Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[C:20](=[O:51])[N:21]([C:30]4[N:35]=[CH:34][C:33]([O:36][CH:37]5[CH2:42][CH2:41][CH:40]([O:43][Si](C(C)(C)C)(C)C)[CH2:39][CH2:38]5)=[CH:32][N:31]=4)[C:22]([CH3:29])=[N:23][C:24]=3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.Cl>>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[C:20](=[O:51])[N:21]([C:30]4[N:35]=[CH:34][C:33]([O:36][CH:37]5[CH2:38][CH2:39][CH:40]([OH:43])[CH2:41][CH2:42]5)=[CH:32][N:31]=4)[C:22]([CH3:29])=[N:23][C:24]=3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][CH:13]=2)=[N:1][N:2]=[N:3]1
Reactant: CCCCc1nc(C)n(-c2ncc(OC3CCC(O[Si](C)(C)C(C)(C)C)CC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Product: CCCCc1nc(C)n(-c2ncc(OC3CCC(O)CC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the ethanol (1 mL) solution of 5-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-6-butyl-3-{5-[4-(tert-butyldimethylsilyloxy)cyclohexyloxy]pyrimidin-2-yl}-2-methylpyrimidin-4 (3H)-one (38 mg, 0.054 mmol), conc. HCl (30 mg, 0.823 mmol) was added and stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo, and the resulting residues were subjected to silica gel column chromatography (chloroform:methanol=5:1) to obtain 5-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-6-butyl-3-[5-(4-hydroxycyclohexyloxy)pyrimidin-2-yl]-2-methylpyrimidin-4 (3H)-one.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[C:19](=O)[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=3)[C:5]=2[CH:6]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[N:22]=[O:23])[C:5]=2[CH:6]=1
Reactant: NO
Reactant: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: O=Nc1c(-c2c(O)[nH]c3ccccc23)[nH]c2ccccc12
Yield: 90 %

Procedure:
Indirubin-3′-oxime was synthesized by reaction of indirubin with hydroxylamine hydrochloride in a pyridine solution (Farbwerke vorm. Meister Lucius & Brüning in Hoechst a.M., Patentschrift des Reichspatentamtes Nr. 283726 (1913)). 13C-NMR-spectroscopy revealed the location of the hydroxyimino residue in 3′-Position (δ(C2)=171.05 ppm; δ(C3′)=145.42 ppm; DMSO-d6, RT).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].[Cl-].[K+].[CH2:34]([CH:36]([C:40](=[O:42])[CH3:41])[C:37]([NH2:39])=[O:38])[CH3:35].COC1C=CC(C=O)=CC=1>C(O)C>[CH2:34]([C@@H:36]([C@@H:40]([OH:42])[CH3:41])[C:37]([NH2:39])=[O:38])[CH3:35]
Reactant: CCC(C(C)=O)C(N)=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CC[C@H](C(N)=O)[C@H](C)O
Reaction time: 60 h
Yield: 49.2 %

Procedure:
Geotrichum candidum (ATCC 34614) was cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H20 (0.5 gram), NaNO3 (2 grams), FeSO4.7H20 (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of 2-ethyl-3-ketobutyramide was dissolved in 2 ml of 95% ethanol, the resulting solution was added to the culture, and shaking was resumed. The reaction was followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After 48-72 hours the reaction was judged complete, and the reaction was terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension was suction filtered through a pad of Celite and the clear yellow filtrate was extracted with ethyl acetate (4×200 ml). The extracts were combined, dried over MgSO4, filtered, and rotary evaporated to leave 1 gram of (2S,3S)-2 ethyl-3-hydroxybutyramide as a yellowish solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Temperature: 0 °C

