Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38][CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1SC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2SC)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.8 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.10 g, 0.006 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (3.51 g, 0.027 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (1.80 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2-methylsulfanyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (250 mg, 11%) as a yellow oil.
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1)[CH3:13].COCCO>O>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)=[CH:17][N:16]=1)[CH3:13]
Reactant: CCOc1ccc(N)cn1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Solvent: COCCO
Solvent: O
Product: CCOc1ccc(Nc2nc3nc[nH]c3c(=O)[nH]2)cn1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 2-bromohypoxanthine (6.3 g; 29.3 mmol), 2-ethoxy-5-aminopyridine (12.1 g; 87.9 mmol), 2-methoxyethanol (90 mL), and water (15 mL) is heated under reflux for 3 h. The reaction mixture is cooled to room temperature, the precipitate collected by filtration and washed with water and methanol to afford N2-(2-Ethoxypyridin-5-yl)guanine (6.4 g), m.p. >350° C.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.CO>CN1C(=O)CCC1>[C:3]1([S:9][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([C:21]4[NH:29][C:28]5[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=5[CH:22]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Sc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To NaH (60 wt % in mineral oil; 0.050 g, 1.259 mmol) in 1 mL NMP was added benzenethiol (0.129 ml, 1.259 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became orange. After 1 h, the reaction was sealed and heated to 70° C. for 1 h. The reaction was cooled and was partitioned between saturated aq. NaHCO3 and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (3×) and saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford a yellow solid. The material was treated with 1 mL MeOH, sonicated, and filtered, rinsing with MeOH, to give 2-(2-(phenylthio)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.042 g, 0.113 mmol, 45% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18-11.45 (1H, m), 8.28 (1H, d, J=8.6 Hz), 8.09 (1H, dd, J=7.5, 1.5 Hz), 7.67-7.79 (3H, m), 7.48-7.61 (4H, m), 7.36 (1H, d, J=8.8 Hz), 7.05 (1H, d, J=2.3 Hz), 6.92-6.98 (1H, m), 3.33-3.42 (2H, m), 2.50-2.55 (2H, m). m/z (ESI, +ve) 371.9 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][C:9]([CH2:11][CH3:12])=[CH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH2:11]([C:9]1[O:8][C:7]2[CH:13]=[CH:14][C:4]([C:1]([O:3][CH3:20])=[O:2])=[CH:5][C:6]=2[CH:10]=1)[CH3:12]
Reactant: CO
Reactant: CCc1cc2cc(C(=O)O)ccc2o1
Agent: O=S(=O)(O)O
Product: CCc1cc2cc(C(=O)OC)ccc2o1

Procedure:
5-Carboxy-2-ethylbenzo[b]furan (2.48 g) and concentrated sulfuric acid (0.30 g) were stirred with heating in methanol (50 ml) at 60° C. for 16 hr. The reaction mixture was concentrated and chloroform mixture was added. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The chloroform layer was separated, dried over magnesium sulfate and concentrated to give the objective compound (2.40 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[C:28]([O:29][CH3:30])=[C:27](F)[CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:27]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([F:17])[C:28]=3[O:29][CH3:30])[CH2:13]2)[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: CCOC(=O)c1ccc(F)c(OC)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(OC)c1F
Reaction time: 18 h
Yield: 76 %

Procedure:
(3R)-3-(1-Tert-butoxycarbonylaminocyclopropyl)-pyrrolidine (4.75 g, 85% content) was dissolved in dimethylsulfoxide (30 mL). After adding thereto ethyl 2,4-difluoro-3-methoxybenzoate (3.2 g) and triethylamine (3.1 mL), the mixture was stirred at 75° C. After 18 hours, the mixture was allowed to cool, incorporated with 10% aqueous citric acid solution, and extracted with AcOEt. An organic layer was dried with anhydrous sodium sulfate and filtered, and then the solvent was distilled away. The resulting residual crystals (6.22 g) (2-position:4-position=17:83) were subjected to chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound as white crystals (4.75 g).
Reaction SMILES: Cl[CH:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH2:22](N(CC)CC)[CH3:23]>O1CCCC1>[CH2:22]([C:6]1[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([CH:3]=[CH:2][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:13][C:7]=1[C:8]([OH:10])=[O:9])[CH3:23]
Reactant: CCOC(=O)c1ccc(CC(Cl)C(=O)OC)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)ccc(C=CC(=O)OC)c1[N+](=O)[O-]

