Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH:11]2[NH2:16].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][N:24]1[CH2:2][C:3]([NH:16][CH:11]1[C:12]2[C:8](=[C:7]([CH3:6])[CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: Cc1cccc2c1CCC2N
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2CC(=O)NC2CCc3c(C)cccc32)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with rac-4-methyl-indan-1-ylamine and 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:6]([S:7][CH3:8])[N:5]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:4]1=[O:23].C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.Br[CH2:39][C:40](Br)=[O:41].[C:43](=[S:45])=[S:44]>>[CH3:1][O:2][CH:3]1[CH:6]([S:7][CH3:8])[N:5]([C:9](=[C:43]2[S:45][C:40](=[O:41])[CH2:39][S:44]2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:4]1=[O:23]
Reactant: S=C=S
Reactant: COC1C(=O)N(CC(=O)OCc2ccc([N+](=O)[O-])cc2)C1SC
Reactant: O=C(Br)CBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Product: COC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C2SCC(=O)S2)C1SC

Procedure:
Following the procedure of Preparation 15, but using p-nitrobenzyl 2-(3-methoxy-4-methylthio-2-azetidinon-1-yl)-acetate (188 mg), hexamethyldisilazane (232 μl), butyllithium (0.68 ml), carbon disulphide (50 μl), and bromoacetyl bromide (48 μl), 108 mg of the desired product were obtained as an oily substance.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](Cl)=[O:15])[CH3:12].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O:10][C:3]1[C:2]([I:1])=[CH:7][C:6]([I:8])=[CH:5][C:4]=1[I:9])=[O:15])[CH3:12]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: Oc1c(I)cc(I)cc1I
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CC)C(=O)Oc1c(I)cc(I)cc1I
Yield: 119.4 %

Procedure:
A solution of 2,4,6-triiodophenol (20.0 g, 42 mmol), 2-ethylhexanoyl chloride (25 ml, 144 mmol, 3.5 eq.) and 4-dimethylaminopyridine (DMAP; 2 mmol, 250 mg, 0.05 eq.) in 150 ml of pyridine was stirred overnite at room temperature. The solution was poured into 1000 ml of 1N aqueous hydrochloric acid and the aqueous solution was extracted twice with ethyl acetate. The combined organic layers were washed with aqueous hydrochloric acid, water, saturated aqueous sodium chloride and then dried over magnesium sulfate. The ethyl acetate solution was then concentrated under vacuum to give an oil (30 g) which was purified by silica gel chromatography (5% ethyl acetate/hexanes eluent) to give the product. Concentration under high vacuum afforded 21 g (79%) of the desired hexanoate ester as an oil. The product was taken up in hexanes and filtered through a pad of basic alumina. The filtrate was concentrated under high vacuum to give 16.9 g of analytically pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH2:23][OH:24].C(O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[N:23][OH:24])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CCC(=NO)CC2)cc1

Procedure:
A mixture of 1-(p-methoxyphenyl)-4-piperidinone (prepared following the procedure reported in: Scherer, T. et al., Recl. Trav. Chim. Pays-Bas (1993), 112(10), 535-48.) (5.13 g, 25 mmol), K2CO3 (6.22 g, 45 mmol), hydroxylamine hydrochloride (2.606 g, 37.5 mmol) and ethanol was refluxed for 20 min. After cooling H2O (50 ml) was added and white crystals of 1-(4-methoxy-phenyl)-piperidin-4-one oxime (4.56 g, 83%, Mp. 116-119°, MS: m/e=220 (M+)) was collected.
Reaction SMILES: [F:1][C:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C1C=CC=CC=1.CCCCC>[Br:30][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([CH3:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(F)CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCC
Product: CC(C)(F)CCCCCBr
Temperature: 0 °C
Yield: 72.4 %

Procedure:
A stirred solution of the product from Step IV (0.427 g, 0.00288 mol) in benzene (5.2 ml) was mixed with triphenylphosphine (0.83 g, 0.00317 mol) cooled in an ice bath and treated, portion-wise, during 26 minutes with N-bromosuccinimide (0.56 g, 0.00317 mol). The mixture was kept in the ice bath for 30 minutes and at ambient temperature for 3.5 hours; it was then diluted with pentane (20 ml), cooled in an ice bath for a few minutes and filtered. The solid was washed with pentane and the filtrate was concentrated. A mixture of the residue and pentane was cooled in an ice bath for a few minutes and again filtered. The filtrate was mixed with Et2O and washed successively with cold 5% aqueous sodium thiosulfate, 0.5 N NaOH and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 1-3% EtOAc-hexane to give 0.440 g of 1-bromo-6-fluoro-6-methylheptane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])(O)=O.[Na+].[CH2:21]([Cl:23])Cl>O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][CH:21]([Cl:23])[CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: ClCCl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(Cl)OC(=O)C(NC(=O)OC(C)(C)C)C(C)C
Yield: 78 %

