Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[I-:12].[Na+]>CC(=O)CC>[I:12][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: [I-]
Reactant: C[Si](C)(C)C#CCCCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: C[Si](C)(C)C#CCCCCI
Reaction time: 10 h
Yield: 96.2 %

Procedure:
A mixture of 6-chloro-1-trimethylsilylhex-1-yne (14.0 g.) and sodium iodide (30 g) in butanone (100 ml) was heated at reflux, with stirring, for 10 hours. After this time the solvent was removed in vacuo and the residue partitioned between diethyl ether and water. The organic phase was separated, washed with water and brine before drying over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to leave 6-iodo-1-trimethylsilylhex-1-yne as a yellow oil (20.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:9])[CH3:8].[BH4-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8]
Reactant: CC(=O)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To an ice-cooled solution of 1-(pyridin-2-yl)ethanone (11 g, 91 mmol) in methanol (120 mL) was slowly added sodium borohydride (8.58 g, 227 mmol). Upon complete addition, the mixture was warmed to 25° C. After 16 h, the reaction was diluted with water (100 mL), and the mixture was concentrated in vacuo. The resulting aqueous solution was extracted with ethyl acetate (3×100 mL). The combined organic extracted were washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (10→30% ethyl acetate in petroleum ether) afforded 1-(pyridin-2-yl)ethanol (10.3 g, 92% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J=4.8 Hz, 1 H), 7.72-7.68 (m, 1 H), 7.30 (d, J=8.0 Hz, 1 H), 7.22-7.20 (m, 1 H), 4.93-4.88 (m, 1 H), 4.39 (br s, 1 H), 1.52 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:9]=[C:8]([C:17]#[C:18][Si](C)(C)C)[N:7]=1)[CH:2]([CH3:4])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:17]([C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])[N:11]=[C:10]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:9]=1)#[CH:18]
Reactant: CC(C)CNc1nc(C#C[Si](C)(C)C)nc(NCC(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1nc(NCC(C)C)nc(NCC(C)C)n1
Yield: 12 %

Procedure:
N2,N4-diisobutyl-6-((trimethyl-silyl)ethynyl)-1,3,5-triazine-2,4-diamine (27, 14.5 mg, 0.045 mmol) was dissolved in THF (1 mL). Tetrabutylammonium fluoride (0.59 mL, 2.04 mmol) was then added and the reaction mixture was left to react at room temperature (30 min). The reaction was monitored by TLC and when complete, the solvent was removed from the reaction mixture by rotary evaporation to give a crude solid that was purified by flash chromatography on silica gel (hexane/ethyl acetate, 2:1) to afford 45 in 12% yield. 6-ethynyl-N2,N2-diisobutyl-1,3,5-triazine-2,4-diamine (28): Rf: 0.14 (hexane/ethylacetate, 2:1). 1H NMR (400 MHz, CDCl3) δ: 0.92-0.94 (d, 12H), 2.15-2.16 (d, 4H), 3.21-3.27 (m, 2H), 5.29 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][O:23][C:24]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:25]=4[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]5)[CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19]
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cccc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH2:15][CH2:14]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O.OC1C2N=NNC=2C=CC=1.ClCCl>[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]2)=[O:23])[CH2:15][CH2:14]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)CCCN2CCOCC2)CC1

Procedure:
The procedure is carried out in a manner similar to that described in Example 63, but starting with 4.20 g of methyl cis-4-aminocyclohexane-1-carboxylate hydrochloride, 4.0 g of 4-morpholinobutyric acid, 50 mg of hydroxybenzotriazole hydrate, 11.2 cm3 of triethylamine, 200 cm3 of dichloromethane and 4.2 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. After a treatment similar to that in Example 60, the crude product is purified by flash chromatography [eluent: dichloromethane/methanol (95/5 by volume)] to give 5.0 g of methyl cis-4-(4-morpholinobutyrylamino)-1-cyclohexanecarboxylate in the form of a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=C[CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[O-:17][Mn](=O)(=O)=O.[K+]>O>[N:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:7](=[O:17])[C:8]3[C:9]([C:10]=12)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: c1ccc2c(c1)ccc1cccnc12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1c2ccccc2-c2ncccc21
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A solution of benzo[h]quinoline (6 g, 33.5 mmol) and KOH (5.6 g, 100.5 mmol) in water (400 mL) was boiled. A hot solution of KMnO4 (14.8 g, 93.8 mmol) in water (240 mL) was added dropwise over 1 hour to the boiling solution. The mixture was refluxed for another 6 hours and filtered hot. The filtrate was allowed to cool to room temperature. The organic layer was extracted with chloroform and water, dried with anhydrous magnesium sulfate. After solvent removal, the residue was purified by column chromatography on silica (acetone-petroleum ether) to give product 2.5 g (42%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[NH2:25][C@@H:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@H]1CCc2ccccc21
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-(+)-1-aminoindan.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([SH:25])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>CN(C)C=O.C1(C)C=CC=CC=1>[F:27][C:18]([F:17])([F:26])[C:19]1[CH:20]=[C:21]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=[O:12])[CH:22]=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: O=Cc1ccccc1CCCCCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To N,N-dimethylformamide (30 ml) and 2-(7-bromoheptyl) benzaldehyde (1.5 g, 5 mmoles) was added a solution of 3-trifluoromethylthiophenol (1.0 ml, 8 mmoles) and triethylamine (3.0 ml, 0.02 mole) in N,N-dimethylformamide (20 ml). The reaction was heated to 90° C. for 1 hour and then stirred for 11/2 hours while slowly cooling to room temperature. The mixture was diluted with toluene and evaporated, followed by dilution with methylene chloride. The solution was evaporated and flash chromatographed using 8% ethyl acetate in hexane to give the desired product.
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.CCCCCC.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)CCN(C)C.CN([CH:52]=[O:53])C>C1COCC1>[CH2:18]([O:25][C:26]1[C:27]([CH:52]=[O:53])=[C:28]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:29]([N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[O:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Temperature: -70 °C
Reaction time: 4 h
Yield: 27.5 %

