Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][N:11]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>C1COCC1.O>[OH:3][CH2:4][CH:6]1[C:14]2[N:13]=[CH:12][N:11]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
To a solution of 1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester (14.0 g, 32 mmol) in THF (100 ml) was added lithium aluminium hydride (24 ml, 1 mol/L in THF, 24 mmol). The mixture was stirred at 20° C. for 45 min, and water (3.5 ml) and sodium hydroxide (3.5 ml, 4 mol/L in water) were carefully added. Water (14 ml) and concentrated aqueous hydrochloric acid (1.13 ml) were added, and the mixture was filtered and concentrated under reduced pressure. The residue was re-dissolved in ethyl acetate (150 ml), dried (magnesium sulphate), filtered, and kept at 20° C. overnight. Filtration yielded 7.0 g (55%) of 4-hydroxymethyl-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole as a colourless solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][N:2]=1.FC(F)(F)S(O[C:20]1[CH2:26][CH:25]2[N:27]([CH3:28])[CH:22]([CH2:23][CH2:24]2)[CH:21]=1)(=O)=O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:20]2[CH2:21][CH:22]3[N:27]([CH3:28])[CH:25]([CH2:24][CH2:23]3)[CH:26]=2)=[CH:3][N:2]=1
Reactant: CN1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Reactant: OB(O)c1cncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C2C=C(c3cncc4ccccc34)CC1CC2
Temperature: 25 °C

Procedure:
A mixture of isoquinolin-4-ylboronic acid, 3-trifluoromethanesulfonyloxy-8-methyl-8-azabicyclo [3.2.1]-oct-2-ene, lithium chloride, [1,1'-bis(diphenylphos-phino)-1-ferrocene]-palladium II chloride, and 2M aqueous sodium carbonate in tetrahydrofuran containing a few drops of methanol is stirred at reflux for about 4 hours. The reaction is cooled to room temperature and then partitioned between ethyl acetate and 2N sodium hydroxide. The phases are separated and the aqueous phase extracted well with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is subjected to flash silica gel chromatography. Fractions containing product are combined and concentrated under reduced pressure to provide 3-(isoquinolin-4-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[K].C(=O)([O-])[O-].[C:43]1([SH:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(O)CO.[OH-].[K+].Cl>[Cu]I.C(O)(C)C>[C:43]1([S:49][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[NH:4][CH:3]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: OCCO
Product: Oc1cccc(-c2cnc3[nH]cc(Sc4ccccc4)c3c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 17.5 %

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol), copper(I) iodide (1.5 mg, 0.004 mmol), and potassium, carbonate (16 mg, 0.155 mmol) under nitrogen atmosphere was added isopropanol (0.2 mL), benzenethiol (8 μL, 0.077 mmol), and ethylene glycol (9 uL, 0.155 mmol). The reaction mixture was stirred at 80° C. for 24 h. A (1:1) mixture of 2 M aqueous KOH and MeOh (1 mL) was added, and the reaction mixture was further stirred at 50° C. for 3 h. The mixture was acidified to pH5 with 1N aqueous HCl and extracted with EtOAc twice. Extracts were combined and concentrated under vacuum. Purification by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier) afforded 3-(3-phenylsulfanyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-phenol as a white solid (4.3 mg, 17% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.74 (dd, J=2.5, 9.0 Hz, 1H), 6.98 (t, J=2.0 Hz, 1H), 7.08 (m, 4H), 7.23 (m, 3H), 7.85 (d, J=2.5 Hz, 1H), 7.98 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 9.55 (broad s, 1H), 12.4 (broad s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=3)[C:34]([Cl:46])=[CH:33][C:32]=2[CH2:47][CH2:48][O:49][CH2:50][C:51]([F:54])([F:53])[F:52])[O:11][C@@H:10]1[CH2:55][O:56]CC1C=CC=CC=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[Cl:46][C:34]1[C:35]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=2)=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:55][OH:56])[O:11]2)=[C:32]([CH2:47][CH2:48][O:49][CH2:50][C:51]([F:54])([F:52])[F:53])[CH:33]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CCOCC(F)(F)F)cc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(CCOCC(F)(F)F)cc2Cl)cc1