Procedure:
The title compound was prepared according to the procedure as described in Example 17 step 1 using 2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (3 g, 13.81 mmol) in DCM (75 mL) and H2O (75 mL), NaHCO3 (4.64 g, 55.23 mmol), TBAHSO4 (469 mg, 1.38 mmol) and a solution of 1-chloroethyl sulfochloridate (2.97 g, 16.57 mmol) in DCM (15 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=100/1 to 50/1) to afford the title compound as a white solid (3 g, 78%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)C.COC(ON=C(C#N)C(N)=O)=O>C(Cl)(Cl)Cl.C(#N)C>[CH3:16][O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CCN(CC)CC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: COC(=O)ON=C(C#N)C(N)=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.7 ml) in chloroform (10 ml) and acetonitrile (5 ml), 2-methoxycarbonyloxyimino-2-cyanoacetic acid amide (0.85 g) is added, and the resulting mixture is stirred at room temperature for 1 hour and allowed to stand over night. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine methyl ester (1.1 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5](/[CH:6]=[CH:7]/[C:8](=[N:17][OH:18])[NH2:9])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: NO
Reactant: N#CC=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(/C=C/c1ccc(Cl)c(C(F)(F)F)c1)=NO
Yield: 40.1 %

Procedure:
12.1 g (0.05 mol) of 4-chloro-3-trifluoromethylcinnamonitrile are added to a solution consisting of 7.2 g (0.10 mol) of hydroxylamine hydrochloride and 7.3 g (0.10 mol) of sodium carbonate in 100 ml of water and 100 ml of ethanol. The mixture is heated at reflux temperature until the reaction is complete (24 hours) and the whole batch is subsequently stirred into 250 ml of water. The solid material which separates off during this process is filtered off with suction, washed with a little water and dried. 5.3 g (39.3% of theory) of (E)-4-chloro-3-trifluoromethylcinnamamide oxime are obtained.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:41])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:40])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:39])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:38])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])=[CH:3][C:4]#[N:5].[Na].Cl>CO.C1COCC1>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:41])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:40])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:39])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:38])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH2:3][C:4]#[N:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC#N
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
21 g of 3,7,11,15,19,23,27,31-octamethyl-2,6,10,14,18,22,26,30-dotriacontaoctaenonitrile was dissolved in 250 ml of methanol and 100 ml of THF, and 24 g of metallic sodium was added. The reaction solution was stirred at room temperature for 30 minutes and was cooled with ice when foaming and heat generation were recognized. After the reaction solution was reacted for 2 hours, 500 ml of 6N hydrochloric acid was added and the reaction product was extracted by 500 ml of n-hexane. The organic layer was concentrated and the concentrate was refined by silica gel column chromatography, providing 16 g of 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenonitrile.
Reaction SMILES: C(NC1C(C)=CC(OC)=CC=1C(N)=O)(=O)C1C=CC=CC=1.NC1C(C)=CC(OC)=CC=1C(N)=O.[Cl:35][C:36]1[CH:37]=[C:38]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH2:54][CH2:55][CH2:56][C:57]([OH:59])=O)[CH:52]=3)[N:47]=[C:46]([C:60]3[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=3)[N:45]=2)[CH:39]=[CH:40][C:41]=1[F:42].[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>>[Cl:35][C:36]1[CH:37]=[C:38]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH2:54][CH2:55][CH2:56][C:57]([N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[O:59])[CH:52]=3)[N:47]=[C:46]([C:60]3[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=3)[N:45]=2)[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: O=C(O)CCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: C1COCCN1
Agent: COc1cc(C)c(N)c(C(N)=O)c1
Agent: COc1cc(C)c(NC(=O)c2ccccc2)c(C(N)=O)c1
Product: O=C(CCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1)N1CCOCC1
Yield: 40 %