Procedure:
The solution of 3.20 g of ethyl 4-(2-chloro-2-methoxycarbonylethyl)-3-nitrobenzoate in 130 ml of tetrahydrofuran is admixed with 6.46 ml of triethylamine and stirred at reflux over 18 hours. The reaction mixture is cooled, poured onto water (300 ml) and extracted with tert-butyl methyl ether (2×300 ml). The organic phases are washed successively with water (2×300 ml) and brine (150 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The crude title compound is obtained as a slightly yellowish solid from the residue. Rf=0.30 (1:2 EtOAc-heptane). Rt=4.50.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:5]=[C:6]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:29]3[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=3)[CH:33]=2)[N:7]=1
Reactant: OB(O)c1cccc(-c2ccncc2)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccncc3)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (0.250 g, 0.65 mmol) and 3-pyridin-4-yl-benzeneboronic acid [CAS-No. 337536-25-1] (0.143 g, 0.71 mmol) according to the general procedure VI. Obtained as a white solid (0.101 g, 40%). MS (ISP) 391.1 [(M+H)+]; mp 143-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][N:3]=1.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:10]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(OCC)c1ccc(Br)nc1
Yield: 92.2 %

Procedure:
In ethanol (60 mL) was dissolved 6-bromonicotinaldehyde (2.00 g, 10.8 mmol). Triethyl orthoformate (5.37 mL, 32.3 mmol) and p-toluenesulfonic acid monohydrate (102 mg, 0.538 mmol) were added and the mixture was refluxed for 2 hours. The solvent in the reaction mixture was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and water were added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 2-bromo-5-(diethoxymethyl)pyridine (2.59 g, 92% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]1[C:7]2[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:9](=[O:10])[NH:26][N:25]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)c(OC)c1
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)c(OC)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(2,4-dimethoxybenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][NH:20][CH3:21])[CH3:16]>>[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][N:20]([CH3:21])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1)[CH3:16]
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: CCN(CC)CCNC
Product: CCN(CC)CCN(C)CCCc1ccc2c(n1)COC2=O
Yield: 65.5 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (63 mg, 0.33 mmol) and N,N-diethyl-N′-methylethylenediamine (43 mg, 0.32 mmol) are reacted to provide the title compound as white solid (64 mg, 63%).
Reaction SMILES: [CH:1]([C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]([CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:2][C:3](=[O:5])[CH3:4].C(OC)(=O)[CH2:24][C:25](OC)=[O:26].[Na]>CO>[C:19]([CH2:18][CH2:17][CH2:16][C:7]1[C:6]([CH:1]2[CH2:24][C:25](=[O:26])[CH:4]=[C:3]([OH:5])[CH2:2]2)=[C:11]([CH3:12])[C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)([OH:21])=[O:20]
Reactant: COC(=O)CCCc1cc(C)c(OC)c(C)c1C=CC(C)=O
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: COc1c(C)cc(CCCC(=O)O)c(C2CC(=O)C=C(O)C2)c1C
Temperature: 60 °C

