Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[OH-:17].[Na+].Cl>C1COCC1>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([OH:17])[N:7]=1)[CH2:9]2
Reactant: [OH-]
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)cc(N2CC3CCC(C2)O3)n1
Temperature: 150 °C
Yield: 221.4 %

Procedure:
In three 2-5 mL microwave vials was each placed 3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9, 100 mg, 0.384 mmol) in THF (2 ml). A 1N solution of sodium hydroxide (2 ml, 2.000 mmol) was added to each vial. The reaction was heated under microwave irradiation at 150° C. for 30 min. The contents of the three microwave vials were combined, 6 mL 2N HCl was added to acidify (pH˜3). Silica gel was added and the mixture was concentrate purify by silica gel chromatography, using a gradient (0-15%) of MeOH in dichloromethane to give 205 mg (0.85 mmol, 74%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]N)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:46]([O:53][C:54]([NH:56][C:57]([N:59]1C=CC=N1)=[NH:58])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:56]([C:54]([O:53][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:55])[C:57]([NH2:59])=[NH:58])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(C(=N)N)C(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (70 mg) in tetrahydrofuran (3 mL) was added N-(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.27 g), and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate-ethyl acetate/ethanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(N-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}-methyl)-5-isopropyl-1H-pyrazole (50 mg). This material was dissolved in methanol (1 mL). To the solution was added sodium methoxide (28% methanol solution, 0.01 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 4-({4-[3-(N′-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (35 mg). This material was dissolved in methanol (2 mL). To the solution was added 10% palladium-carbon powder (15 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (27 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[CH2:7]([O:9]CC)[CH3:8].[ClH:12]>C(O)C>[ClH:12].[CH3:1][C:2]([CH3:6])([OH:5])[C:3](=[NH:4])[O:9][CH2:7][CH3:8]
Reactant: CCOCC
Reactant: CC(C)(O)C#N
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Four grams of 2-methyllactonitrile is added to 100 ml. of diethyl ether containing 10 ml. of ethanol followed by saturation of the resulting solution with hydrogen chloride gas. The reaction mixture is allowed to stir at room temperature for 18 hrs. and subsequently concentrated to an oil which on slurrying in ether gave 7.2 g. of the desired product.
Reaction SMILES: C(OC([C:6]1[NH:7][CH:8]=[C:9]2[C:14]=1[CH:13]1[CH2:15][CH2:16][CH:10]2[CH:11]=[CH:12]1)=O)C.[OH-].[Na+]>C(O)CO>[CH:6]1[NH:7][CH:8]=[C:9]2[C:14]=1[CH:13]1[CH2:15][CH2:16][CH:10]2[CH:11]=[CH:12]1
Reactant: CCOC(=O)c1[nH]cc2c1C1C=CC2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: C1=CC2CCC1c1c[nH]cc12
Temperature: 175 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
Fed into a light-shielded reaction vessel equipped with a reflux condenser were 1.95 g (9.6 mmol) of ethyl-4,7-dihydro-4,7-ethano-2H-isoindole-1-carboxylate synthesized in Step 1-2, 100 ml of ethylene glycol, and 2.0 g of sodium hydroxide. Then, the vessel was replaced with nitrogen and the mixture was stirred at 175° C. for 2 hours. After that, the reaction solution cooled to room temperature was poured into ice water, the whole was extracted with chloroform, and the extract was washed with a saturated salt solution. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to yield 4,7-dihydro-4,7-ethano-2H-isoindole (0.98 g, 70.4% yield).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:31](=[O:33])[CH3:32])(=O)C>N1C=CC=CC=1>[C:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][O:22][C:31](=[O:33])[CH3:32])[C@@H:18]([O:19][C:18](=[O:19])[CH3:20])[C@H:16]2[O:17][C:16](=[O:17])[CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Nc4ccccc4)nc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)nc(Nc4ccccc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
In 100 parts by volume of pyridine is suspended 10 parts by weight of 2-phenylaminoinosine and 50 parts by weight of acetic anhydride is added dropwise. The mixture is stirred for 3 hours, at the end of which time it is concentrated under reduced pressure. The residue is recrystallized from 5 parts by volume of methanol. The procedure gives 2 parts by weight of 2-phenylamino-2',3',5'-tri-O-acetylinosine in the form of colorless flocs.
