Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.[OH-].[Na+]>[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: OCc1ccc(OCCF)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: FCCOc1ccc(COCc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A mixture consisting of 5.3 g of 4-(2-fluoroethoxy)benzyl alcohol, 5.0 g of 4-chlorobenzyl chloride, 0.5 g of triethylbenzylammonium bromide and 20 g of a 50% aqueous solution of sodium hydroxide was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (200 g) column chromatography (developing solvent: benzene) to give 8.2 g of the desired 4-(2-fluoroethoxy)benzyl 4-chlorobenzyl ether as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].O>CN(C)C=O>[C:3]([N:6]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CC(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCCN1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.9 %

Procedure:
Oily sodium hydride (60%, 2.45 g) was added to a solution of acetanilide (7.0 g) in N,N-diemthylformamide (50 ml), and the mixture was stirred at 0° C. for 15 minutes. Then a solution of N-(4-bromobutyl)phthalimide (15.3 g) in N,N-dimethylformamide (80 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then the solvent was distilled off. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate-chloroform (1:9, v/v) to obtain N-[4-(N-acetyl-N-phenylamino)butyl]phthalimide (9.21 g, 52.9%), which was then recrystallized from isopropyl ether. Colorless prism, mp: 83°-84° C.
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:21]([CH3:23])[CH3:22])[CH:3]=1.[N:24]([C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1)=[C:25]=S>C(Cl)CCl>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([N:21]([CH3:23])[CH3:22])=[CH:3][C:2]4[NH:1][C:25]([NH:24][C:27]5[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=5)=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: Cc1cccnc1N=C=S
Reactant: CN(C)c1cc(N)c(N)cc1C(=O)Nc1ccc2cn[nH]c2c1
Solvent: ClCCCl
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N(C)C)cc2[nH]1

Procedure:
4,5-diamino-2-dimethylamino-N-(1H-indazol-6-yl)benzamide (see Example 160; 0.3 mmol) was reacted with 2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from 2-amino-3-methylpyridine and thiophosgene employing procedure described in Example 115) followed by cyclization in situ using EDC as described in general procedure B to provide 6-dimethylamino-2-(3-methylpyridin-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide. MS: m/z 427 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Yield: 100 %

Procedure:
A mixture of 6.0 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 29 ml of 1,5-dibromopentane and 2.2 g of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux. Additional portions (2.2 g) of potassium carbonate were added at 5, 21, 29 and 38 hours. Reflux was maintained for a total of 69 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a yellow oil which was purified by chromatography on 100 g of silica gel. Elution with 25% ethyl acetate-hexane gave 9.2 g (100%) of [4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: Cl.C1(NN)C=CC=CC=1.[C:10]1([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH2:25][CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:30](C(CC)C(O)=O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)(=O)C>[C:30]([N:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27](=[O:28])[CH2:26][CH2:25][CH:24]([C:23]=23)[CH:16]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(C(=O)O)C(=O)c1ccccc1
Reactant: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccccc12
Agent: Cl
Solvent: NNc1ccccc1
Solvent: CC(=O)O
Product: O=C1CCC2c3c1cccc3N(C(=O)c1ccccc1)C2c1ccccc1
Yield: 160.1 %

Procedure:
(Step 1) Synthesis of 2-phenylindole-3-propionic acid Phenylhydrazine hydrochloride (50 g) and benzoylbutyric acid (55.4 g) were suspended in acetic acid (500 ml), followed by heating to reflux for 1.5 hours. After allowing the suspension to cool, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous solution of sodium chloride, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent, followed by washing with a methylene chloride/hexane mixed solvent to yield 69 g (90%) of the titled compound as pale brown crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH:18]([OH:21])[CH2:19][O:20][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CC(O)CO)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(CC(O)CO[Si](C)(C)C(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of (±)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-1,2-diol (50.23 g, 0.174 mol) in N,N-dimethylformamide (600 mL) was added tert-butyldimethylsilyl chloride (28.88 g, 0.192 mol) followed by triethylamine (22.03 g, 0.218 mol) and 4-(dimethylamino)pyridine (2.12 g, 0.017 mol) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was quenched by the addition of water (1000 mL) and was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×300 mL), aqueous hydrogen chloride (1.0 N, 400 mL), saturated aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 58.14 g (83%) of (±)-1-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol as a colorless oil. Rf=0.48 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C23H34O4Si: C, 68.62; H, 8.51. Found: C, 69.20; H, 8.91.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]1([C@@H:34]2[CH2:38][O:37][C:36](=[O:39])[NH:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:35]3[C@H:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:38][O:37][C:36]3=[O:39])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4c4ccccc4)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 15.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-(−)-4-phenyloxazolidin-2-one (326 mg), the title compound (163 mg) was obtained.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[OH:28][C@@H:29]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42](O)[CH:41]=1)[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>>[O:20]=[S:16]1(=[O:19])[CH2:15][CH2:14][CH:13]([CH2:12][O:11][C:42]2[CH:41]=[C:40]([C@H:29]([OH:28])[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH:45]=[CH:44][CH:43]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCS(=O)(=O)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCS(=O)(=O)CC2)c1

Procedure:
Reaction between (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) following the method used in Example 7 gave (R)-tert-butyl (3-(3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate as colorless oil. Yield (58%); 1H NMR (400 MHz, DMSO-d6): δ 7.20 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.78 (d, J=4.0 Hz, 1H), 5.19 (d, J=4.4 Hz, 1H), 4.51-4.49 (bs, 1H), 3.87-3.85 (d, J=8.0 Hz, 1H), 3.22-3.15 (m, 2H), 3.08-3.05 (m, 2H), 2.96-2.94 (m, 2H), 2.15-2.11 (m, 3H), 1.79-1.74 (m, 2H), 1.67-1.65 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[OH:17].[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>C1COCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:18](=[O:19])[O:17][C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
A solution of 4-amino-3′-nitro-biphenyl-3-ol (0.115 g, 0.5 mmol) in dry THF (2.5 mL) was treated with a solution of 1,1′-carbonyldiimidazole (0.098 g, 0.6 mmol) in dry THF (2.5 mL). The reaction mixture was stirred at room temperature under a blanket of nitrogen for 6 hours. A precipitate formed, was collected and washed with methylene chloride (50 mL) to give 6-(3-nitro-phenyl)-3H-benzooxazol-2-one (0.095 g, 74%) as a white solid: mp 280-281° C.; 1H-NMR (DMSO-d6) δ 11.7 (s, 1H), 8.43 (t, 1H, J=1.15 Hz), 8.2-8.13 (nm, 21), 7.79-7.72 (m, 2H), 7.59 (dd, 1H, J=8.08, 2.31 Hz), 7.21 (d, 1H, J=8.08 Hz), MS (ES) m/z 255([M−H]−, 100%); Anal. Calc. For C13H8N2O4: C, 60.94, H, 3.15, N, 10.93. Found: C, 59.95, H, 3.17 N, 10.77.
Reaction SMILES: [N:1]#[N:2].C([O:10][C:11]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@@H:28]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:29]([OH:43])[CH2:30][C@@:31]2([C:40]([NH2:42])=[O:41])[CH2:35][CH2:34][CH2:33][N:32]2[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])=[CH:15][CH:14]=1)=[O:12])C1C=CC=CC=1>C(O)(C)C.[Pd]>[N:1]#[N:2].[C:11]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@@H:28]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:29]([OH:43])[CH2:30][C@@:31]2([C:40]([NH2:42])=[O:41])[CH2:35][CH2:34][CH2:33][N:32]2[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])=[CH:15][CH:14]=1)([OH:12])=[O:10]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc(C(=O)OCc2ccccc2)cc1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CC(C)O
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc(C(=O)O)cc1)C(N)=O
Yield: 80.6 %

