])[S:23][CH3:24].CI>CS(C)=O>[Br:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[C:11](=[C:22]([S:25][CH3:26])[S:23][CH3:24])[C:10]=2[CH:9]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CSC(=S)SC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 0.08 h

Procedure:
Sodium tert-butoxide (1.24 g, 12.9 mmol) was added portionwise over 2 min to a solution of 2,7-dibromofluorene (2.0 g, 6.2 mmol) in DMSO (40 ml) at RT under nitrogen. To the resulting red solution was added dimethyl trithiocarbonate (0.94 g, 6.8 mmol) via a syringe. The reaction was stirred for 5 min and methyl iodide (1.8 g, 12.6 mmol) was added over 2 min. The reaction was stirred for 1 h worked up as above. Recrystallization from ethyl acetate/THF (2:1) afforded 2.4 g (91%). The sample was identical in all respects to that described above.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(C)CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylate (150 mg, 0.3 mmol) in MeOH (5 mL) was added NaOH (60 mg, 1.5 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 85° C. for 2 h. The pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was the desired product 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylic acid (100 mg, yield: 80%). ESI-MS (M+1)+: 438.3, HPLC: 100%. 1HNMR (400 MHz, DMSO-d6) δ: 10.21 (s, 1H), 8.02 (br, 1H), 7.93˜7.88 (m, 2H), 7.67 (br, 1H), 7.48 (s, 1H), 7.26 (d, 1H), 4.51˜4.45 (m, 2H), 3.35 (s, 2H), 3.32 (br, 1H), 2.92 (br, 1H), 2.29˜2.14 (m, 4H), 1.92˜1.76 (m, 4H), 1.47˜1.12 (m, 9H), 0.93 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1>>[OH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:32][CH2:33]1
Reactant: OC1CCNCC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCC(O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperidin-4-ol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cu]([C:12]#[N:13])C#N>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[CH:3][CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1

Procedure:
Bromo-4-methyl-benzene of general formula H-1, where B, R1, R2, R3 and R4 are as defined above is reacted with copper cyanide in a polar solvent as dimethylformamide at elevated temperature to obtain the 4-methyl-benzonitrile of general formula H-2. The 4-methyl-benzonitrile of general formula H-2 is brominated by the treatment with N-bromosuccinimide in refluxing tetrachloromethane in the presence of a radical initiator like AIBN to obtain the 4-Bromomethyl-benzonitrile of general formula H-3.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH3:19][N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1>>[CH3:19][N:20]1[C:24]([NH:25][C:15]([C:7]2[C:8]3[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=2)=[O:17])=[CH:23][CH:22]=[N:21]1
Reactant: Cn1nccc1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3ccnn3C)c2o1
Yield: 33.3 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.23 g) and 2-methyl-2H-pyrazol-3-ylamine (0.1 g). Purification by column chromatography on silica eluting with 5% methanol in dichloromethane afforded the title compound as a cream solid (0.10 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=1.CN1CCCC1=O.[CH2:26]([Mg]Br)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>O.C1COCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: Br[Mg]CCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CCc2ccccc2)cc1

Procedure:
76A (2.27 g, 8 mmol), N-methylpyrrolidinone (4.4 mL), Fe(acac)3 (140 mg, 0.4 mmol) and dry THF (50 mL) were stirred under nitrogen at room temperature. Phenethylmagnesium bromide (1.0 M in THF, 10 mL) was added by syringe. After stirring for fifteen minutes, HCl (1 M, 20 mL) was slowly added. The mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, were dried over MgSO4 and were concentrated. Purification was achieved using flash chromatography on SiO2 with hexanes/toluene 50:50. A colourless oil was obtained (1.575 g, 82%). NMR 1H (ppm, CDCl3): 7.94 (d, J3 8.2 Hz, 2H), 7.29-7.13 (m, 7H), 3.89 (s, 3H), 3.01-2.89 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[CH:28]1([CH2:27][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:25])=[CH:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCC2CC2)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available (bromomethyl)cyclopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.78 min.; [M+H]+: 396.27 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:31])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23]CC3C=CC=CC=3)[CH:15]=2)[CH3:9])[CH:3]=1.[H][H]>[Pd].CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:31])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([OH:23])[CH:15]=2)[CH3:9])[CH:3]=1
Reactant: Cc1ccnc(C(C)NC(=O)C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccnc(C(C)NC(=O)CCc2ccc(N)c(O)c2)c1
Yield: 99.8 %

Procedure:
A mixture of 4-methyl-2-[1-[3-benzyloxy-4-nitrocinnamoylamino)ethyl]pyridine (12.5 g) and 10% palladium on carbon (2 g) in a mixture of methanol (250 ml) and tetrahydrofuran (100 ml) was hydrogenated under one atmospheric pressure of hydrogen gas at ambient temperature for 4 hours. Insoluble material was filtered off, and the filtrate was evaporated in vacuo to give 4-methyl-2-[1-{3-(4-amino-3-hydroxyphenyl)propionamido}ethyl]pyridine (8.95 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C([Sn](CCCC)(CCCC)[C:26]1[NH:30][N:29]=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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.[Cu]I>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[C:26]2[NH:30][N:29]=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(Cc2nc(-c3ccncc3)sc2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)n[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)[nH]n1
Yield: 12.2 %

Procedure:
An argon degassed mixture of 5-bromo-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole (583 mg, 1.59 mmol), ethyl 5-(tributylstannyl)-1H-pyrazole-3-carboxylate (456 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium(0) (61.4 mg, 0.0531 mmol), copper(I) iodide (60.7 mg, 0.319 mmol), and lithium chloride (135 mg, 3.19 mmol) in dioxane (7.46 mL) was heated in a microwave at 150 degrees for 30 minutes. The reaction mixture was slurried in ethyl acetate (100 mL) and water (2 mL) and the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/DCM=0/100→100/0) to give the crude product. This material was purified by preparative reverse phase chromatography to give 55 mg (12% yield) of the title compound as a white solid. LC/MS (FA) ES+ 425, 427. 1H NMR (300 MHz, DMSO-d6) δ: 8.71-8.69 (m, 2H), 7.85-7.83 (m, 2H), 7.36-7.33 (m, 2H), 7.28-7.25 (m, 2H), 7.09 (s, 1H), 4.41 (s, 2H), 4.34 (q, 1H, J=7.2 Hz), 1.31 (t, 1H, J=7.2 Hz).