Procedure:
4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl) quinazolin-6-yl)-1-morpholinobutan-1-one was prepared in a manner analogous to that described for 2-benzamido-5-methoxy-3-methylbenzamide in Method D, replacing nicotinic acid and 2-amino-5-methoxy-3-methylbenzamide with 4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl) butanoic acid and morpholine to give 32 mg of xxxv-a in a 40% yield as a beige solid. LCMS m/z=506.2, 508.1 (M+1) (Method 1) (retention time=1.85 min). 1H NMR (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.52 (d, J=1.6 Hz, 1H), 8.69-8.65 (m, 2H), 8.39-8.38 (m, 1H), 8.27 (dd, J=6.8, 2.8 Hz, 1H), 7.94-7.90 (m, 1H), 7.86-7.84 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.52 (m, 2H), 3.56-3.53 (m, 4H), 3.46-3.41 (m, 4H), 2.85 (t, J=8.0 Hz, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.97 (t, J=7.6 Hz, 2H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:36]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:35])=[O:12])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2.5 g of Z-Pal-OH (8.7 mMol) are dissolved in 50 ml of THF, mixed with 1.55 g CDI (9.5 mMol), stirred for 45 minutes at ambient temperature, then mixed with 1.12 ml of N-methyl -benzylamine (8.7 mMol ) and stirred for a further 64 hours at ambient temperature. The reaction mixture is concentrated on the rotary evaporator, the residue is taken up in ethyl acetate, extracted once with cold water and once with 10% NaCl solution. The organic phase is filtered, concentrated and chromatographed over a silica gel column by means of ether as eluant. Z-Pal-N(Me)Bzl is obtained as colourless oil from the eluant. [α]D20 (MeOH )=-0.3°.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][C:4]#[N:5].[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:14]1
Reactant: CNN
Reactant: N#CCC(=O)c1ccccn1
Solvent: CCO
Product: Cn1nc(-c2ccccn2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of crude 3-oxo-3-(2-pyridyl)propanenitrile (48.6 g, 331 mmol) in ethanol (500 mL) was added methyl hydrazine (25 g, 543 mmol). The resulting mixture was stirred for about 30 min at rt and then heated at about 75° C. for about 18 h. After cooling to rt the reaction mixture was concentrated in vacuo. The residue was treated with toluene (300 mL). The formed solid was collected by filtration and washed with toluene (150 mL). The solid was dried under vacuum to give 2-methyl-5-(2-pyridyl)pyrazol-3-amine (36.2 g, 208 mmol, 63%). 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.62 (3H, s); 5.34 (2H, br s); 5.90 (1H, s); 7.21 (1H, m); 7.73 (1H, dt, J=10 Hz, 2 Hz); 7.83 (1H, dt, J=10 Hz, 1 Hz); 8.51 (1H, dt, J=6 Hz, 2 Hz).
Reaction SMILES: [C:1]1([N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[CH:9]=[C:10]3C(=CC=2)C=C(C=O)C=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1S.[CH3:34][S:35]([CH3:37])=O>O>[S:35]1[C:37]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[N:7]=[C:34]1[C:28]1[CH:29]=[C:30]2[C:31](=[CH:32][CH:27]=1)[C:8]([N:7]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:9][CH:10]=[CH:11]2
Reactant: O=Cc1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Reactant: CS(C)=O
Reactant: Nc1ccccc1S
Solvent: O
Product: c1ccc(N(c2ccccc2)c2cccc3cc(-c4nc5ccccc5s4)ccc23)cc1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
A mixture of N,N-diphenyl-6-amino-2-naphthaldehyde, (3.98 g., 0.0123 mol.), 2-aminothiophenol (1.5 ml, 0.014 mol.) and DMSO (20 ml) was heated to 180° C., held at this temperature for 45 minutes, and poured into water. The separated greenish solids were collected, air dried, transferred to a column of silica gel and eluted with 2:1 toluene-heptaneto get the product, 3.91 g. (74% yield), m.p. 186.1-187.3° C. Recrystallization from 1:1 toluene-heptane raised the m.p. to 188.1-189.5° C. Mass Spec: m/z 428 (M+). Analysis calculated for C29H20N2S: C, 81.29; H, 4.70; N, 6.54; S, 7.47. Found: C, 81.04; H, 4.88; N, 6.62; S, 7.31.
Reaction SMILES: C[C:2]1[CH2:6][CH2:5][CH2:4][Si:3]=1Cl.[C:8]1(C)C=CC=CC=1.[C:15]1(=[O:22])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(N(CC)CC)C>[CH3:8][C:16]1([Si:3]2[CH2:4][CH2:5][CH2:6][CH:2]=2)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:15]1=[O:22]
Reactant: Cc1ccccc1
Reactant: CC1=[Si](Cl)CCC1
Reactant: O=C1CCCCCN1
Solvent: CCN(CC)CC
Product: CC1([Si]2=CCCC2)CCCCNC1=O
Reaction time: 1 h

