Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.[H-].[Na+].FC(F)(F)C([O-])=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:23][CH:22]([C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[OH:24])[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 14.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 6. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 4-methylstyrene oxide (1 mL, 7.5 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 mL) at 120° C. for 16 h (overnight) to obtain 50 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([OH:30])[CH:15]2[O:29][C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][C:26]=4[C:17]=3[CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[OH:30][CH:14]([CH:15]1[O:29][C:18]2[CH:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][C:26]=3[C:17]=2[CH2:16]1)[C@H:11]1[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:40]2[CH:41]=[CH:42][C:36]3[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=3[CH:39]=2)=[O:31])[CH2:9][CH2:10]1
Reactant: COc1ccc2ncc3c(c2c1)CC(C(O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)O3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1)CC(C(O)[C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)O3

Procedure:
The titled compound is prepared as a white lyophilized powder following Scheme 5 and in analogy to Example 1 using {trans-4-[hydroxy-(8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-yl)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1>>[CH3:28][S:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:22][CH:23]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: CSc1ccc(Br)cc1
Product: CSc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)cc1
Yield: 40.8 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (130 mg, 0.50 mmol) synthesized in Reference example 56 and 4-bromothioanisole (203 mg, 1.0 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 78 mg (yield 41%).
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:29])[C:5](=[O:28])[NH:6]2.N(OCCC(C)C)=O.[I:38]CI>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([N:4]([CH3:29])[C:5](=[O:28])[NH:6]3)=[C:2]([I:38])[N:10]=2)=[N:12]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Reactant: ICI
Agent: CC(C)CCON=O
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Temperature: 85 °C

Procedure:
1.725 g (3.358 mmol) of the compound from example 41 were dissolved in 7 ml of diiodomethane and admixed with 7.19 ml (53.732 mmol) of isopentyl nitrite. The reaction mixture was heated to 85° C. for 16 h and, after cooling, concentrated on a rotary evaporator. The residue was by means of preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, gradient 55:40:5→0:95:5). 64 mg of the title compound were obtained (4% of theory).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19](Cl)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCC1CCNCC1

Procedure:
In 20 ml of ethanol is dissolved 10.5 g of ethyl 4-(1-benzyloxycarbonyl -4-piperidyl)-2-chlorobutyrate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmosphereic pressure using 5 g of 10% palladium-carbon (50% in water ) as a catalyst. After absorption of hydrogen stops, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give ethyl 4-(4-piperidyl)butyrate. This product is dissolved in a mixture of 200 ml of ethyl acetate and 100 ml of water, 6 g of sodium hydrogencarbonate is added to the solution, followed by stirring at room temperature. Benzyloxycarbonyl chloride (6 ml) is added dropwise to the mixture, and after the addition is completed, the mixture is stirred at room temperature for 1.5 hours. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica-gel column chromatography (hexane:ethyl acetate=3:1) to give 5.3 g of ethyl 4-(1-benzyloxycarbonyl-4 -piperidyl)butyrate as a colorless oily material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:15]1[C:16]2[C:12](=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)[CH3:28]
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ccc23)nc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
4-(5-Nitropyridin-2-yloxy)-1H-indole (3.34 g, 13.1 mmol) was dissolved in DMF (20 mL). To the solution were added 60% sodium hydride (0.523 g, 13.1 mmol) and ethyl bromoacetate (1.45 mL, 13.1 mmol) under cooling with ice, and the resulting solution was stirred for 1 hour. Ice water (150 mL) was added to the solution, and the mixture was extracted with ethyl acetate (150 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. Thus obtained residue was purified by silica gel column chromatography (AcOEt:n-hexane=1:3), and then the obtained solid was recrystallized from ethyl acetate and n-hexane to yield 1.84 g of the title compound as a yellow powder.
Reaction SMILES: P([O-])([O-])([S-])=[S:2].[C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])#[N:7]>C(OCC)(=O)C.Cl>[C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[S:2])[NH2:7]
Reactant: COC(=O)c1cccc(OCC#N)c1
Reactant: [O-]P([O-])(=S)[S-]
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OCC(N)=S)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
4 N Hydrogen chloride-ethyl acetate solution (50 ml) and dithiophosphate=O,O-diethyl (4.47 ml, 26.67 mmol) were added in that order to methyl 3-cyanomethoxybenzoate (5.00 g, 26.15 mmol), and the resulting solution was stirred at room temperature for 12 hours. Crystals precipitated in the reaction solution were collected by filtration and washed with diethyl ether to give methyl 3-thiocarbamoylmethoxybenzoate (4.60 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH3:26][C:27]1[C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][C:32]([C:31]2[C:27]([CH3:26])=[N:28][O:29][C:30]=2[CH3:35])=[O:33])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: Cc1noc(C)c1C(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1c(C)noc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.9 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of 3,5-dimethyl-isoxazole-4-carbonyl chloride (43 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 12.4 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH:10]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C@H:5]([N:7]=[N+:8]=[N-:9])[CH3:6].C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>Cl>[ClH:39].[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH2:10])[C@H:5]([N:7]=[N+:8]=[N-:9])[CH3:6]
Reactant: ClCCl
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)N=[N+]=[N-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)[C@@H](C)N=[N+]=[N-]
Reaction time: 2.5 h
Yield: 97 %