Procedure:
1.3 M sec-butyl-lithium in cyclohexane/hexane (54 ml, 0.07 moles) was dropped into a solution under nitrogen of 3-benzyloxy-N,N-diethyl-4-methoxy-benzamide (20 g, 0.064 moles), obtained as described in example 31, tetramethylethylendiamine (10.56 ml, 0.07 moles) in THF (2.25 1) under stirring in a dry ice bath at −70° C. After 2 hours at constant temperature, DMF (21.75 ml, 0.28 moles) was added. The temperature was kept constant for 4 hours then left overnight. The mixture was poured into a NaH2PO4/Na2HPO4 buffer solution (1 l) at pH=7, the phases were separated, the organic one was washed with water (1 l), dried and brought to dryness. The crude was chromatographed (eluent: benzene:ethyl acetate 1:1) to give 6 g of the title compound (yield: 27.4%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[F:36][CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][C:40]1=[O:46]>>[F:36][CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:41][C:40]1=[O:46]
Reactant: O=c1cc(I)ccn1CCF
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(CCF)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 1-(2-fluoroethyl)-4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.09 min, m/z=515, 493, 475, 435.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[S:14][N:13]=[C:12]([SH:15])[C:11]=2[C:16]#[N:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1[OH:34])(C)(C)C.S(=O)(=O)(O)O.[BH4-].[Na+].Cl>>[C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[S:14][N:13]=[C:12]([SH:15])[C:11]=2[C:16](=[O:34])[NH2:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: N#Cc1c(S)nsc1NC(=O)Oc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Product: NC(=O)c1c(S)nsc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of (4-cyano-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester (0.70 g, 2.5 mmol), 2,6-di-tert-butyl-4-methylphenol (BHT)(one crystal) and concentrated sulfuric acid (3 mL) was stirred for 18 hours at room temperature. The mixture was diluted with ice water, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 10 mL of ethanol at 0° C. and was treated with 0.096 g (2.5 mmol) of NaBH4. After stirring for 30 minutes, the mixture was acidified with 1 M HCl, extracted into ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo, affording 0.60 g (81%) of (4-carbamoyl-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester as a yellow solid. 1H NMR (400 MHz, acetone-d6) δ 13.0 (s, 1H), 11.0-10.9 (bs, 1H), 10.3 (s, 1H), 7.47 (1.2H, J=6.8 Hz), 7.37-7.30 (m, 4H) ppm; MS (APCI, m/z): 296 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:36])[C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22]1>C(O)C.N1CCCCC1>[CH3:19][N:20]([CH3:36])[C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:27])[CH2:22]1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)N2CC[C@@H](N(C)C)C2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-[(3R)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 81%).
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[NH:10][C:11](=[O:17])[C:12]([O:14]CC)=[O:13])#[N:4].Cl>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[NH:10][C:11](=[O:17])[C:12]([OH:14])=[O:13])#[N:4]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(O)c(NC(=O)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a mixture of 30 ml of 4% potassium hydroxide solution and 30 ml of methanol was added 2 g of ethyl 5-cyano-2-hydroxyoxanilate and the mixture was stirred overnight at room temperature. To the reaction mixture was added 15 ml of 10% hydrochloric acid solution and white crystals formed were recovered by filtration and recrystallized from water to provide 1.2 g of 5-cyano-2-hydroxyoxanilic acid.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH2:13].[NH:14]1[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[N:15]1>>[S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH:13][C:19]([C:17]1[CH:18]=[N:14][NH:15][CH:16]=1)=[O:20]
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Reactant: O=C(Cl)c1cn[nH]c1
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1cn[nH]c1
Yield: 42.1 %