Reaction SMILES: [CH:1]([N:4]([CH:12]([CH3:14])[CH3:13])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:2].Br[CH2:16]CC(OCC)=O.CC1CCCC(C)N1.[ClH:31]>O.C(O)C>[ClH:31].[CH3:14][CH:12]1[CH2:13][CH2:16][CH2:2][CH:1]([CH3:3])[N:4]1[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CCBr
Agent: CC1CCCC(C)N1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN1C(C)CCCC1C

Procedure:
Ethyl 3-(2,6-dimethylpiperidino)propionate hydrochloride may be obtained by working according to the method described in Example 6 for the preparation of ethyl 3- diisopropylaminopropionate, but starting with ethyl 3bromopropionate (18.1 g), 2,6-dimethylpiperidine (27 cc) and ethanol (30 cc). The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is taken up with water (50 cc) and 4N aqueous hydrochloric acid solution (30 cc). The aqueous phase is washed with ethyl ether (2×80 cc) and neutralized with 4N aqueous sodium hydroxide solution (40 cc). The insoluble oil is extracted with ethyl ether (3×120 cc); the organic extracts are then washed with water (2×80 cc) and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is dissolved in ethyl ether (100 cc). A 4.5N solution (13.4 cc) of gaseous hydrochloric acid in ethyl ether is added to the solution obtained. A product precipitates. It is separated by filtration, washed and dried in the air. Ethyl 3-(2,6-dimetylpiperidino)-propionate hydrochloride (14.4 g), m.p. 146° C., is thereby obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12]C(=O)C)=[CH:5][C:4]=1[CH3:16].[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH2:12])=[CH:5][C:4]=1[CH3:16]
Reactant: COc1nc([N+](=O)[O-])c(NC(C)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc([N+](=O)[O-])c(N)cc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The crude product (1.93 g) of N-(6-methoxy-5-methyl-2-nitro-3-pyridinyl) acetamide was dissolved in methanol (36 ml), 5N sodium hydroxide solution (6 ml) was added, and the reaction mixture was stirred for 15 minutes at room temperature. After water was added to the reaction solution, it was extracted with ethyl acetate and dried over magnesium sulfate, and the solvent was evaporated, thereby yielding the title compound (1.06 g, 5.79 mmol) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][CH2:31][NH2:32])=[CH:25][CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:32][CH2:31][CH2:30][S:29][C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCSc1ccncc1
Product: CCCc1c(OCCCCCC(=O)NCCSc2ccncc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 2-(4-pyridinylthio)ethyl amine according to procedure A and the product was purified by crystallization from ethyl acetate-hexane to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[2-(4-pyridinylthio)ethyl]hexanamide, the title compound, mp 63°-65°, in 52% yield.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][CH:16]=3)=[CH:14][C:9]=2[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([CH2:21][N:46]4[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]4)[N:20]=3)=[CH:14][C:9]=2[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CN1c2cc(-c3cccc(CO)n3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1c2cc(-c3cccc(CN4CCN(S(C)(=O)=O)CC4)n3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To (6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}pyridin-2-yl)methanol (25-1) (30 mg, 0.079 mmol, 1.0 eq) was dissolved in NMP (1 mL) and triethylamine (0.04 mL, 0.24 mmol, 3.0 eq) was added followed by mesyl chloride (0.008 mL, 0.1 mmol, 1.2 eq). After 10 minutes, 1-(methylsulfonyl)piperazine (28.6 mg, 0.17 mmol, 2.1 eq) and DIPEA (0.061 mL, 0.35 mmol, 4.4 eq) were added. The resulting mixture stirred at 80° C. for 10 minutes. The mixture was cooled and purified by reverse phase chromatography (Waters Sunfire MSC18, 10-100% acetonitrile in water with 0.1% TFA modifier) to afford 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (25-2) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.99 (s, 1 H); 7.98 (d, J=8.0 Hz, 1 H); 7.84 (dd, J=1.6, 8.4 Hz, 1 H); 7.77 (d, J=1.6 Hz, 1 H); 7.44 (dd, J=1.6, 6.0 Hz, 1 H); 7.13 (d, J=8.4 Hz, 1 H); 4.66 (s, 2 H); 3.97 (d, J=7.2 Hz, 2 H); 3.62 (brs, 8 H); 3.39 (s, 3 H); 2.99 (s, 3 H); 2.21 (m, 1 H); 1.65 (m, 1 H); 1.44 (m, 1 H). HRMS m/z (M+H) 528.1538 found, 528.1545 required.