Procedure:
Methyl 4-(2-(but-1-en-3-one-1-yl)-3,5-dimethyl-4-methoxyphenyl)butyrate (5.0 g) and sodium dimethyl malonate (6 g equiv) were stirred and heated at reflux in dry methanol (60 ml) for 6 hr. The solvent was evaporated under reduced pressure and the residue was heated at reflux with a 10% excess of an aqueous potassium hydroxide solution (60 ml) for 8 hr. The cooled mixture was extracted with diethyl ether. The aqueous fraction was heated to 60° C. and was acidified by slow addition of a dilute aqueous hydrochloric acid solution. The cooled mixture was extracted with ethyl acetate. The dried (MgSO4) organic fraction was evaporated to give 5-(6-[3-(carboxy)propyl]-2,4-dimethyl-3-methoxyphenyl)-3-hydroxycyclohex-2-en-1-one as a pale yellow foam. Pmr spectrum (acetone-d6 ; δ in ppm): 1.6-3.7 (11H,m); 2.28 (3H,m); 2.43 (3H,s); 3.65 (3H,s); 5.52 (1H,s); 6.91 (1H,s); 8.6 (2H,brs).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14]C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCOC1
Reactant: CCNCC1CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A mixture of 3-ethylaminomethyl-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol), dihydrofuran-3-one (0.155 mL, 2.0 mmol), diisopropylethylamine (0.347 mL, 2.0 mmol) and 4 Å molecular sieves (600 mg) in DCM (10 mL) was stirred at RT for 30 min. Sodium triacetoxyborohydride (424 mg, 2 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (257 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 4.04-3.92 (3 H, m), 3.83 (1 H, dd, J=8.89, 6.90 Hz), 3.75 (1 H, q, J=8.07 Hz), 3.64 (1 H, dd, J=8.87, 6.21 Hz), 3.56-3.55 (2 H, m), 3.14 (1 H, m), 2.67-2.66 (2 H, m), 2.51 (1 H, dd, J=12.33, 7.20 Hz), 2.17 (3 H, s), 2.05 (1 H, s), 1.89-1.79 (1 H, m), 1.44 (9 H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:6]([N:19]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:20]=[O:21])=[C:5]2[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Li]CCCC.[CH3:41][C:42]([CH3:44])=[O:43].[NH4+].[Cl-]>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:42]([OH:43])([CH3:44])[CH3:41])=[CH:10][CH:9]=3)[C:5]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:6]2[N:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[O:21])=[CH:13][CH:14]=1
Reactant: O=CN(c1cccnc1)c1c(OCc2ccccc2)c2cc(Br)ccc2n1Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)c(OCc1ccccc1)c(N(C=O)c1cccnc1)n2Cc1ccc(F)cc1
Temperature: -100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 201 mg of {5-Bromo-1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)indol-2-yl}-N-(3-pyridyl)formamide in 10 mL of THF at −100° C. was added 0.5 mL of n-BuLi (1.6 M in hexanes) and the mixture was stirred at −100° C. for 30 min. To this cold solution, 190 μL of acetone was added and the reaction mixture was allowed to warm to room temperature. At this time, aqueous NH4Cl was added, the product was extracted with ethyl acetate and the organic phase was washed with brine and dried over anhydrous Na2SO4. Flash chromatography (100% hexane to hexane/ethyl acetate 1:2) and swish with CH2Cl2/hexane yielded 61 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[CH2:29][CH2:28][N:27]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:14])[CH2:26][CH2:25]1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: COc1ccccc1C1CCNCC1
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C(=O)c2cnoc2-c2ccc(C)cc2)CC1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 4-(2-methoxyphenyl)piperidine (9.5 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H24N2O3: 376.1787, found 376.1790.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3](=[S:27])[NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:26])[CH:13]=2)[CH2:7]1.[F:29]C(F)C(O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>>[F:28][CH:2]([F:1])[C:3](=[S:27])[NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:29])[C:15]([N:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:25])[CH2:22][CH2:23]3)=[C:14]([F:26])[CH:13]=2)[CH2:7]1
Reactant: O=C(O)C(F)F
Reactant: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1

