Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18]([N:1]2[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]2)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: O[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@H](O)C2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.6 %

Procedure:
(S)-Pyrrolidin-3-ol (0.276 g, 3.17 mmol) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 2.11 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.61 g, 3.17 mmol) in dichloromethane (7 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 48 h. The mixture was diluted with DCM (10 mL) and washed with water (1×15 mL), 10% aqueous citric acid solution (2×15 mL) and brine (2×15 mL), and dried over sodium sulphate. The solvents were reduced in vacuo to afford the title compound as colourless oil (0.46 g, 81%). 1H NMR (400 MHz, CDCl3): δ 4.55-4.48 (1 H, m), 4.17 (2 H, s), 4.05-4.04 (2 H, m), 3.50-3.47 (5 H, m), 2.01-2.00 (2 H, m), 1.43 (9 H, d, J=0.96 Hz).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][SiH:21](Cl)[CH2:20][CH2:19]2)=[CH:12][C:11]=1[F:25]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]2[CH2:23][CH2:22][Si@H:21]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:20][CH2:19]2)=[CH:12][C:11]=1[F:25]
Reactant: CCCCCCCBr
Reactant: Fc1cc(OCC2CC[SiH](Cl)CC2)ccc1Cl
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(Cl)c(F)c2)CC1

Procedure:
The general procedure of Example 1 was repeated using n-heptyl bromide and 4-(4-chloro-3-fluorophenyloxymethyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Clc1nccc2cnccc12
Reactant: C1COCCN1
Product: c1cc2c(N3CCOCC3)nccc2cn1

Procedure:
To 1-chloro-2,6-naphthyridine (164.3 mg, 0.998 mmol) (prepared as described in Van den Haak et al, J. Org. Chem 1982, 47 (9), 1673-7) was added morpholine (15 mL) and the mixture was heated at reflux for 4 h. Removal of the volatile components gave 216.6 mg of 1-morpholin-4-yl-[2,6]naphthyridine as a beige solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[CH:10]([CH3:12])[CH3:11].[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[CH:10]([CH3:12])[CH3:11])[CH3:14]
Reactant: Cc1nc(O)c(C(C)C)c(Cl)n1
Reactant: CCN
Product: CCNc1nc(C)nc(O)c1C(C)C
Temperature: 90 °C

Procedure:
A mixture of 3.00 g (16.1 mmol) of 6-Chloro-2-methyl-5-(1-methylethyl)-4-pyrimidinol and 10.4 mL (7.24 g, 161 mmol, 10 equiv.) of ethylamine as a 70% w/w aqueous solution was sealed in a glass flask, heated at 90° C. for 5 days, and then cooled to 23° C. The mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 50 mm column, 500 mL 4:1 EtOAc:hexane then EtOAc as eluent, mixed fractions rechromatographed) to provide 1.32 g (7.01 mmol, 44%) of recovered starting material and, after recrystallization from EtOAc, 1.70 g (8.70 mmol, 54%) of analytically pure product as a dense white crystalline solid, m.p. 179.5°-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:21]=[C:20]([CH:34]2[CH2:37][CH2:36][CH2:35]2)[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([C:18]1[N:19]=[C:20]([CH:34]2[CH2:35][CH2:36][CH2:37]2)[CH:21]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[CH2:26][CH2:25]2)[N:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: Oc1ccncn1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3ccncn3)CC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
0.2 g of 4-hydroxy-pyrimidine (2.08 mmol) were dissolved in 15 ml of dimethylformamide. After addition of 0.58 g of potassium carbonate (4.16 mmol) and 0.73 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (2.08 mmol), the mixture was stirred at 90° C. for 3 h. The dimethylformamide was removed under reduced pressure and the resulting residue was partitioned between 40 ml of ethyl acetate and 20 ml of water. The aqueous phase was re-extracted with ethyl acetate, the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel with ethyl acetate-methanol (2-10%). Fractions containing the product were combined. The solvent was evaporated. The product crystallized upon standing (yield: 0.2 g).
Reaction SMILES: C(OC(N[C@H](C(O)=O)C(C)(C)C)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[CH:33]1([CH2:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:74][C:75]([C:77]1([NH:82][C:83]([CH:85]2[CH2:89][CH:88]([O:90][C:91]3[C:100]4[C:95](=[CH:96][C:97]([O:101][CH3:102])=[CH:98][CH:99]=4)[N:94]=[C:93]([C:103]4[CH:108]=[CH:107][CH:106]=[CH:105][CH:104]=4)[CH:92]=3)[CH2:87][N:86]2[C:109](=[O:129])[NH:110][CH:111]([C:116](=[O:128])NC2C3C(=CC=CC=3)CC2O)[C:112]([CH3:115])([CH3:114])[CH3:113])=[O:84])[CH2:79][CH:78]1[CH:80]=[CH2:81])=[O:76])C>>[CH:33]1([CH2:39][NH:40][C:116]([C@@H:111]([NH:110][C:109]([N:86]2[CH2:87][C@H:88]([O:90][C:91]3[C:100]4[C:95](=[CH:96][C:97]([O:101][CH3:102])=[CH:98][CH:99]=4)[N:94]=[C:93]([C:103]4[CH:108]=[CH:107][CH:106]=[CH:105][CH:104]=4)[CH:92]=3)[CH2:89][C@H:85]2[C:83]([NH:82][C@:77]2([C:75]([OH:76])=[O:74])[CH2:79][C@H:78]2[CH:80]=[CH2:81])=[O:84])=[O:129])[C:112]([CH3:115])([CH3:114])[CH3:113])=[O:128])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: NCC1CCCCC1
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)NCC1CCCCC1)C(C)(C)C)C(=O)O