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-(2-(2,2,2-trifluoroethoxy)ethyl)phenyl)tetrahydro-2H-pyran (30 mg, 0.034 mmol) and 10% Pd/C (30 mg) in 6 mL of MeOH:THF (1:1) was stirred under H2 atmosphere (1 atm) for 2 h. The mixture was filtered, and the filtrate was concentrated to provide the crude product, which was purified by HPLC to yield 9 mg of title compound. 1H-NMR (CD3OD, 300 MHz) δ 7.40 (s, 1H), 7.27 (s, 1H), 7.10 (s, 4H), 4.44-4.41 (m, 1H), 4.06 (d, J=15.3 Hz, 1H), 4.00 (d, J=15.3 Hz, 1H), 3.95-3.79 (m, 5H), 3.67-3.61 (m, 1H), 3.48-3.46 (m, 2H), 3.39-3.36 (m, 2H), 3.15-3.05 (m, 1H), 2.98-2.91 (m, 1H), 2.58 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H); MS ESI (m/z) 519 (M+1)+, calc. 518.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:8]=[C:7]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:19]2)[C:3]=1[C:4]([OH:6])=[O:5].[CH2:34]1COCC1>CO>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:8]=[C:7]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:19]2)[C:3]=1[C:4]([O:6][CH3:34])=[O:5]
Reactant: Nc1nc(-c2ccccc2O)cc(C2CCCN(C(=O)OCc3ccccc3)C2)c1C(=O)O
Reactant: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a solution of 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinic acid (1.1 g, 2.5 mmol) in THF (10 mL) and MeOH (5 mL) was added dropwise trimethylsilyldiazomatane (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hrs, and the reaction was quenched by acetic acid. The mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate, 3:1) followed by recrystallization from a mixture of CH2Cl2 and hexane to give methyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinate as a yellow solid (0.39 g, yield; 34%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])[N:5]=[C:4]([NH:25][CH:26]=[O:27])[N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH:26]=[O:27])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOP(=O)(CCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(CCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Temperature: 120 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
4-Chloro-6-[[4-(diethoxyphosphoryl)butoxy]amino]-2,5-diformamidopyrimidine (0.330 g, 0.78 mmol) was dissolved in diethoxymethyl acetate (4 ml) and the resulting solution was stirred at 120° C. for 2 hr. The reaction mixture was then allowed to cool and evaporated to dryness. The residue was dissolved in methanol: conc. aq. NH3 solution (9:1, 5 ml) and stirred at 23° C. for 5 min. The solvents were evaporated under vacuum and the product was purified by column chromatography on silica gel (eluted with chloroform: ethanol, 96:4) to yield the title compound (0.225 g, 71%), m.p. 98° C. (acetonitrile). 1H NMR: δH ((CD3)2SO) 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.76 (6H, m, CH2CH2CH2P), 3.98 (4H, m, (OCH2CH3)2), 4.43 (2H, t, J=6Hz, NOCH2), 8.8 (1H, s, H-8) 9.36 (1H, br.s, NHCHO), 11.29 (1H, br.s, D2O exchangeable, NHCHO).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:1]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(=O)O)c2)c1-c1ccccc1

Procedure:
3-Aminobenzoic acid (10 mmol, 1.4 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in chloroform-ether, then the insoluble material was filtered from the reaction product. The soluble material was purified over silica gel which yielded the named product (m.p. 161.0° C.-162.7° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].CI.[C:26](OCC)(=O)C>CN(C=O)C.[Ag-]=O>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][CH3:26])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Agent: O=[Ag-]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
(3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (100 mg, 0.32 mmol) was dissolved in DMF (3 mL). Then, molecular sieves (4 A), silver(I)oxide (355 mg, 1.53 mmol) and methyl iodide (0.40 ml, 6.38 mmol) was added and the black suspension stirred at room temperature for 48 hour. The reaction mixture was filtrated through celite and the filtrate evaporated. The crude yellow residue was subjected to silica gel flash chromatography (ISCO Companion CombiFlash; 40 g Gold silica gel cartridge, heptane/ethyl acetate gradient; ethyl acetate: 2% (2 min), 2-20% (3 min), 20% (8 min), 20-30% (2 min), 30% (8 min), 30-50% (3 min) and 50% (8 min) to yield (3aR,4S,7aR)-4-methoxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (15 mg, 0.04 mmol, 14% yield) as colorless oil. MS [2M+Na]677; RT=8.147 min HPLC Method III