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[S:2].N1CC[CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]C1>O1CCCC1>[NH2:8][C:1]([N:3]1[CH2:4][CH2:15][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH2:7]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
To a solution (200 mL) of 1,1′-thiocarbonyldiimidazole (15.0 g) in tetrahydrofuran was added ethyl piperidine-4-carboxylate (12.59 g) at room temperature, and the mixture was stirred at room temperature for 3 hrs and then at 55° C. for 1 hr. Tetrahydrofuran (ca. 100 mL) was distilled off under reduced pressure and 2M ammonia methanol solution (150 mL) was added. After stirring the reaction mixture at room temperature for 15 hrs, the mixture was concentrated. The residue was diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1, v/v) to give ethyl 1-(aminocarbonothioyl)piperidine-4-carboxylate as colorless crystals (4.76 g, yield 27%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 97-98° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C(O)(=O)CC.[C:18]1([NH:24][C:25](=O)[CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B.[N:35]1[C:43]2[C:38]3[C:39](=[CH:44][CH:45]=[CH:46][C:37]=3[C:36]=1S)[CH:40]=[CH:41][CH:42]=2>O1CCCC1>[N:28]1([CH2:27][CH2:26][CH2:25][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:36]2[C:37]3[CH:46]=[CH:45][CH:44]=[C:39]4[C:38]=3[C:43](=[CH:42][CH:41]=[CH:40]4)[N:35]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: O=C(CCn1ccnc1)Nc1ccccc1
Agent: B
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCC(=O)O
Solvent: C1CCOC1
Product: c1ccc(N(CCCn2ccnc2)C2=Nc3cccc4cccc2c34)cc1

Procedure:
The reaction of 1,1'-carbonyldiimidazole and 3-(1e,uns/H/ -imidazol-1yl)propanoic acid in tetrahydrofuran solution, followed by treatment with aniline leads to the formation of N-phenyl-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-phenyl-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-phenyl-3-(1H-imidazol-1-yl)propanamide. The latter compound with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol leads tot eh formation of the title compound, under the conditions of Example 55.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+].[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:17][CH:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]([OH:28])=[O:27])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.6 mmol (1.71 g) of 2-naphthylsulphonyl chloride in 10 ml of dichloromethane and a solution of 7.9 mmol (0.32 g) of sodium hydroxide in 10 ml of water are added slowly in succession to 7.6 mmol (1.25 g) of phenylalanine and 7.6 mmol (0.3 g) of sodium hydroxide in 10 ml of water. The reaction mixture is stirred for 1 hour at room temperature. After decanting, the aqueous phase is washed with dichloromethane and rendered acidic to pH=2 with a dilute hydrochloric acid solution. After extraction with dichloromethane, the organic phase is dried over sodium sulphate and concentrated to yield the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:25]=[CH:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Yield: 91.2 %

Procedure:
To a solution of 1.0 g (2.71 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) and 0.36 ml (3.25 mmol) ethyl acrylate in 30 ml toluene were added 0.67 g (8.15 mmol) sodium acetate, 82.6 mg (0.27 mmol) tri(o-tolyl)phosphine and 0.04 mg (0.1 mmol) allylpalladium chloride dimer. The reaction mixture was heated under reflux for 20 h, then poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with 10% aqueous citric acid solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (0.032–0.063 mm) with n-hexane:ethyl acetate (9:1) as eluant to afford the desired compound as a yellow solid (91.2%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1)(=[O:18])=[O:17])[CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])C.[Li+].[BH4-]>C1COCC1>[F:25][C:23]1[CH:24]=[C:19]([S:16]([NH:15][CH:5]([CH2:4][OH:3])[CH:6]([C:7]([F:10])([F:8])[F:9])[C:11]([F:12])([F:13])[F:14])(=[O:17])=[O:18])[CH:20]=[C:21]([F:27])[C:22]=1[F:26]
Reactant: CCOC(=O)C(NS(=O)(=O)c1cc(F)c(F)c(F)c1)C(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of 4,4,4-trifluoro-2-(3,4,5-trifluoro-benzenesulfonylamino)-3-trifluoromethyl-butyric acid ethyl ester (0.54 g, 1.207 mmol) in THF (10 mL) was added LiBH4 in THF (2.40 mL, 4.81 mmol) at 0° C. The reaction was allowed to warm to 25° C. for 19 h. The reaction was cooled to 0° C., quenched with 2N HCl (slow addition), and diluted with Et2O (40 mL). The organic layer was washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), dried over MgSO4, filtered and concentrated to obtain a crude oil (0.49 g). The crude product was purified by Biotage Flash™ chromatography, eluent: 1:7 EtOAc-hexanes, to afford 3,4,5-trifluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzene sulfonamide as a white solid (0.150 g, 29.6%). Mass Spectrum (+ESI): 422 [M+H]+.
Reaction SMILES: CO.[CH3:3][C:4]([CH3:6])=O.[ClH:7].Cl.Cl.[OH:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:21])=[NH:18])=[CH:13][CH:12]=1>C(#N)C>[ClH:7].[CH2:23]([NH:22][C:20]1[NH:19][C:17]([NH:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:32][CH:31]=2)=[N:18][C:4]([CH3:6])([CH3:3])[N:21]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(O)cc1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(O)cc2)N1
Temperature: 40 °C
Reaction time: 63 h

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 16 g (4.6 mmol) of N1-(4-hydroxybenzyl)-N5-octyl-biguanide dihydrochloride, and the mixture was stirred at 40° C. for 63 hours, and refluxed for 8 hours. The solvent was distilled off under reduced pressure, to give a residue, which was dissolved in 80% aqueous acetonitrile. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:2)) to obtain 16 g of a colorless resinous solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1COCCN1
Product: Brc1cccc(CN2CCOCC2)n1
Yield: 61.4 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.415 g, 2.23 mmol) and morpholine (0.195 g, 2.23 mmol). The crude product was purified (SiO2: 0-3% 2 M NH3 in MeOH/DCM) to give the title compound (0.352 g, 61%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:35]N(C=O)C.CI>>[CH3:35][O:12][CH2:11][CH2:10][CH:9]([N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)c4ccccc4)c3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCCC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0° C. The reaction was stirred for 20 min and methyl iodide (22 μL, 0.00035 mol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give 4-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 88%) as a semisolid. m/z=464 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:23])[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([OH:21])[CH:12]=1)[OH:10].[C:24]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:22][C:6]1[CH:5]=[N+:4]([O-:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH3:24])[CH:12]=1)[OH:10]
Reactant: O=C([O-])[O-]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(O)c2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
(S)-3,5-Dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (2 g, 5.46 mmol) was dissolved in DMF (16 mL) then K2CO3 (2 g, 14.47 mmol) and iodomethane (1.72 g, 12.12 mmol) were added and the mixture was stirred at r.t. for 4 h. The mixture was poured into 200 mL of water, filtered, washed with water and dried under vacuum at 40° C. 1.98 g of whitish solid was obtained.