Procedure:
mixture of 4-hydroxy-6-nitroquinoline-3-carbonitrile (11.0 g) and 50 mL of POCl3 was heated at reflux for 7 hours. The volatile materials were removed under vacuum at 70° C. The residue was stirred at 0° C. with methylene chloride and H2O, and solid K2CO3 was carefully added until the pH was 8-9. After stirring for 30 min at rt, the organic layer was separated, washed with H2O, dried and evaporated under vacuum to give a crude solid. Purification on a silica gel column gave the 4-chloro-6-nitroquinoline-3-carbonitrile (Compound 17) as an off-white solid (4.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Si:26]([O:25][CH2:24][CH2:23][N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:21])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:14][CH:13]=2)[CH2:20][CH2:19]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(N3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)cc2)OC1(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (0.1 g, 0.5 mmol, from Boron Molecular), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.18 g, 0.75 mmol) and cesium carbonate (0.32 g, 1.0 mmol) in acetonitrile (2.0 mL) was stirred at 40° C. overnight. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-30%) to afford the desired product (0.2 g, 88%). LCMS calculated for C24H44BN2O3Si (M+H)+: m/z=447.3. Found 447.3.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: N#Cc1cccc(Cl)c1N
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (2.86 g, 17.2 mmol) and 2-amino-3-chlorobenzonitrile (2.62 g, 17.2 mmol) in DCM (60 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (7.2 mL, 51.6 mmol) was added, followed by dropwise additiona of titanium (IV) chloride solution (1 N in DCM, 10.3 mL, 10.3 mmol). The reaction mixture was stirred at 0° C. for 2 hours, then at room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue obtained was used in the following step without further purification.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]4([C:58](=O)[CH3:59])[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]5[CH2:44][CH2:43][N:42]([C:45]6[CH:50]=[CH:49][C:48]([C:51]7[N:56]=[CH:55][CH:54]=[CH:53][N:52]=7)=[CH:47][N:46]=6)[CH2:41][CH:40]5[CH3:57])=[O:38])[CH2:32]4)=[O:30])[CH:26]=3)[NH:21][N:20]=2)=[CH:15][CH:14]=1>CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]4([C:58](=[N:4][O:2][CH3:3])[CH3:59])[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]5[CH2:44][CH2:43][N:42]([C:45]6[CH:50]=[CH:49][C:48]([C:51]7[N:52]=[CH:53][CH:54]=[CH:55][N:56]=7)=[CH:47][N:46]=6)[CH2:41][CH:40]5[CH3:57])=[O:38])[CH2:32]4)=[O:30])[CH:26]=3)[NH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: CON
Reactant: CC(=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Added methoxylamine hydrochloride (100 mg, 1.197 mmol) and triethylamine (0.2 ml, 1.43 mmol) to a solution of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (11N) (100 mg, 0.15 mmol) in MeOH (5 ml), then stirred for 3 hours at room temperature. The solvent was evaporated and the residue was extracted with MeCl2, washed with water, dried over Na2SO4, filtered and solvent was evaporated yielding a solid which chromatographed on silica gel eluting with 7% v/v MeOH/MeCl2 containing 2% NH4OH yielding 2 isomers:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[C:45]([C:46](O)=O)=[CH:44][C:43]([CH3:49])=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:46]([C:45]2[N:41]([CH3:40])[N:42]=[C:43]([CH3:49])[CH:44]=2)[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Reactant: Cc1cc(C(=O)O)n(C)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C)nn2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.014 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.71 (s, 1H), 5.44 (s, 2H), 4.12 (s, 3H), 2.97 (t, 2H), 2.30 (s, 3H), 1.80-1.72 (m, 2H), 1.04 (t, 3H); MS (ES) m/z 395 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:17])=[CH:8][C:7]=1[Cl:26]>C(N(CC)CC)C.CN(C=O)C>[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]2)=[O:17])=[CH:8][C:7]=1[Cl:26]
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Reactant: N#CCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Temperature: 60 °C
Yield: 53 %

Procedure:
A mixture of chloroacetonitrile (2.15 ml) and (4piperidinyl)-methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (11 g) in N,N-diethylethanamine (7 ml) and DMF (150 ml) was stirred at 60° C. until the reaction was complete. Then, the mixture was cooled. The solvent was evaporated. The residue was partitioned between DCM and water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from ACN and the precipitate was filtered off and dried (vacuum, 50° C.), yielding 6.6 g (53%) [1-(cyanomethyl)-4-piperidinyl]-methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (intermediate 14).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([C:24]([C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[CH:32][CH:31]=[CH:30]5)([CH3:26])[CH3:25])[N:22]=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:12]=[N:11]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CO>O>[N:33]1[C:34]2[C:29](=[CH:28][C:27]([C:24]([N:21]3[C:19]4=[N:20][C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)=[CH:16][CH:17]=[C:18]4[N:23]=[N:22]3)([CH3:25])[CH3:26])=[CH:36][CH:35]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(c1ccc2ncccc2c1)n1nnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: O
Product: CC(C)(c1ccc2ncccc2c1)n1nnc2ccc(-c3cnn(CCO)c3)nc21

Procedure:
The title compound was prepared by following the procedure described for example 146 from example 189 (0.050 g, 0.104 mmol), camphor sulphonic acid (0.121 g. 0.521 mmol), methanol (0.5 ml) and water (0.5 ml). Brown solid (0.031 g, 74%). M.P.: 95-98° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.85 (d, J=2.8 Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.85 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.53 (m, 2H), 4.87 (t, J=5.3 Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 3.70 (q, J=5.4 Hz, 2H), 2.46 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCN(C)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 200 mg (0.455 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile (Reference Example 20) and 273 mg (2.73 mmol) of N-methylpiperazine in 1 mL of 1-methyl-2-pyrrolidinone was heated at 105° C. for 16 hours. The solvents are removed in vacuo. A 10 mL portion of water is added to the residue, from which a tan solid precipitates out. The solid is filtered off and washed with water. After drying in vacuo, the solid is suspended in ethyl acetate and stirred for 1 hour. The solid is filtered off, washed with ethyl acetate and dried in vacuo to provide 0.175 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(4-methypiperazin-1-yl)-quinoline-3-carbonitrile as a yellow solid, mp 270-272° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.COCCOC.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>[Cl:22][C:4]1[C:3](=[CH:2][C:28]2[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=2)[CH:12]=[C:11]2[C:6](=[CH:7][CH:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)[CH:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
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: CCO
Solvent: COCCOC
Product: CCOC(=O)C1C=c2cc(Cl)c(=Cc3ccc(C=O)cc3)cc2OC1C(F)(F)F
Temperature: 50 °C
Yield: 47.1 %