Procedure:
Methylsilacyclopentenyl chloride, 1 mol, was added over a period of 30 minutes to an anhydrous solution of 750 ml. of toluene, 146 g. of triethylamine and 1.05 mol of epsilon-caprolactam in a flask. After 1 hour of stirring the reaction mixture was filtered to remove (CH3CH2)3N.HCl and the filtrate was fractionally distilled to give a moderate yield of methylsilacyclopentenyl-epsilon-caprolactam, b.p. = 120° to 140° C. at approximately 0.5 kilopascals of pressure. Infrared spectroscopy indicated that the bonding in this silyl lactam, between the methylsilacyclopentenyl radical and the epsilon-caprolactamo radical, is predominently silicon-nitrogen bonding.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(Cl)Cl>[C:12]([S:15][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)([CH3:14])([CH3:13])[CH3:11]
Reactant: N#Cc1ccc(CBr)nc1
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)SCc1ccc(C#N)cn1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 6-bromomethyl-pyridine-3-carbonitrile (6.2 g, 31.4 mmol) in anhydrous DMF (60 mL) under nitrogen. Add tert-butylthiol (5.32 mL, 47.2 mmol) followed by cesium carbonate (15.3 g, 47.2 mmol) and stir the resulting suspension overnight. Dissolve the reaction mixture in DCM (200 mL) and add water (200 mL). Extract the aqueous phase with DCM (2×200 mL) and dry the combined organic extracts over MgSO4. Filter, add silica gel and concentrate the mixture in vacuo. Purify the residue by chromatography on silica gel (40 g) eluting with cyclohexane/EtOAc (98:2 to 65:35 gradient) to obtain the desired material as a yellow solid (4.92 g, 76%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]Cl)[CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:32]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Reactant: COC(=O)Cc1cccc(CCl)c1
Product: COC(=O)Cc1cccc(COc2ccc(C(C)C(O)(c3cnc4ccccc4c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 140, step 5) was reacted with (3-chloromethyl-phenyl)-acetic acid methyl ester to give {3-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenoxymethyl]-phenyl}-acetic acid methyl ester. This compound was hydrolyzed in analogy to Example 141 to give the title compound as an off-white solid. MS (m/e)=530.1 [M+H+].
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19.8 %

Procedure:
To a solution of the crude (S)-tert-butyl 4-chloro-1-cyclohexyl-3-oxobutan-2-ylcarbamate (5.8 g, 0.019 mol) in 9:1 THF/H2O (100 mL) at 0° C. was added NaBH4 (1.8 g, 0.047 mmol). After stirring for 45 min at rt, the solvent was removed in vacuo. The residue was diluted with water (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was purified by flash chromatography to give a mixture of isomeric alcohols, which was recrystallized from n-hexane three times to give pure tert-butyl (2S,3S)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (1.15 g, 40%). 1H NMR: 0.82 (m, 1H), 0.96 (m, 1H), 1.08-1.40 (m, 5H), 1.43 (s, 9H), 1.65 (m, 4H), 1.82 (m, 1H), 3.08 (m, 1H), 3.52 (m, 1H), 3.58 (r, 1H), 3.79 (m, 2H), 4.51 (m, 1H). MS (E/Z): 306 (M+H+). The mother liquor was concentrated and recrystallized from n-hexane three times to give pure tert-butyl (2S,3R)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.3 g, 10.3%).
Reaction SMILES: C(C1(C)[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5]C1)#N.[OH-].[Na+].O1CCCC1.C(O)(=O)[CH2:36][C:37]([CH2:42]C(O)=O)([C:39]([OH:41])=[O:40])O>C(O)C>[CH3:42][C:37]1([C:39]([OH:41])=[O:40])[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:36]1
Reactant: CN(c1cccc2cc(C3=NCC(C)(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(C)(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 69 %

Procedure:
A mixture of N-[2-(5-cyano-5-methyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.15 g), 2N aqueous sodium hydroxide solution (0.36 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was heated under reflux for 4 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.11 g, yield 69%) as yellow crystals from a fraction eluted with tetrahydrofuran. melting point >232° C. (decomposition).
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[C:13]([CH:14]=O)=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[C:6](=[O:16])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2[nH]c1=O
Temperature: 23 °C

Procedure:
A solution of 5-2 (1.53 g, 6.88 mmol, 1 equiv), diethyl malonate (2.09 mL, 13.8 mmol, 2.00 equiv), and piperidine (0.340 mL, 3.44 mmol, 0.500 equiv) in ethanol (20 mL) was heated at reflux for 16 h. The reaction mixture was allowed to cool to 23° C. The white crystals which formed were filtered and washed with ethanol (20 mL) to give 2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (5-3). 1H NMR (400 MHz, CDCl3) δ 11.9 (br s, 1H), 8.85 (dd, 1H, J=4.8, 1.7 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J=7.9, 1.6 Hz), 7.27 (dd, 1H, J=7.9, 4.8 Hz), 4.45 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz).