Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1OC1C>C(COC)OC>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]3[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=3)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc2ccc(N)nc2c1
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(ccc3ccc(OC)cc32)n1
Reaction time: 16 h

Procedure:
50 ml of 2-amino-7-methoxyquinoline [C.A., Vol. 79, p. 92024t] were dissolved in 50 ml of dimethoxyethane and then a mixture of 3 g of ethyl bromopyruvate and 1 g of propylene oxide in 5 ml of dimethoxyethane was added thereto. The mixture was allowed to stand at 5° C. for 16 hours and the intermediate quaternary salt thus precipitated was filtered off, washed with diethyl ether and then was dissolved in 50 ml of ethanol. The solution was refluxed for 1 hour and then was reduced in volume under vacuum. Diethyl ether was subsequently added thereto to precipitate ethyl 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate hydrobromide which was filtered off and was washed with diethyl ether. The hydrobromide was partitioned between 50 ml of dilute sodium carbonate solution and 100 ml of chloroform and the organic solution was separated, washed with 50 ml of water, was dried over MgSO4 and was evaporated to dryness under reduced pressure. The residue was crystallized from diethyl ether to obtain buff crystals of ethyl 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 146°-148° C.
Reaction SMILES: [F:1][CH:2]([F:16])[S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(O)(=[O:19])C.OO.[OH2:23]>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:16][CH:2]([F:1])[S:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:19])=[O:23]
Reactant: FC(F)Sc1ccc(-c2ccccc2)cc1
Reactant: O
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: O=S(=O)(c1ccc(-c2ccccc2)cc1)C(F)F
Temperature: 60 °C

Procedure:
To a 1-L three-necked flask equipped with an overhead stirrer, thermometer, and vented addition funnel was charged 71.8 g (0.304 mol) of 4-[(difluoromethyl)thio]-1,1'-biphenyl, 280 mL of glacial acetic acid, and 3.0 g of sodium tungstate predissolved in 10 mL of water. The mixture was heated to 60° C., heating was removed, and 90 mL (0.87 mol, 2.9 equiv) of 30% hydrogen peroxide was added dropwise, maintaining the temperature at 60-70° C. After the addition was complete, the mixture was heated at 80° C. for 2 h to finish the conversion. The solution was cooled to 25° C. and 140 mL of water was added gradually to complete precipitation of the product. The product was filtered, washed with three 50-mL portions of water, suction-dried, then washed with 150 mL of isopropanol, suction-dried, and oven-dried at 50° C./150 mm to afford 78 g (96%) of ca. 98%-pure 4-[(difluoromethyl)sulfonyl]-1,1'-biphenyl, m.p. 81-83° C. An analytical sample prepared by recrystallization from isopropanol/water had m.p. 83-85° C. IR(KBr): 1593, 1334, 1159, 1113, 1080, 754, 607 cm-1. 1H-NMR(CDCl3): δ6.22 (t, 1H, J=60 Hz), 7.5 (m, 3H), 7.62 (dd, 2H, 7.82 (d, 2H), 8.05 (d, 2H). 13C-NMR (CDCl3): δ114.7 (t, JCF =286 Hz), 127.4, 128.1, 129.1, 129.2, 130.1, 131.1, 138.6, 148.8 ppm. 19F-NMR (CDCl3): δ-120.5 (d, JHF =53.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].C(O)(=O)C.[C-:15]#[N:16].[K+].ClCCl>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[C:15]#[N:16]
Reactant: [C-]#N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CC(O)c1c(Cl)cccc1Cl

Procedure:
To a stirred and cooled (15° C.) solution of 350 parts of 2,6-dichlorobenzaldehyde and 1600 parts of acetic acid was added dropwise a solution of 162.8 parts of potassium cyanide in water during 30 minutes at 15°-20° C. After stirring for 16 hours at 20° C., 1300 parts of dichloromethane and 1000 parts of water were added. The separated aqueous layer was washed three times with dichloromethane. The combined organic layers were washed with water, dried, filtered and evaporated at 40° C., yielding 396 parts of 2,6-dichloro-α-hydroxybenzeneacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][NH:25][CH:26]3[CH3:31])=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[CH:30][C:21]=4[C:20]4[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:26]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3cccnc3F)cccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cccc(-c3cccnc3F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)C.[Na].O.Cl>C(O)C>[CH2:17]([O:16][C:14]([C:13]1[NH:12][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:4]=1[OH:3])=[O:15])[CH3:18]
Reactant: CCOC(=O)CNC1=C(C(=O)OCC)CCCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2c(c1O)CCCC2
Reaction time: 3 h

Procedure:
294 g of 2-(ethoxycarbonylmethylamino)-cyclohexene-1-carboxylic acid ethyl ester in 400 ml of ethanol are added dropwise, under nitrogen, to a well-stirred solution of 35 g of sodium in 1.5 liters of ethanol. After the solution has boiled for three hours, it is cooled and 600 ml of water are then added, followed by 150 ml of concentrated hydrochloric acid. After the batch has stood for six hours at -10° C., 142 g of 3-hydroxy-4,5,6,7-tetrahydroindole-2-carboxylic acid ethyl ester, of melting point 94°-95° C., are filtered off.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH3:11])[N:4]=[C:3]([N:2]([CH3:1])[C:21]([NH:20][S:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)(=[O:18])=[O:19])=[O:22])[N:8]=1
Reactant: O=C=NS(=O)(=O)c1cccs1
Reactant: CNc1nc(C)cc(OC)n1
Solvent: CC#N
Product: COc1cc(C)nc(N(C)C(=O)NS(=O)(=O)c2cccs2)n1

Procedure:
To a mixture, 1.5 g of 2-methylamino-4-methoxy-6-methylpyrimidine in 50 ml of acetonitrile is added 1.9 g of 2-thiophenesulfonyl isocyanate. Filtration affords N-[N-(4-methoxy-6-methylpyrimidin-2-yl)-N-methylaminocarbonyl]-2-thiophene sulfonamide.
Reaction SMILES: [Si:1]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19]Cl)=[O:16])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[C:21]([O-])(=[S:23])C.[K+]>C(O)C>[Si:1]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][S:23][CH3:21])=[O:16])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCO[Si](CCCNC(=O)NCCCl)(OCC)OCC
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NCCSC)(OCC)OCC
Temperature: 25 °C
Yield: 96.5 %

Procedure:
(EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—Cl (81.52 g, 0.25 mol, 1.00 eq) is initially charged in ethanol (85 ml) in a 500 ml three-neck flask with stirrer, reflux condenser and internal thermometer. Potassium thioacetate (28.48 g, 0.25 mol, 1.00 eq) is added and the mixture is heated to reflux. After a reaction time of 3.5 h, the mixture is cooled to room temperature and the suspension is filtered. The filtrate is freed of the solvent on a rotary evaporator and dried under reduced pressure. The (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—S—CH3 product (81.64 g, 89% of theory) is obtained as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.S(Cl)(Cl)=O.Cl.CN.C[CH2:19][N:20](C(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:20][CH3:19])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
5-Bromo-pyridine-2-carboxylic acid (2.59 g, 12.8 mmol) and thionylchloride (2.79 ml) were heated at reflux in toluene (25 ml) for 16 hours. Excess reagents were removed in vacuo and the residue was diluted in dichloromethane (50 ml). A mixture of methyl amine hydrochloride (2.60 g, 38.5 mmol) and DIPEA (6.7 ml, 38.5 mmol) in dichloromethane (10 ml) was added dropwise to the stirred solution and the resulting mixture was maintained at room temperature for 5 hours. The solution was washed with saturated aqueous NaHCO3 (25 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting brown solid was recrystallised (Heptane/EtOAc) to provide the title compound as off-white needles (1.74 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32]([OH:34])=[O:33]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:31][CH2:30][CH2:29][CH:28]2[C:32]([OH:34])=[O:33])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CCCN1
Product: CCOC(=O)C1=C(CN2CCCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 25.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with pyrrolidine-2-carboxylic acid (0.23 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.27 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].S(Cl)(Cl)=O.[CH2:31](O)[C:32]#[CH:33].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:33][C:32]#[CH:31])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C#CCOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To P-ethyl-2-nitro-5-(2-chloro-4-trifluoro-methylphenoxy)phenylphosphinic acid chloride, prepared from P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)-phenylphosphinic acid (500 mg, 1.22 mmol) and thionyl chloride (3 ml) by the procedure of Example 25, in methylene chloride (3 ml) is added propargyl alcohol (3 ml) and triethyl amine (0.2 ml). The mixture is stirred at RT for 4 hours, after which the reaction is taken up in methylene chloride, washed, dried and evaporated. The crude product is purified by prep. TLC to give propargyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate, m/s 447 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][C:13]([CH3:15])=O.C[Si]([C:20]#[N:21])(C)C>C(#N)C.[Cl-].[Zn+2].[Cl-]>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:13]([CH3:15])([CH3:12])[C:20]#[N:21])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)=O
Reactant: Nc1cccc2cnccc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(C)(C#N)Nc1cccc2cnccc12
Yield: 81.8 %

Procedure:
5.0 g (34.7 mmol) of 5-aminoisoquinolin, 5.1 ml (69.4 mmol) of acetone and 945 mg (6.94 mmol) of zinc chloride were dissolved in 100 ml of acetonitrile and treated at 0° C. with 6.9 g (69.4 mmol) of trimethylsilyl cyanide. The mixture was refluxed for 3 hours, the solvent was then evaporated off and the residue was taken up in 200 ml of sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined organic phases were dried and the residue remaining after evaporation was purified by flash chromatography (SiO2, methylene chloride/methanol=95/5) to give 6.0 g (82%) of the desired product.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C=O>[C:34]([NH:1][C@H:2]([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])(=[O:36])[CH3:35]
Reactant: NC(=O)CC[C@H](N)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](CCC(N)=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 80.7 %

Procedure:
A solution of 30.6 g (83 m mol) of 6-[4-(L-glutaminylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid, 56 ml (0.4 mol) of triethylamine, 19 ml (0.2 mol) of acetic anhydride, and 400 ml dimethylformamide is stirred at room temperature for 3 hrs. The reaction solution is evaporated to dryness under reduced pressure and the residue treated with ice and water. The solid is filtered, washed with water, methanol, ether and dried to give 27.6 g of 6-[4-(N-acetyl-L-glutaminylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; [α]D23 +19° (cl, DMSO). ##EQU45##
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH3:33])=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:38]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@H:21]([C:31]([OH:38])=[O:32])[C:20]([CH3:33])=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3,4-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 193, 1.68 g, 3.38 mmol) following the procedure described for Intermediate 19. The workup yielded organics that were dried over magnesium sulfate, filtered and concentrated crude material to afford a light orange foam (1.48 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].[CH:29]12[O:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][NH:31][CH2:30]2>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:20]([N:31]3[CH2:30][CH:29]4[O:36][CH:33]([CH2:34][CH2:35]4)[CH2:32]3)=[O:21])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: C1CC2CNCC1O2
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)Oc1ccccc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CC4CCC(C3)O4)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and 8-oxa-3-aza-bicyclo[3.2.1]octane, the title compound was prepared as white crystals (67% yield), mp 229-231° C. MS: m/e=405(M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH:2]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CCC(N)c2cccnc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To 10 ml of the solution of 0.35 g of methyl 4-[3-amino-3-(3-pyridyl)propyl]benzoate in dichloromethane were added 0.22 ml of triethylamine and 0.33 g of p-chlorobenzene sulfonylchloride, and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water, which was then extracted with dichloromethane, washed in saturated aqueous sodium chloride, and dried over magnesium sulfate. The residue was subjected to chromatography on a silica gel column, to obtain 0.34 g of methyl 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]benzoate. The spectrometric data supports the structure of [36] as follows.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[S:20][C:21]([CH:25]=[O:26])=[C:22]([Cl:24])[N:23]=1>O1CCCC1>[Cl:24][C:22]1[N:23]=[C:19]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[S:20][C:21]=1[CH:25]=[O:26]
Reactant: NCc1ccncc1
Reactant: O=Cc1sc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1sc(NCc2ccncc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(aminomethyl)pyridine (516, 1.16 mL, 11.5 mmol) and N,N-diisopropylethylamine (3.8 mL, 22 mmol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 2.0 g, 11.0 mmol) in tetrahydrofuran (5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The crude compound 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517) was used for the next step without purification.