Procedure:
The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (2.0 g, 5.0 mmol) and Pd(PPh3)4 (174 mg, 0.15 mmole) were mixed in DME (50 mL) and the mixture was heated at 50° C. for 10 min. The solution of 4-formylphenylboronic acid (1.12 g, 7.5 mmole) in EtOH/DME (1:1, 4 mL) was added to above mixture and followed by adding 2 M Na2CO3 (5 mL, 10 mmole). The mixture then was heated to 90° C. for overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 and filtered. The filtrate was concentrated to afford the crude product, which was purified by Biotage chromatography eluted with 5 to 10% EtOAc in hexane to give 1 g the desired product as a yellow solid (47%), which had suitable purity to use without fuirther purification.
Reaction SMILES: [CH2:1](O)[CH3:2].[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:1][CH3:2])=[O:10]
Reactant: CCO
Reactant: O=C(O)CCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCl
Yield: 71.5 %

Procedure:
Toluene (100 ml), ethanol (10.12 g, 219.65 mmol) and 5-chlorovaleric acid (25 g, 183.04 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (5.22 g, 27.46 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (4.63 g, 45.76 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl 5-chlorovalerate (21.54 g, 72%) was isolated in distillation.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][CH:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C:14](Cl)=[O:15]>O>[CH3:11][CH:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C:14]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:15]
Reactant: c1ccccc1
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(CC(=O)c1ccccc1)CC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 143.4 grams of aluminum chloride and 351.6 grams of benzene was stirred at room temperature while 100 grams of 3,5,5-trimethylhexanoyl chloride was added to the reaction keeping the reaction temperature at approximately 35° C. over a period of 1.5 hours. The mixture was then stirred for 3 hours. The reaction mixture was poured into 500 grams of ice and stirred until all the ice dissolved. Water was added with cooling to give a homogenous mixture followed by extraction with 400 mL of ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate and stripped to dryness to give 3,5,5-Trimethylhexanoylbenzene.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[F:18][C:15]([F:16])([F:17])[CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.2 %

Procedure:
A suspension of 1.26 g (0.0045 mole) of [1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester in 10 mL of 4 M HCl in dioxane solution was stirred at room temperature for 24 hours. Volatiles were removed under reduced pressure, methanol was added to the residue followed by ether. The resulting solid was collected by filtration, washing with ether to give 0.92 g of 1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamine; hydrochloride as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:40]([C:36]3[S:35][CH:39]=[CH:38][CH:37]=3)=[O:41])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Cl)c1cccs1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3cccs3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, thienoyl chloride.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:11])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH3:1][CH:2]([NH:11][C:25]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:10]
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)N1CCOCC1)C(O)c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 15.2 grams of norephedrine in 200 ml. of CH2Cl2 was cooled to 0-5° C. To this 11.0 grams of triethylamine was added with stirring. To the stirred mixture a solution of 14.9 grams of morpholine carbonyl chloride in 10 ml. of CH2Cl2 was added dropwise. The mixture was then stirred for 2 hours and left to stand at room temperature for 16 hours. The mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. The organic layer was then filtered and evaporated to a small volume. The hydroxyethylurea, N-(1-methyl-2-phenyl-2-hydroxyethyl)-4-morpholinecarboxamide was filtered off as a white solid and recrystallized from CH2Cl2.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9]1([CH:15]([OH:32])[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:32]([CH:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=2)[CH2:22][CH2:23]1)[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(CCC(O)C3CCCCC3)CC2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
After adding tert-butyldimethylsilyl chloride (203 mg, 1.5 mmol) to a solution of 1-(3-cyclohexyl-3-hydroxypropyl)-4-(5-methylpyridin-2-yl)aminopiperidine (405 mg, 1.22 mmol), triethylamine (0.20 mL) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) in methylene chloride (5 mL) while cooling on ice, the mixture was stirred at room temperature for 18 hours. Triethylamine (0.20 mL), 4-dimethylaminopyridine (30 mg, 1.5 mmol) and tert-butyldimethylsilyl chloride (203 mg, 1.5 mmol) were further added to the reaction mixture and stirring was continued at room temperature for 70 hours. NH silica Chromatorex DM1020 was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1) to obtain the title compound as a colorless oil (423 mg) (77.7% yield).