Procedure:
274 mg of N2 -[3(S)-[[N-[4-(benzyloxycarbonyl)benzoyl]-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 100 ml of isopropanol were hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 193 mg of N2 -[3(S)-[[N-(4-carboxybenzoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a white solid from methanol/ethyl acetate; MS: m/e 596 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(-c2ccc(C(O)CCC(=O)O)cc2)cc1

Procedure:
6 gm (0.02 mol) of 4-(4'-nitro-4-biphenylyl)-4-hydroxy-butyric acid in 200 ml of methanol were hydrogenated in the presence of 3 gm of Raney nickel as a catalyst, at room temperature and at a pressure of 5 atmospheres. After absorption of the calculated quantity of hydrogen, the catalyst was vacuum-filtered off and the solvent was distilled off. The residual 4-(4'-amino-4-biphenylyl)-4-hydroxy-butyric acid, after recrystallization from methanol, had a m.p. of 145° C. (decomp.). Melting point of the cyclohexylamine salt: 178° C. (decomp.; precipitated from ethyl acetate/absolute ethanol). Yield: 5.5 gm.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4=[N:18][CH:19]=[C:20]([C:22]#[N:23])[CH:21]=[C:16]4[N:15]=3)[C:5]2=[O:30])[CH2:3][CH2:2]1>CO.N.[Ni]>[NH2:23][CH2:22][C:20]1[CH:21]=[C:16]2[N:15]=[C:14]([CH2:13][N:6]3[C:7]4[CH:8]=[N:9][CH:10]=[CH:11][C:12]=4[N:4]([CH:1]4[CH2:2][CH2:3]4)[C:5]3=[O:30])[N:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]2=[N:18][CH:19]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(C#N)cnc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(CN)cnc21