Procedure:
Following the procedure described in Example 6 for the preparation of 13 the amine 27 (prepared according to the procedure described in U.S. Pat. No. 6,342,523) is first condensed with difluoroacetic acid and the resulting amide is allowed to react with Lawesson's Reagent to give the title compound 26 which is purified by silica gel chromatography with 5% MeOH—CH2Cl2.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10](=O)[CH2:9][C:8]2([CH3:18])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:7](=[CH:6][C:5]=1[O:4][CH3:3])[C:8]([CH3:18])([CH3:17])[CH:9]=[CH:10]2
Reactant: COc1cc2c(cc1OC)C(C)(C)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)C(C)(C)C=C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14 %

Procedure:
Then, 1.1 g (28 mmol) of sodium borohydride were added to a solution of 1.9 g (9.2 mmol) of 5,6-dimethoxy-3,3-dimethylindan-1-one in methanol (30 ml), and the mixture was stirred for 5 minutes at room temperature. After methanol was removed from the reaction mixture by concentration under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. An organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Added to a solution of the resultant residue in toluene (50 ml) was 90 mg (0.47 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was stirred for 20 minutes at 120° C. The reaction mixture was concentrated under reduced pressure, and the resultant crude oil was purified by column chromatography on silica gel to obtain 264 mg (yield: 15%) of 5,6-dimethoxy-1,1-dimethylindene as a colorless oil.
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11][Br:3])[N:10]=1
Reactant: Cc1sc(Br)nc1CO
Reactant: O=S(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1sc(Br)nc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a stirred solution thionyl bromide (2.27 g, 10.94 mmol, 1.1 eq.) in 25 ml dry DCM, cooled to 5° C., was added dropwise a solution of (2-bromo-5-methyl-1,3-thiazol-4-yl)methanol (2.07 g, 9.94 mmol, 1 eq.) and pyridine (0.865 g, 10.94 mmol, 1.1 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 100 ml of water and 100 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give 2-bromo-4-(bromomethyl)-5-methyl-1,3-thiazole (1.94 g, 72% yield) as a white solid.
Reaction SMILES: C(OO)(=[O:3])C.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([Cl:18])[N:8]=1.CCCCCC>C(Cl)(Cl)Cl>[NH2:6][C:7]1[N+:12]([O-:3])=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([Cl:18])[N:8]=1
Reactant: CC(=O)OO
Reactant: COC(=O)Nc1cc(Cl)nc(N)n1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C

Procedure:
32 ml (0.20 mol) of 40% peracetic acid are added slowly to a solution of 20.2 g (0.10 mol) of methyl 2-amino-6-chloro-4-pyrimidinecarbamate in 500 ml of chloroform. The suspension obtained is warmed to 50° for 4 hours, whereby a clear solution gradually results. After cooling to room temperature, there is obtained by the slow addition of hexane a crystalline precipitate which is recrystallized from chloroform/methanol. There is obtained methyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide of melting point 220°-221°.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14].Cl>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Clc1nc2c(Br)cccn2n1
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2cccn3nc(Cl)nc23)c1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) and 3-methanesulfonyl-phenylamine; hydrochloride (245.0 mg, 1.180 mmol) in a manner analogous to Example 2d. Product was isolated as a pale yellow solid (0.268 g, 77%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=6.7 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.03 (s, 1H), 6.99 (t, J=6.9 Hz, 1H), 3.09 (s, 3H). MS=323, 325 (MH)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]2=[CH:3][CH:2]=1.[NH:13]1[CH2:18][CH2:17]O[CH2:15][CH2:14]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([N:13]([CH2:18][CH3:17])[C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH3:15]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(CC)C1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
10.0 g of pseudosaccharine chloride are initially introduced in 150 ml of toluene. 4.4 g of morpholine diluted with 25 ml of toluene are added dropwise at room temperature over the course of 30 minutes. Since the reaction is exothermic, the mixture is cooled with an ice bath. After a further 30 minues, 50 ml of pyridine in 25 ml of toluene are added and the mixture is subsequently stirred at room temperature for 2.5 hours. The solvent is then removed in vacuo and the residue is stirred up with 350 ml of water. The colorless precipitate is filtered off to give 10.8 g (86%) of 3-diethylaminobenzoisothiazole 1,1-dioxide.