Procedure:
N-(tert-butoxycarbonyl)-L-tert-butylglycine was attached to the resin as described for the preparation of compound 16 followed by reaction with cyclohexanemethylamine as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC>95%. M+H+726.3.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CN(C=O)C.[H-].[Na+].Br[CH2:17][CH:18]([CH3:20])[CH3:19]>CCOC(C)=O>[CH2:17]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with resorcinol (20.0 g, 182 mmol) and DMF (400 mL). To the resultant solution was added NaH (4.82 g, 200 mmol) in two portions, 10 min apart. The mixture stirred at rt 30 min. 1-Bromo-2-methylpropane (37.4 g, 273 mmol) was then added, and the mixture was heated at 80° C. overnight. The mixture was cooled, diluted with EtOAc (300 mL), and washed with H2O (2×250 mL). The aqueous phases were back-extracted with EtOAc (2×100 mL). The combined organic phases were then diluted with hexanes (500 mL) and washed with half-saturated aqueous NaHCO3 (6×200 mL). The solution was filtered through phase separation paper and concentrated in vacuo to give 13.4 g of 71 as a yellow oil containing 27% dialkylated material as determined by HPLC. The substance was carried on as is. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 68% with a retention time of 3.9 min and 27% dialkylated material with a retention time of 12.0 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[S:11][C:12]([Br:21])=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1.[Br-].[Br-].[Br-].[In+3]>C1(C)C=CC=CC=1>[Br:21][C:12]1[S:11][C:10]([C:8]([C:6]2[CH:7]=[C:2]3[C:3]([CH:22]=[C:23]([C:24]4[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:29])=[CH:38][CH:39]=4)[NH:1]3)=[CH:4][CH:5]=2)=[O:9])=[CH:14][C:13]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c(N)c2)sc1Br
Agent: [Br-]
Agent: [In+3]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)[nH]c3c2)sc1Br
Yield: 74.2 %

