Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:15])[O:12][CH:11]([CH2:13][CH3:14])[CH2:10][O:9]2)=[C:4]([O:16][CH:17]([F:19])[F:18])[CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[F:19][CH:17]([F:18])[O:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH2:15][Br:20])[O:12][CH:11]([CH2:13][CH3:14])[CH2:10][O:9]1
Reactant: BrBr
Reactant: CCC1COC(C)(c2ccc(Cl)cc2OC(F)F)O1
Solvent: ClC(Cl)Cl
Product: CCC1COC(CBr)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.7 parts of the 2-(4'-chloro-2'-difluoromethoxyphenyl)-2-methyl-4-ethyl-1,3-dioxolane prepared in (a) are dissolved in 100 ml of abs. chloroform and the solution is warmed to 30° C. Under irradiation with a 150 watt spot lamp, 7.3 parts of bromine in 30 ml of abs. chloroform are added dropwise over 1 hour and the reaction mixture is then stirred for 2 hours at room temperature. The reaction mixture is then washed with 2×100 ml of water, dried over sodium sulfate, and filtered. The solvent is removed by evaporation and the oily residue is purified by high vacuum distillation; b.p. 113°-115° C./0.05 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][CH2:50][CH2:51][CH3:52]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][CH2:50][CH2:51][CH3:52])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCNc1cc(C(=O)OC)ccc1N
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCNc1cc(C(=O)OC)ccc1NC(=O)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
In chloroform (10 ml), 5-t-butoxycarbonylamino valeric acid (574 mg), WSCI hydrochloride (690 mg), and HOBt (487 mg) were dissolved. Then, the solution was stirred at room temperature for 30 minutes. The solution was added with the compound (503 mg) obtained in Example 3-1 and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After having been washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous ammonium chloride solution, and a saturated saline solution, the resultant was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (540 mg) as a colorless viscous substance.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39]CC2C=CC=CC=2)=[CH:26][CH:25]=1>C1COCC1.C(O)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([CH2:2][NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)[OH:4])=[CH:6][C:7]=1[CH2:19][O:20][CH3:21]
Reactant: COCc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: COc1ccc(CCOCCCCCCNCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1cc(C(O)CNCCCCCCOCCc2ccc(OC)cc2)ccc1O
Reaction time: 20 h
Yield: 48.1 %

Procedure:
A solution of 2-bromo-1-[3-(methoxymethyl)-4-(phenylmethoxy)phenyl]ethanone (1.38 g), N-[6-[2-(4-methoxyphenyl)ethoxy]hexyl]benzenemethanamine (1.35 g) and DEA (1.02 g) in THF (21 ml) was allowed to stand under nitrogen for 20 h. The mixture was filtered and the filtrate evaporated in vacuo to give an oil, a solution of which in ethanol (35 ml) was hydrogenated over pre-reduced 10% PdO-C (50% aqueous, 500 mg) and 5% PtO-C (400 mg). The mixture was filtered through hyflo and evaporated in vacuo to give an oil. Purification by FCC eluting with System B (900:100:5) gave the title compound as a cream solid (0.82 g) m.p. 97.5°-98.5°.
Reaction SMILES: C([NH:20][S:21](=[O:46])(=[O:45])[O:22][CH2:23][C@@H:24]1[C@@H:31]2[C@@H:27]([O:28]C(C)(C)[O:30]2)[C@H:26]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[CH2:43][CH3:44])[O:25]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.O>[S:21](=[O:46])(=[O:45])([O:22][CH2:23][C@@H:24]1[C@@H:31]([OH:30])[C@@H:27]([OH:28])[C@H:26]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[CH2:43][CH3:44])[O:25]1)[NH2:20]
Reactant: CCc1ncnc2c1ncn2[C@@H]1O[C@H](COS(=O)(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@H]21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncnc2c1ncn2[C@@H]1O[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O
Yield: 84.7 %

Procedure:
A solution of [(3aR,4R,6R,6aR)-6-(6-ethyl-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl tritylsulfamate (149.0 mg, 0.23 mmol) in TFA/water (5.0 mL, 9:1) was stirred for 30 minutes, concentrated to dryness, dissolved in methanol and concentrated again. The residue was purified by prep HPLC to yield the title compound (70 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9]C)=O)[N:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CO>[Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:9])[N:6]=1
Reactant: COC(=O)c1nc(Br)sc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Br)sc1-c1ccccc1
Yield: 20.3 %

Procedure:
2.0 g (6.7 mmol) of methyl 2-bromo-5-phenyl-4thiazolecarboxylate and 1.61 g (10.1 mmol) of t-butyl (2-aminoethyl)carbamate were stirred under reduced pressure for 2.5 hours at 110° bath temperature, whereby the methanol formed was distilled off continuously. After chromatography on 100 g of silica gel with methylene chloride and a 4:1 mixture of methylene chloride and ethyl acetate there was obtained 0.58 g (26%) of t-butyl [2-(2-bromo-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as a pale yellow, crystallizing oil which was used directly.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:28]=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:34]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[C:27]([CH:26]=1)[C:35]([O:37][CH3:38])=[O:36])#[N:7]
Reactant: CNCCc1cc(C(=O)OC)cc(C(=O)OC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COC(=O)c1cc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc(C(=O)OC)c1