Procedure:
A solution of Trt-Azido-Thr-OMe (3) (4.8 g, 12.0 mmol) was dissolved in a 95% TFA/DCM solution (60 ml) at rt with stirring. After 2.5 h, the reaction was complete by LCMS. The bright yellow solution was diluted with 0.5 N aq. HCl (300 ml). The aqueous layer was extracted with DCM (2×30 ml) and then lyophilized to dryness. The white solid was dissolved in AcCN/water (50:50) (100 ml) and again lyophilized to dryness to produce a consistent powder and remove as much of the TFA as possible. The azido-Thr product (4), 2.26 g (97% yield, 95% pure) of a white solid, was obtained as the HCl salt.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1cc(Cl)ccc1C#C[Si](C)(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 102.9 %

Procedure:
To a solution of methyl 2-bromo-5-chlorobenzoate (14.8 g, 59 mmol) in TEA (124 ml, 889.82 mmol) was added copper(I) iodide (338 mg, 1.78 mmol) and triphenylphosphine (778 mg, 2.97 mmol) at room temperature and under nitrogen. This mixture had nitrogen bubbled through it for 10 minutes before the addition of ethynyl(trimethyl)silane (12.45 ml, 89 mmol) and Pd(OAc)2 (266 mg, 1.19 mmol). The reaction mixture was stirred at 50° C. for 20 hours before being concentrated under reduced pressure. The residue was dissolved in deionized water (50 ml) and EtOAc (50 ml) and filtered through Celite. The filter cake was washed with EtOAc (50 ml) before the phases were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 16.2 g (102.4%) of methyl 5-chloro-2-[2-(trimethylsilyl)ethynyl]benzoate as an orange oil that solidified upon standing. Sample contained heptane. LC-MS 91%, 2.57 min (3 minute LC-MS method), m/z=267.4/268.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.89 (d, J=2.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.41 (dd, J=8.3, 2.3 Hz, 1H), 3.92 (s, 3H), 0.27 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:16]1[CH:17]=[CH:18][C:19]2[N:11]3[CH2:10][CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[C:12]3=[CH:13][C:14]=2[N:15]=1
Reactant: COc1ccc2c(ccn2CCCc2ccccc2Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(cc3n2CCCc2ccccc2-3)n1

Procedure:
Under an inert atmosphere, 500 mg (1.45 mmol) of the compound obtained in Step A, 81 mg (72.5 μmol) of tetrakis(triphenylphosphine)palladium(0) and 142 mg (1.45 mmol) of potassium acetate in 15 ml of N,N-dimethylacetamide are heated at 160° C. for 2 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 9:1) to yield the title compound in the form of a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCN(C)C)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][C:19]=2[CH:18]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OCCN3CCOCC3)ccc2s1
Agent: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: Nc1ccccc1NC(=O)c1cc2cc(OCCN3CCOCC3)ccc2s1

Procedure:
was prepared from (2-{[5-(2-Morpholin-4-yl-ethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (11) in an analogous manner to that described for the preparation of (1) example 1, step 5; white solid, mp. 166–169° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30][C:31]([F:35])([F:34])[CH2:32]I.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:28][CH:29]=3)=[N:9][N:10]([CH2:32][C:31]([F:35])([F:34])[F:30])[CH:11]=2)=[CH:5][CH:6]=1
Reactant: FC(F)(F)CI
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(4-Pyridin4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (26.5 g) in dimethyl formamide (140 mL) was added 1,1,1-Trifluoro-2-iodo-ethane (21 mL, 2.0 eq.) and cesium carbonate (68.3 g, 3 eq.) and the reaction mixture heated at 60° C. for 24 h. The reaction mixture was diluted with water, extracted 3× methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via flash chromatography eluting with 5% methanol/70% ethyl acetate/hexanes provided the title compound 20.85 g as an 8:1 regioisomeric mixture. Preparative HPLC eluting with acetonitile/methanol (98:2) on a chiralpak AD column with a flow rate of 430 ml/Min provided the pure title compound as a free base 13.4 g. 1H NMR (400 MHz, CDCl3) δ 8.45 (m, 2 H), 8.16 (d, J=8.3 Hz, 1 H), 8.04 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.3 Hz, 1 H), 7.69 (m, 1 H), 7.64 (d, J=8.3 Hz, 1 H), 7.50 (m, 1H), 7.36 (d, J=8.7 Hz, 2 H), 7.14 (d, J=6.2 Hz, 2H), 6.98 (d, J=9.1 Hz, 2 H), 5.35 (s, 2H), 4.75 (q, J=8.3 Hz, 2 H); MS: (M+H m/z=427.1).MS: (M+H m/z=461.2).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8](=[O:11])[CH2:9][CH3:10])[N:6]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:8]([NH:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCC(=O)Nc1csc(Br)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)Nc1cscn1
Yield: 17.9 %