Procedure:
To a 25 mL flask containing freshly distilled toluene (10 mL) was added benzyl 4-((2-amino-4-(5-bromo-4-(2-ethoxy-2-oxoethyl)thiophene-2-carbonyl)phenyl)ethynyl)benzoate (100 mg, 0.17 mmol) and indium tribromide (24 mg, 0.06 mmol) under N2. The resulting mixture was refluxed for one hour. The solvent was removed in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave 4 as a yellow solid (76 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 9.50 (brs, 1H), 8.16 (d, J=8.0 Hz, 2H), 8.02 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.65 (q, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.48-7.34 (m, 5H), 6.98 (s, 1H), 5.39 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.64 (s, 2H), and 1.28 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.53, 170.09, 166.24, 143.98, 140.75, 136.91, 136.16, 136.07, 135.92, 135.09, 132.96, 131.53, 130.74, 129.74, 128.90, 128.59, 128.53, 125.56, 122.10, 121.94, 120.81, 113.74, 101.86, 67.14, 61.66, 35.37, and 14.43.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([Cl:21])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:22].[Na+]>CC(C)=O>[I:22][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([Cl:21])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [I-]
Reactant: CCOC(=O)C(Br)Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 37.3 g. (0.1 moles) of ethyl α-bromo-β-(3-chloro-4-cyclohexylphenyl)propionate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-β-(3-chloro-4-cyclohexylphenyl)propionate.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>[Cu]I.C(Cl)Cl.O>[F:10][C:11]1[CH:24]=[C:23]([N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]2=[O:9])[CH:22]=[CH:21][C:12]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1
Reactant: CN1CCN(Cc2ccc(I)cc2F)CC1
Reactant: Cc1c[nH]c(=O)c(C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(=O)n(-c2ccc(CN3CCN(C)CC3)c(F)c2)c1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A mixture of 3,5-dimethylpyridin-2(1H)-one (0.07 g, 0.57 mmol), 1-(2-fluoro-4-iodobenzyl)-4-methylpiperazine (0.19 g, 0.57 mmol), K2CO3 (0.08 g, 0.58 mmol), CuI (0.005 g, 0.026 mmol) and DMF (1 mL) was refluxed under N2. The reaction process was monitored by TLC. After the reaction was completed, the mixture was cooled to rt. To the resulting mixture was added H2O (5 mL) and CH2Cl2 (10 mL×3). The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (0.07 g, 37%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([CH:33]=O)[CH:31]=2)[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:23]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[CH:31]=2)[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cnc2c(c1)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cnc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To 10 mL of a chloroform solution containing 139 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 69 mg of 2,3-dihydro-1,4-dioxino[2,3-b]pyridine-7-carbaldehyde, 28 mg of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 133 mg of sodium triacetoxyborohydride was added, and stirred overnight. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel N, eluent; chloroform:methanol=10:1] to give 162 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-b]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: C1COCCN1
Product: N#Cc1c(N2CCOCC2)nc(Cc2cccc(Cl)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 150 mg (0.51 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 448 mg (5.14 mmol) of morpholine to give 109 mg (63% of theory) of the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C@H:20]2[O:12][CH2:11][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][CH:17]=1
Reactant: CCCC1CCC(C(CO)CO)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(F)cc3)OC2)CC1