Procedure:
Reaction of 1f with 2i produced 3ai. MS found M+H=511. The oxalate salt of 3ai was recrystallized from hexane/ethyl acetate; mp 100-103° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1B(O)O>C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:22]=1[C:2]1[N:3]=[CH:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc3ccccc3c2)c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of E1 (1.0 eq.) in benzene (0.1 M solution), 2-naphthylboronic acid (1.5 eq.) and sat. aq. Na2CO3 solution under argon was added PdCl2((PPh)3)2. The mixture was stirred for 72 hr at 60° C., then cooled and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel eluting with 20-50% EtOAc/petroleum ether to obtain E2 as yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.31 (1H, s), 7.88-7.70 (5H, m), 7.48-7.39 (3H, m), 5.28 (2H, s), 3.54 (2H, t, J=8.2 Hz), 0.94 (2H, t, J=8.2 Hz), 0.00 (9H, s). MS (ES) C19H24N2OSi requires: 324, found: 325 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCCc3c[nH]c4ccccc34)n2)cc1
Yield: 81 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and Tryptamine (18 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (44 mg, 81% yield.) MS/ES+: m/z=474.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[C:6]([O:5][C:4]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:2]([CH3:1])[CH:3]=2)([CH3:11])[CH3:10])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: Cc1cc(C)cc(OC(C)(C)C(=O)O)c1
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: Cc1cc(C)cc(OC(C)(C)C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)c1
Yield: 81.8 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 755 mg of 2-(3,5-dimethylphenoxy)-2-methylpropionic acid and 1.0g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.10 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl>[C:44]([NH:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1)(=[O:47])[CH:45]=[CH2:46]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@H](C(=O)N(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
(1S,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CH2Cl2 (25 ml) and cooled to 0° C., followed by addition of DIEA (0.017 ml, 0.099 mmol) then acryloyl chloride (8.86 μl, 0.109 mmol) slowly. The reaction mixture was stirred at 0° C. for 30 minutes. After the reaction was complete, the reaction mixture was loaded directly onto silica and purified via flash chromatography (0-10% CH2Cl2/MeOH; 12 g column) to afford (1R,3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.043 g, 0.077 mmol, 78% yield). MS (ES+) C27H29Cl2N5O4 requires: 558, found: 559 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:33][C:34](=[O:37])[CH2:35][C:27]1[C:21]2[NH:20][C:19]([S:18][CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]([O:9][CH3:8])=[O:28])=[N:23][C:22]=2[CH:24]=[CH:25][CH:26]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1ccccc1CSc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1nc2cccc(CC(=O)OC(C)(C)C)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
Sodium hydride (400 mg, 10.0 mmol) and dimethylformamide (30 ml) were added to a previously dried reaction vessel. To the mixture were added 2-(benzimidazole-2-ylthiomethyl)benzoic acid methyl ester (1500 mg, 5.0 mmol) and bromoacetate t-butyl ester (1463 mg, 7.5 mmol), and the mixture was stirred at 80° C. for 2 hours. Water was added thereto, followed by extraction with ether. After the ether phase was dried with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 2-(2-((2-(methoxycarbonyl)phenyl)methylthio)benzimidazolyl)acetic acid t-butyl ester (1298 mg, yield 63%).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[CH:9][S:10][CH:11]=1.IC>O1CCCC1>[CH3:1][C:9]1[S:10][CH:11]=[C:7]([CH3:6])[C:8]=1[C:12]([OH:14])=[O:13]
Reactant: [Li]CCCC
Reactant: Cc1cscc1C(=O)O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1csc(C)c1C(=O)O
Temperature: -78 °C
Yield: 82.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46 mmol) was added to a pre-cooled solution of 4-methylthiophene-3-carboxylic acid (3.0 g, 21 mmol) in dry tetrahydrofuran (THF, 35 mL) at −62° C. The reaction mixture was stirred at −78° C. for an hour, allowed to warm to −40° C. and re-cooled to −78° C. before adding iodomethane (3.28 mL, 7.49 g, 53 mmol). After addition, the reactants were stirred at −78° C. for an hour and then allowed to warm to room temperature over 14 hours and quenched with water (20 mL). The organic phase was extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined aqueous extracts were washed with ether (2×30 mL), cooled in an ice bath and acidified to pH 3 using concentrated hydrochloric acid. The resultant precipitate was extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate, concentrated under reduced pressure and recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 82%): mp 164–165° C.; 1H NMR (CDCl3) δ 6.65 (q, 1H), 2.73 (s, 3H), 2.43 (d, 3H); EI/MS 156 m/e (M+); IR (liq film) 1664 cm−1; Calcd for C7H8O2S: C, 53.8; H, 5.16; Found: C, 53.8; H, 5.11.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:17]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+].C([OH:22])C>O>[O:22]1[CH2:2][CH:3]1[C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: BrCCc1cccc2c1CCc1ccccc1-2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)CCc1cc(C3CO3)ccc1-2
Reaction time: 0.08 h