Procedure:
A solution of 2-bromo-4-propionamidothiazole (4g) and sodium acetate (1.4g) in methanol (100 ml.) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst (1.0g) until the theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the extracts evaporated in vacuo. The residue was recrystallised twice from carbon tetrachloride to give the title compound (1.9g) m.p. 129°-32° C. (Found: C, 46.3; H, 5.2; N, 17.7. C6H8N2OS requires C, 46.1; H, 5.2; N, 17.9%).
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH:23](C(OC)=O)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CC(C)([O-])C.[K+].Cl.CN([CH:44]=[O:45])C>C1COCC1>[CH2:1]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:20]([O:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:44]=2[OH:45])=[O:21])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1ccc(CC(=O)OC(C(=O)OC)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCOc1ccc(C2=C(O)C(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
In a mixture of THF (10 ml) and DMF (1 ml) was dissolved methoxycarbonylphenylmethyl 4-undecyloxyphenylacetate (1.4 g, 3 mmol.). To the solution was added at room temperature potassium tertiary butoxide (1.5 g, 0.012 mol.) The mixture was stirred at room temperature for one hour, to which was added 2N HCl (30 ml), followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure Resultant crude crystals were recrystallized from IPE-ethyl acetate to give 2-(4-undecyloxyphenyl)-3-hydroxy-4-phenyl-2-buten-4-olide (4-g, 0.9 g, 69%). Physico-chemical properties and NMR spectrum of this compound are shown in Table 7.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:38]([O:44][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCO
Product: CCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with hexanol, mp 66°-68° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[OH:29][C@H:24]1[C@H:25]([O:27][CH3:28])[CH2:26][N:22]([C:3]2[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C[C@H]1O
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C[C@H]1O

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using 5-bromo-6-(trans-3-hydroxy-4-methoxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 72.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.16 min, m/z=476.0 [M+H]+, m/z=474.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.95 (d, J=11.25 Hz, 1H) 3.14 (d, J=11.98 Hz, 1H) 3.23 (s, 3H) 3.28-3.35 (m, 1H) 3.46 (dd, J=11.98, 4.40 Hz, 1H) 3.61-3.65 (m, 1H) 4.08 (br. s, 1H) 5.19 (d, J=3.67 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.85 (d, 2H) 8.12 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.89 (s, 2H) 9.21 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(O)C.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=1>O>[Cl:13][C:14]1[CH:19]=[C:18]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)[N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=1
Reactant: OCCN1CCNCC1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: O
Solvent: CCO
Product: OCCN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reaction time: 8 h

Procedure:
N-hydroxyethylpiperazine (7.81 g.) diluted with 20 ml. of absolute ethanol is added to a slurry obtained by adding 6.75 g. of 4,6-dichloro-2-phenylpyrimidine to 25 ml. of absolute ethanol. The resulting mixture is refluxed for fifteen minutes, then poured into 850 ml. of water. A gummy material which separates solidifies on standing overnight. The crude product weighs 7.8 g. which is recrystallized from n-heptane to afford 4-(4-chloro-2-phenylpyrimidin-6-yl)-1-piperazineethanol, m.p. 103°-105°C.
Reaction SMILES: [OH-].[Na+].[Na].[CH3:4][SH:5].CS.[Na].[C:9]1([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:9]1([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:5][CH3:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS
Reactant: O=C(Nc1ccccc1)c1ccccc1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CSc1ccccc1C(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and acondenser, 46.3 g (0.2 mol) of N-phenyl-2-chlorobenzamide obtained in Production Example 1, 100 g of toluene, and 9.3 g of an aqueous solution of 50% by weight tetra-n-butylammonium bromide are placed. Separately, 12.0 g (0.30 mol) of sodium hydroxide and 113.7 g of water are placed intoanother container under a nitrogen gas atmosphere, and 14.5 g (0.30 mol) ofmethanethiol are added to the above mixture at room temperature over about 1 hour to prepare 140.2 g of sodium salt solution of methanethiol. 140.2 g(0.3 mol) of the aqueous solution of sodium methyl mercaptan thus prepared is added to the mixture containing N-phenyl-2-chlorobenzamide described above at 80° C. while stirring, to be allowed to react with each other under reflux for 1 hour. After completion of the reaction, the reaction mixture is cooled to room temperature to precipitate white crystals, which are washed with water and then with toluene and dried, to give 46.2 g of N-phenyl-2-(methylthio)benzamide (melting point 148°to 149° C.). The yield of the product against N-phenyl-2-chlorobenzamide is 95%.