Reaction SMILES: [OH-].[Na+].C([SiH2][O:8][C:9](C)(C)[C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])(C)(C)C>CO>[Cl:22][C:21]1[CH:20]=[CH:19][C:12]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH2:9][OH:8]
Reactant: CCC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)NCc1ccc(Cl)c(CO)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Aq. 1M NaOH (92 mL) was added to a sol. of N-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-propionamide (5.08 g, 14.9 mmol) in MeOH (184 mL). The mixture was heated to 80° C., and stirred at this temperature for 30 min. The mixture was allowed to cool to rt, and the solvents were partially removed under reduced pressure. The aq. residue was diluted with water, and was extracted with EtOAc (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2→MeOH/CH2Cl2 1:9) yielded the title compound (2.99 g, 88%). LC-MS: tR=0.67 min; ES+: 269.31.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:36]=[C:24]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][N:23]3[N:22]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2].Cl.O1CCOCC1>ClCCl>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:36]=[C:24]3[CH2:25][NH:26][CH2:27][CH2:28][N:23]3[N:22]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(=O)OC(C)(C)C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCNC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of 205e (280 mg, 0.41 mmol), 4.0 M HCl/dioxane (4 mL), and dichloromethane (4 mL) was stirred at room temperature for 2 h. It was then concentrated under reduced pressure to afford 205f as a yellow solid (165 mg, 66%), which was used for the next step without further purification. MS-ESI: [M+H]+ 583.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11].[Br:30][CH:31]([CH3:35])[C:32](Br)=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CCOCC>[Br:30][CH:31]([CH3:35])[C:32]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:6]2=[O:11])=[O:33]
Reactant: CC(Br)C(=O)Br
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C(C)Br)c3C2=O)ccc1OC
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A solution of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (500 mg, 1.20 mmol) and 2-bromopropionyl bromide (0.140 mL, 1.34 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight. An additional 0.1 mL of 2-bromopropionyl bromide (1 mol) was added and the mixture stirred overnight. To the mixture was added brine (4 mL), Sodium bicarbonate (sat, 10 mL) and methylene chloride (15 mL). The organic layer was separated, was washed with brine (10 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give a yellow oil. The oil was slurried in ether (10 mL). The resulting suspension was filtered and the solid washed with ether to give 2-bromo-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide as a white solid (500 mg, 76% yield): 1H NMR (CDCl3) δ 1.46 (t, J=6.9 Hz, 3H, CH3), 1.97 (d, J=6.9 Hz, 3H, CH3), 2.86 (s, 3H, CH3), 3.75 (dd, J=4.5, 14.4 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.49-4.59 (m, 2H, CHH, CH), 4.09 (q, J=6.9 Hz, 2H, CH2), 5.87 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.09-7.13 (m, 2H, Ar), 7.53 (d, J=7.3 Hz, 1H, Ar), 7.68 (t, J=7.5 Hz, 1H, Ar), 8.73 (d, J=8.4 Hz, 1H, Ar), 10.19 (s, 1H, NH); 13C NMR (CDCl3) δ 14.61, 22.42, 41.54, 43.78, 48.67, 54.44, 55.87, 64.45, 111.39, 112.3, 116.10, 116.79, 120.35, 124.76, 129.14, 131.13, 136.02, 136.82, 148.55, 149.70, 167.28, 168.42, 169.11.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[N:3]=[C:4]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cc3ccc(Cl)cc3)cc(C(C)(C)O)n2)CC1
Temperature: 150 °C
Yield: 29.7 %

Procedure:
To a mixture of 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidin-4-yl]-propan-2-ol (500 mg, 1.68 mmol), 4-amino-1-Boc-piperidine (404 mg, 2.02 mmol), sodium tert-butoxide (243 mg, 2.52 mmol) in dioxane (2.5 mL) was added under an argon atmosphere palladium(II) acetate (30 mg, 0.14 mmol) and 2-(dicyclohexylphosphino)biphenyl (94 mg, 0.27 mmol) and the reaction mixture was heated to 150° C. for 30 minutes in a microwave oven. It was diluted with ethyl acetate (15 mL) and washed with water (15 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 60:40) afforded the title compound (230 mg, 30%) as a light brown oil.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[C:6]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(=[S:8])[NH2:7]>C(Cl)(Cl)Cl>[CH3:4][C:3]1[N:7]=[C:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[S:8][CH:2]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1csc([C@@H]2CCCN2C(=O)OCc2ccccc2)n1
Yield: 53.5 %

Procedure:
Part A. Chloroacetone (36 mg, 0.37 mmol) was added to a solution of benzyl (S)-2-thiocarbamoyl-pyrrolidine-1-carboxylate (90 mg, 0.34 mmol) in dry chloroform (2 mL). The resulting solution was heated to reflux for 24 h then purified by preparative HPLC yielding benzyl (S)-2-(4-methylthiazol-2-yl)-pyrrolidine-1-carboxylate as a colorless oil (55 mg, 54% yield): HPLC (method 1) tR=3.11 min, Purity 100%; LCMS (method 4) tR=1.57 min, m/z 303 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(CCCCN)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:9]([CH2:8][CH2:7][CH2:6][CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: Cc1ccccc1
Agent: C[Al+]C
Agent: NCCCCc1ccccc1
Agent: [Cl-]
Product: O=C1N(CCCCc2ccccc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 4-Phenyl-butylamine. MS (ESI): 461.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CO[CH:16](OC)[CH2:17][CH:18](OC)OC.O.[NH4+].[OH-]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]3[N:13]=[CH:16][CH:17]=[CH:18][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(CC(OC)OC)OC
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2cc3ncccn3n2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazole-5-amine (5.0 g, 0.028 mol) in acetic acid (50 mL) is added 1,1,3,3-tetramethoxypropane (5.79 g, 0.035 mol). The mixture is stirred at 110° C. for 1 h. The reaction mixture is then poured into water, basified with NH4OH and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. 6.8 g (79%) of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine are obtained as a beige solid which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH3:21].C[Si]([C:26]#[N:27])(C)C>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:13][CH:14]=2)[C:26]#[N:27])=[CH:5][C:4]=1[CH3:21]
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C
Reactant: C[Si](C)(C)C#N
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methoxy-3-methylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 63%).
Reaction SMILES: [NH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[C:3]([CH2:14][NH:15][CH3:16])=[N:2]1.[C:17]([BH3-])#N.[Na+].C=O.[OH-].[Na+]>CO.O.[Cl-].[Na+].C(OCC)(=O)C.C(O)(=O)C>[NH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[C:3]([CH2:14][N:15]([CH3:17])[CH3:16])=[N:2]1
Reactant: CNCc1n[nH]c2c1CCc1ccccc1-2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CN(C)Cc1n[nH]c2c1CCc1ccccc1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-methylamine (3.1 g), sodium cyanoborohydride (1.1 g) and glacial acetic acid (2 cm3) in methanol (50 cm3) was cooled to 0° C. and formaldehyde solution (38% formaldehyde in methanol; 2 cm3) was added. The mixture was stirred at 0° C. for 90 minutes, with mild effervescence observed. The mixture was basified with aqueous sodium hydroxide (1 mol dm-3 ; 30 cm3), diluted with water (50 cm3) and saturated with sodium chloride before extraction with ethyl acetate (2×50 cm3). The organic phases were dried (MgSO4), filtered and concentrated to give (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-dimethylamine as an orange foam (3.17 g; 96%); δH (360 MHz; CDCl3) 2.35 [6H, s, N(CH3)2 ], 2.73 (2H, t, J 7.7, --CH2 --), 2.95 (2H, t, J 7.7, --CH2 --), 3.59 (2H, s, --CH2N), 7.17-7.26 (3H, m, 3 of ArH) and 7.77 (1H, d, J 7, 1 of ArH); m/z (CI+ ; NH3) 455 (M2H+ ; 3%) and 228 (MH+ ; 100).