Procedure:
To a boiling solution of 1.51 g (5 mmol) of (28) in ethanol (40 mL), a solution of 285 mg (7,5 mmol) of NaBH4 in 5 mL of water was added dropwise. Boiling was continued for 5 min, the solution was cooled, diluted with water, and extracted with ether. The ether extract was washed with water, dried, and the solvent was removed at reduced pressure to provide (29) as a colorless oil. This soldified on trituration with a few drops of ether to yield (29), m.p. 65°-66° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4][C:3]1=2.[Br:19]Br>CC(O)=O>[Br:19][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:18])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]=1[OH:14]
Reactant: BrBr
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br

Procedure:
3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound L, 155 mg, 0.62 mmol) was dissolved in 1 ml of HOAc. To this solution was added Br2 (0.033 ml, 0.62 mmol). The reaction mixture was left at room temperature for over night. A stream of air was passed through the reaction mixture to remove the unreacted Br2. The remaining solid was dissolved in small amount of THF and purified by column chromatography (ethyl acetate/hexane 1/1) to yield the desired product as a cream colored solid.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[C:23]([OH:25])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[C:23]([NH2:3])=[O:25]
Reactant: CCN(CC)c1ccccc1
Reactant: O=C(O)c1c(O)ccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(O)ccc2ccccc12
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 345.7 %

Procedure:
Diethylaniline (0.27 μL, 1.7 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (0.8 mg, 1.5 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 2-Hydroxy-1-naphthoic acid (0.37 mg, 2.0 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 mg, 2.0 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.25 mg, 1.8 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 13 h 20 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (85% ethyl acetate-hexanes) to give the 2-hydroxy-naphthalene-1-carboxylic acid amide derivative (1.1 mg, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[CH3:26][CH:27](Cl)[CH2:28][N:29]([CH3:31])[CH3:30]>>[Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH:27]([CH3:26])[CH2:28][N:29]([CH3:31])[CH3:30])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: CC(Cl)CN(C)C
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)c1
Product: Cc1cccc(-c2nc3ccc(OC(C)CN(C)C)cc3n2Cc2ccccc2Br)c1

Procedure:
The title compound was prepared essentially as described above except that the compound of Example 126 was reacted with 1-methyl-2-(N,N-dimethylamino)ethyl chloride.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)N2C(=O)C(C)(C)c3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Yield: 19 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3,3 dimethyl-2H-indol-2-one (Example 3) and following the method described in Example 23, but using 3,4-dimethoxy benzoyl chloride instead of isonicotinoyl chloride, afforded the desired compound.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]([Cl:24])[CH3:23])=[O:20]>ClCCl>[C:19](=[O:20])([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[O:21][CH:22]([Cl:24])[CH3:23]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCOC(=O)OC(C)Cl
Reaction time: 8 h
Yield: 93 %

Procedure:
To a stirred solution of decanol (6.0 g, 7.23 mmol) in dichloromethane (150 ml) was added dry pyridine (3.66 ml, 45.6 mmol). The solution was cooled in an ice bath. To this was added 1-chloroethyl chloroformate (6.5 g, 45.6 mmol) dropwise. The reaction mixture was allowed to proceed overnight, diluted with dichloromethane and washed with 0.5N HCl solution, twice with a saturated sodium bicarbonate solution and finally with distilled water. The solvent was dried over magnesium sulphate, filtered through silica and concentrated to dryness. Yield: 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13]1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:12]3[CH2:13][CH2:14]3)[CH2:21][CH2:20]2)[N:28]=1)=[O:5]
Reactant: Nc1cccc(OC2CCN(CC3CC3)CC2)n1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(OC2CCN(CC3CC3)CC2)n1)c1ccc(F)cc1Cl
Reaction time: 15 h
Yield: 79.4 %

Procedure:
Add 2-chloro-4-fluorobenzoyl chloride (149 mg, 0.58 mmol) to a solution of 6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 70, 130 mg, 0.53 mmol) in pyridine (7 mL) and beat at 55° C. for 15 hr. Remove pyridine in vacuo, dissolve the residue in CH2Cl2, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 5% 2M NH3-Methanol in CH2Cl2) provides 170 mg (79%) of the title compound: mass spectrum (ion spray): 404.1 (M+1); 1H NMR (CDCl3, ppm): 8.08 (s, 1H), 7.63 (m, 2H), 7.52 (t, 1H), 7.11 (m, 1H), 6.99 (m, 1H), 6.41 (d, 1H), 4.82 (m, 1H), 2.72 (m, 2H), 2.26 (m, 2H), 2.17 (d, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 0.77 (m, 1H), 0.40 (m, 2H), 0.00 (m, 2H). Hydrochloride salt: Analytical calc. for C21H23ClFN3O2.HCl.0.5H2O: C, 56.13; H, 5.61; N, 9.35. Found: C, 56.12; H, 5.30; N, 9.35.