Procedure:
Acylation 8H-Indeno[1,2-d]thiazol-2-ylamine 1b (Prepared in Example 1, Step 2, 377 mg; 2.00 mmol) with 4-pyrazolecarbonyl chloride 12 (208 mg; 1.6 mmol) in a manner similar to that described in Example 7, provided 190 mg of 1H-Pyrazole-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide 13 as a dark powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:26]2([C:31]([F:34])([F:33])[F:32])[CH2:30][CH2:29][NH:28][CH2:27]2)[CH:21]=[C:22]([Cl:25])[C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:26]2([C:31]([F:34])([F:33])[F:32])[CH2:30][CH2:29][N:28]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=3)[CH2:27]2)[CH:21]=[C:22]([Cl:25])[C:23]=1[Cl:24]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 100 °C
Yield: 95 %

Procedure:
Ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (1.2 g) [see J. Med. Chem., 43, 3995 (2000)], 3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.5 g), and potassium carbonate (0.7 g) were added to N,N-dimethylformamide (50 mL) and the mixture was heated at 100° C. for 5 hours. After cooling, the reaction solution was poured over ice water, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (2.4 g, 95%).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13](O)=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.S(Cl)([Cl:22])=O>ClCCl>[S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]([Cl:22])=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: O=C(O)c1ccc(C=Cc2cc3ccccc3s2)s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C=Cc2cc3ccccc3s2)s1
Yield: 95.4 %

Procedure:
To a stirred suspension of 5-[2-(benzo[b]thiophen-2-yl)ethenyl]thiophene-2-carboxylic acid (9.11 g) and dichloromethane (900 ml) was added over 5 mins thionyl chloride (7.56 g). The mixture was refluxed overnight. The solvent was removed in vacuo to give 9.25 g of 5-[2-(benzo[b]thiophen-2-yl)ethenyl]thiophene-2-carboxylic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:3]=1.[ClH:38].O1CCOCC1>O1CCOCC1>[ClH:38].[NH2:1][C:2]1[N:3]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCc3ccccc3)nc(N)c2C#N)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(C2CCCNC2)cc(-c2c(O)cccc2OCc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of tert-butyl 3-{2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (239 mg, 0.48 mmol) in dioxane (25 mL) was added 4N HCl/dioxane (25 mL). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with ethyl acetate and hexane, dried under reduced pressure to give 2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinonitrile hydrochloride (184 mg, yield; 88%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Yield: 102.9 %

Procedure:
A solution of 25 g (110 mmol) of 3-bromobenzylamine hydrochloride and 24.5 g (110 mmol) of tert-butyl dicarbonate in 250 mL of dichloromethane in the presence of 15.6 mL (110 mmol) of triethylamine is stirred at room temperature for 16 hours. The reaction medium is washed with water, the phases are separated by settling and the organic phase is dried over sodium sulfate. The solvent is evaporated off and 32.4 g (100%) of tert-butyl (3-bromobenzyl)carbamate are obtained in the form of crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OCC)=[CH:4][CH:3]=1.[Mg].II.[CH2:14]([O:21]C1C=CC=CC=1C=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.O>[C:15]1([CH:14]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 178 %

Procedure:
A Grignard reagent was prepared from 1-bromo-4-ethoxybenzene (1.5 g), magnesium (0.19 g), a catalytic amount of iodine and tetrahydrofuran (2 mL) in the usual manner. To the obtained Grignard reagent solution was added dropwise a solution of 2-benzyloxybenzaldehyde (1.1 g) in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added a saturated aqueous ammonium chloride solution (10 mL) and water (20 mL), and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. Thereafter, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give a diphenylmethanol compound (1.7 g). The obtained diphenylmethanol compound (1.7 g) was dissolved in ethanol (25 mL). To the solution were added concentrated hydrochloric acid (0.42 mL) and a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (100 mL), and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=8/1) to give 2-(4-ethoxybenzyl)phenol (0.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[OH:29][NH2:30].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=[N:30]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)ccc1[C@H](CC(=O)c1ccnc(CO)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1[C@H](C/C(=N\O)c1ccnc(CO)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-(hydroxymethyl)pyridin-4-yl)propan-1-one (example 282, step 1) and hydroxyl-amine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=459.2 ([M+H]+).
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7]C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C.Br>C(O)(=O)C>[CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:7]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1
Agent: Br
Solvent: CC(=O)O
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Temperature: 90 °C

Procedure:
To a solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (1.03 g, 2.328 mmol) in acetic acid (8 ml) was added HBr (6 M, 1.940 ml, 11.64 mmol). The reaction was heated to 90° C. for 20 hours in a sealed vial and then cooled. To this was then added further HBr (6 M, 1.00 ml, 6 mmol) and the reaction was heated at 90° C. for 36 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by reverse phase chromatography (C18 silica, 5-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.