Procedure:
Compound 27 (125 mg, 0.31 mmol) in methanol/NH3 (100 mL) was hydrogenated at 20° C. with Raney Nickel (50 mg) as a catalyst overnight. After uptake of H2 (2 eq), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography using dichloromethane/MeOH/NH3. The title compound 17 was isolated as a white solid (25.5 mg, 20%). m/z=406 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:9]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:8]=2[C:7]=1[OH:26])=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[OH:26][C:7]1[C:8]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:9]=2[C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[N:11][C:6]=1[C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2nccs2)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2nccs2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 32.3 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-4-thiazol-2-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (25 mg, 0.06 mmole) and glycine (96 mg, 1.28 mmole) in 0.5 M sodium methoxide/methanol (2.4 ml) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (25 ml) and extracted with dichloromethane (2×50 ml). The remaining aqueous solution was acidified to pH=2 with 0.1 N HCl (1.8 ml). The resulting suspension was extracted with isopropanol/chloroform (50 ml, 1:3) dichloromethane, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a yellow solid which was further purified by MPLC on a C18 column with a gradient of formic acid, acetonitrile and water to give the title compound as a yellow solid (8 mg). 1H NMR (DMSO-d6, 200 MHz): δ=8.21 (m, 2H), 8.01 (m, 1H), 7.89 (m, 1H), 7.63 (m, 3H), 6.51 (m, 1H), 4.10 (d, J=5.4 Hz, 2H); MS: (+) m/z 413.22 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[NH:10][NH2:11])=[CH:4][CH:3]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: NNC(=S)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccc(Cl)cc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A suspension of 20.1 g (0.10 mole) of 4-(4-chlorophenyl)3-thiosemicarbazide in 80 mL of absolute ethanol was treated with 16.5 g (0.10 mole) of ethyl 2-chloroacetoacetate and the mixture stirred for 1.0 hr at room temperature. Alcoholic hydrogen chloride (2N, 60 mL) was added and the dark precipitate dissolved while heating the mixture at reflux for 1.0 hr. The solution was filtered while hot, and the filter cake washed with absolute ethanol. The filtrate was evaporated under reduced pressure and the residue triturated in cold absolute ethanol and filtered. Both filter cakes were found to be the same compound by TLC (10% methanol in benzene on silica gel). The two were combined, dissolved in hot absolute ethanol (the hydrochloride salt was water insoluble), partially neutralized with saturated aqueous sodium bicarbonate, and the solid filtered (10.4 g, mp 212°-226° C.). A second crop was obtained by treating the filtrate with saturated aqueous sodium bicarbonate (11.5 g, mp 220°-225° C.). The second crop was recrystallized from absolute ethanol to give 3.8 g of product, mp 223°-225° C. This solid was dried at 100° C./0.1 mmHg/3 hr; then for ~16 hr at RT/0.1 mmHg.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH3:5][O:6][C:7](=[CH:9][CH3:10])[CH3:8]>P(=O)(O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:5][O:6][C:7]([O:4][CH2:1][C:2]#[CH:3])([CH2:9][CH3:10])[CH3:8]
Reactant: C#CCO
Reactant: CC=C(C)OC
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Product: C#CCOC(C)(CC)OC
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A mixture of 130 mg (0.3 μmol) of phosphoric acid (19% w/w in acetone) and 22.80 g (399 mmol) of propargyl alcohol is filled into a dropping funnel. 53.5 g (598 mmol) of 2-methoxy-but-2-ene (96.2% GC) was transferred into a second dropping funnel. Both solutions were added simultaneously within 30 minutes to the cooled flask (8° C.). The internal temperature was maintained between 8° C. and 12° C. during the addition of the reactants. The reaction mixture was held at 10° C. for about 2 hours. The reaction mixture was neutralized with 0.5 g of sodium carbonate and concentrated under reduced pressure (40° C., 80 mbar). The crude product was analyzed by GC. 58.0 g of crude 2-methoxy-2-prop-2-ynyloxy-butane were obtained with a purity of 85.5% (yield 96.9% based on propargyl alcohol).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:18]([C:14]1[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=1[CH3:17])(=[O:19])=[O:20])([CH2:5][OH:6])[CH3:7]
Reactant: CC(N)(CO)CO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(CO)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 17.3 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1,3-propanediol (1.86 g, 17.7 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.5 g, 5.89 mmol) and triethylamine (0.9 ml, 6 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.33 g, 17%) as a white solid. MS (ISP) 322.2 [(M−H)−]; mp 201° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.CC1(C)COB([C:28]2[S:32][C:31]([C:33]([OH:35])=[O:34])=[CH:30][CH:29]=2)OC1.[F-].[Cs+]>O.COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:28]2[S:32][C:31]([C:33]([OH:35])=[O:34])=[CH:30][CH:29]=2)[CH:3]=1
Reactant: CC1(C)COB(c2ccc(C(=O)O)s2)OC1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2ccc(C(=O)O)s2)n1
Temperature: 85 °C
Yield: 53.7 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [277 mg, 0.83 mmol, Intermediate (44)], 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-thiophene-2-carboxylic acid (300 mg, 1.25 mmol), cesium fluoride (378 mg, 2.5 mmol) and tetrakis(triphenylphosphine) palladium (77 mg, 0.07 mmol) in water (2 mL) and ethylene glycol dimethyl ether (8 mL) is degassed with bubbling nitrogen for 5 minutes and is heated at 85° C. for 16 hours. The reaction mixture is cooled, diluted with water (150 mL) and brine (50 mL), and extracted three times with EtOAc (150 mL) and the extracts are concentrated in vacuo. The residue is subjected to flash column chromatography on silica (10 g) eluting with 0 to 15% MeOH in ethyl acetate. The product is triturated twice with heptanes (5 mL) and twice with ether (5 mL) and dried to afford 5-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-thiophene-2-carboxylic acid (189 mg, Example 87) as a solid. MS: 424 (M+H); 1H NMR [300 MHz, (CD3)2SO]: δ 13.2 (1H, s); 7.7 (3H, m); 7.6 (1H, s); 7.35 (2H, s); 6.6 (1H, s); 4.85 (3H, s); 3.6 (2H, m); 3 (2H, t). IC50=0.16 nM