Reaction SMILES: C(OC(N1C[CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CC[CH:34]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH2:33]C1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:34]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH2:33][CH2:12]3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: CC(=O)NCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: CC(=O)NCC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 279 is synthesized from Intermediate C and N-piperidin-4-ylmethyl-acetamide according to General Method H. (LC/MS method 16: ES+ m/z 382.4 [M+H]+, Rt=2.50 min)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31][C:32]([F:42])([F:41])C1C=CC=CC=1C=O>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C:32]([F:42])([F:41])[F:31])[CH2:17][C:16]2=[O:18]
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccccc2C(F)(F)F)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(2-trifluoromethylphenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 3.0 ml of 2-trifluoromethylbenzaldehyde. The product was triturated from ethanol. 1H NMR (300 MHz, d6-DMSO) δ: 9.48 (s, 1H), 8.07 (m, 1H), 7.86-7.79 (m, 2H), 7.66 (m, 1H), 7.15 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.95 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 13.8, 2.4 Hz), 3.38 (dd, 1H, J −16.9, 13.8 Hz), 2.66 (dd, 1H, J −16.9, 3.0 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>O.CCOC(C)=O>[Cl:34][C:33]([Cl:36])([Cl:35])[CH2:32][O:31][C:29](=[O:30])[NH:10][C:8]1[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:15]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
To a stirred mixture of Intermediate 113b (1.14 g, 3.28 mmol) in water (6 mL) and EtOAc (12 mL) was added NaOH (263 mg, 6.57 mmol). After 10 min, 2,2,2-trichloroethyl chloroformate (543 μL, 3.94 mmol) was added and the reaction mixture was stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to afford the title compound (1.57 g, 91%). LCMS (Method 4): Rt 3.99 min, m/z 522, 524 [MH+].
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C@H:5]([CH3:26])[CH2:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]([CH3:19])[C:10]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:8].O.[OH-].[Li+]>C(O)(C)C.O>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:9]2[C:7](=[O:8])[CH2:6][C@@H:5]([CH3:26])[CH2:4][C:3]([OH:27])=[O:2]
Reactant: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)OC)c2cc(Cl)ccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)O)c2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of Methyl-5-(5-chloro-2-hexyl-1-methyl-1H-indol-3-yl)-3-(R)-methyl-5-oxopentanoate in iso-propanol and water was added lithium hydroxide monohydrate and was stirred at RT for three hours. The product was purified by column chromatography.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:6]([C:8](OC)=[O:9])[CH2:5]1)#[N:2].O1CCCC1.[BH4-].[Li+]>CO>[OH:9][CH2:8][CH:6]1[CH2:7][C:4]([CH2:3][C:1]#[N:2])([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:5]1
Reactant: COC(=O)C1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
To a mixture of methyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarboxylate (7.0 g, 0.015 mol) in tetrahydrofuran (100 mL, 1 mol) was added lithium tetrahydroborate (0.327 g, 0.0150 mol) at 0° C. The reaction was then heated at 50° C. for 3 h. To the reaction was added 60 mL of methanol. The resulting mixture was heated at 50° C. for another 15 min, then evaporated to dryness. The residue was treated with 1 N HCl, then neutralized with solid sodium bicarbonate, extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 100% EtOAc, to give the desired product as cis- and trans-mixture (5.85 g, 88.91%). LCMS calculated for C22H31N6O2Si(M+H)+: 439.2; Found: 439.4.