Procedure:
In 40 cm3 of dichloromethane, 1.5 g (0.008 mol) of 2-(4'-propylcyclohexyl) propane-1,3-diol, 1.4 g (0.01 mol) of 4-fluorobenzaldehyde (manufactured by Aldrich), and 0.1 g of TsOH were refluxed for 3 hours over a hot water bath fitted with a Dean-Stark trap and the water formed was continuously removed from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.1 g (0.004 mol) of trans-2-(4'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR25## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.Cl>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cn1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride (22.0 g, 0.1 mol) and 2-amino-5-bromopyridine (17.3 g, 0.1 mol) in toluene (250 mL) was refluxed for 4 hours, allowing gaseous HCl to escape the reaction vessel through an open, water cooled condenser. The reaction mixture was cooled to room temperature, diluted with hexanes (200 mL) and filtered to give the title compound (33.9 g, 95%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=C4/C(=O)N(CC(O)=O)C(=O)S/4)=[CH:25][CH:26]=3)[C:21]([Cl:40])=[N:20]2)=[C:16]([C:43]([F:46])([F:45])[F:44])[CH:15]=1>>[Cl:40][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24](/[CH:28]=[C:4]3/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/3)[CH:23]=2)[N:19]([CH2:18][C:17]2[CH:41]=[CH:42][C:14]([Cl:13])=[CH:15][C:16]=2[C:43]([F:44])([F:45])[F:46])[N:20]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
N-[(5Z)-5-({3-Chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxo-thiazolidin-3-yl)-methanesulfonamide (from Example 360) and 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-chloro-1H-indazol-5-carbaldehyde (from Example 287) following General Procedure F.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[N:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:34])=[N:3]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:50][C:51]([NH2:53])=[O:52]>O>[NH2:53][C:51](=[O:52])[CH2:50][N:19]1[C:20](=[N:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[CH:21]=[CH:22][C:17]([O:16][C:12]2[CH:11]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:34])[CH:5]=3)=[O:8])[CH:15]=[CH:14][CH:13]=2)=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A mixture of 1,3-dimethyl-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (1.11 g, 2.32 mmol), N,N-diisopropylethylamine (424 μL, 2.44 mmol) and N,N-dimethylformamide (7 mL) was stirred at room temperature for 2 hr, iodoacetamide (451 mg, 2.44 mmol) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (883 mg, 71%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=NO)[CH2:19][CH2:18]4)=[C:12]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:11]=2)[CH2:6][CH2:5]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:50]1CCCC1>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:50])[CH2:19][CH2:18]4)=[C:12]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:11]=2)[CH2:6][CH2:5]1
Reactant: OCCN1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=C1CCc2cc(-c3oc(C4CCN(CCO)CC4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of the product of Step 1 (0.135 g, 0.26 mmol) in dry tetrahydrofuran (5 ml) was cooled to 0° C. and treated dropwise with tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran, 0.078 ml, 0.78 mmol) and allowed to warm to room temperature. After stirring for 2 hours, the reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was then washed with saturated aqueous brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to afford the title compound (0.027 g, 26%); MS(ES+) m/e 403 [M+H]+.
Reaction SMILES: C(Br)(Br)(Br)Br.[CH:6]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH:30]=O.[Li]CCCC.[NH4+].[Cl-]>C(Cl)Cl.C1COCC1>[C:30]([C:29]1[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=1)#[CH:6]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1cc(OC)c(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a flame-dried 50 mL round-bottom flask was added CBr4 (2.54 g, 7.65 mmol). DCM (20 mL) was added and the solution cooled to 0° C. Ph3P (4.01 g, 15.30 mmol) was added and the solution stirred at 0° C. for 15 min. 3,4,5-Trimethoxybenzaldehyde (1.0 g, 5.10 mmol) in DCM (6.0 mL) was added dropwise. The solution was stirred at 0° C. for 5 min. The solvent was removed under reduced pressure, and the resulting oil was filtered through a plug of silica and washed with Hex:EtOAc (9:1, 500 mL; 4:1, 500 mL). The combined organics were concentrated to give the crude dibromo-olefin (2.31 g, 128%), which was dissolved in THF (60 mL) and cooled to −78° C. n-BuLi (13.1 mL, 19.68 mmol, 1.5 M) was added dropwise and the solution stirred at −78° C. for 30 min. Saturated NH4Cl (10 mL) was added and the solution warmed to room temperature. The layers were separated, and the organics were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (SiO2, 80 g) using 10% EtOAc in hexanes as the eluent to afford 5-Ethynyl-1,2,3-trimethoxybenzene as a colorless oil (0.770 g, 79%): Rf=0.30 (4:1, Hex:EtOAc); 1H NMR (CDCl3) δ 6.71 (s, 2H), 3.84 (s, 3H), 3.83 (s, 6H), 3.03 (s, 1H); 13C NMR (CDCl3) δ 153.1, 117.1, 109.4, 103.3, 83.8, 76.4, 61.0, 56.2, 56.1; HRFAB [M+Li] 199.0952 (calculated C11H12O3Li: 199.0946).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=1.C(O)(=O)C>O>[N:1]1([CH2:7][C:8]2[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: C1CCNC1
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(CN2CCCC2)[nH]c(=O)[nH]1
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a solution of 1.78 g of pyrrolidine in water (20 ml), 1.33 g of 6-chloromethyluracil were added. The resulting mixture was stirred at roomtemperature for 24 hours and neutralized with acetic acid. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was washed with methanol and then filtered, whereby 466 mg of thetitle compound were obtained (yield: 29%).