Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[CH3:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[CH3:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccccc1N
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccccc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
2.5 g of sodium triacetoxyborohydride (12.0 mmol) was added to a solution of 1.87 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (10.0 mmol), 10.7 g of 2-methylaniline (10.0 mmol) and 0.57 ml of acetic acid (10.0 mmol) in methylene chloride (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 2.43 g of the title compound (yield: 87%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24]Cl>C(#N)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:22][O:23][CH3:24])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCCl
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cc(O)c(C(=O)OC)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (1.05 g, 5.0 mmol) and anhydrous potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (25 ml) was treated with chloromethyl methyl ether (0.4 ml, 5.27 mmol) and the mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue treated with water (30 ml). The solid material was collected by suction filtration, rinsed with water (2×20 ml) and sucked dry under reduced pressure to afford methyl 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoate (1.02 g, 80%) as a colourless solid. 1H NMR (DMSO-d6) 10.61 (1H, br s), 7.58 (1H, s), 6.62 (1H, s), 5.30 (2H, s), 3.88 (3H, s), 3.42 (3H, s), 3.17 (1H, m), 1.17 (6H, d). MS: [M+H]+ 255.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[S:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=[S:11].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[C:15]2[S:9][C:10](=[S:11])[NH:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C=C2SC(=S)NC2=O)o1
Yield: 89.1 %

Procedure:
A mixture of 5.51 g (50.0 mmol) of 5-methylfuran-2-carboxaldehyde (purchased from Wako Junyaku Kogyo), 6.66 g (50.0 mmol) of rhodanine (purchased from Tokyo Kasei) 12.3 g (150 mmol) of anhydrous sodium acetate (purchased from Kokusan Kagaku) in 35 ml of acetic acid (purchased from Wako Junyaku Kogyo) was refluxed for 30 minutes, cooled and added to 500 ml of water, and the precipitate was collected, washed with water, ethanol and ether in order and dried to give 10.04 g (yield: 89.1%) of of (5-methylfurfurylidene)rhodanine as an orange brown crystalline.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15]/[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:13]\[CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COc1cccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OC/C=C(\C)CCC=C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-6-methoxybenzaldehyde (4.72 g, 30.43 mmol) in dry DMF (50 ml) was added geranyl bromide (7.5 g, 33.50 mmol) followed by solid potassium carbonate (5.5 g, 39.86 mmol). The mixture was stirred at room temperature for 48 h. The suspension was filtered through a layer of dry sodium sulfate (top) and silica gel (bottom), washed with 200 ml ethyl acetate and decanted into a separatory funnel. The mixture was washed sequentially with aqueous ammonium chloride, water (twice), brine, and the organic phase was dried over Na2SO4. The solution was concentrated in vacuo on a rotovap. The brown gel material was then purified by chromatography via silica gel using 8:2 hexanes:ethyl acetate eluent to provide 2-((E)-3,7-dimethylocta-2,6-dienyloxy)-6-methoxybenzaldehyde as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.Cl.Cl.[CH3:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:35]2[CH2:34][CH2:33][N:32]([CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:23]4[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[N:24]=4)[CH2:26][CH2:27]3)[CH2:37][CH2:36]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nccc(N2CCC(CN3CCNCC3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCC(CN3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonylchloride (367 mg) in methylene chloride (5 ml) was added dropwise over 5 minutes to a mixture of 4-[1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine trihydrochloride (625 mg) and triethylamine (1.04 ml) in dichloromethane (20 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1-2% methanol in dichloromethane. Filtration from ether gave 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)-4-piperidyimethyl]piperazine (358 mg), as a solid, mp 135-136° C.
Reaction SMILES: [Br-:1].[Na+].CN(C=O)C.S([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)([O-])(=O)=O>O>[Br:1][CH2:13][CH2:14][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:12][CH2:17][CH2:18][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCC(C)CCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (20 ml) was added to a methylene chloride (50 ml) solution of the 3-methyldodecan-1-ol (4″) (12.8 g, 63.9 mols), and p-toluenesulfonyl chloride (12.8 g, 67.1 mmols) was further added under ice-cooling. The reaction mixture was stirred overnight at 4° C., then poured into diluted hydrochloric acid, and extracted with hexane. The organic layer was washed (water, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure to obtain 21.7 g of a tosylate. Sodium bromide (9.9 g, 96 mols) was added to a DMF solution (100 ml) of the resulting tosylate, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and extracted with hexane. The organic layer was washed (water and a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure to obtain 1-bromo-3-methyldodecane (5″) (15.1 g, 90%). 1H-NMR (90 MHz, CDCl3) 0.8-1.0 (6H,m,Me), 1.0-2.0 (19H,m,2˜11-H), 3.43 (2H,br t,J=7,1-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:36][O:35][C:33](=[O:34])[CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, Step 5) was reacted with methyl 4-(bromomethyl)phenylacetate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e)=528.1 [M+H+].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([CH2:10][O:11][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=1
Reactant: OCc1cncc(Br)c1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2cncc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
To a suspension of NaH (1.12 g, 28.0 mmol) in DMF (75 mL) was added a solution of (5-bromopyridin-3-yl)methanol (4.21 g, 22.4 mmol) in DMF (8 mL) at 0° C. The mixture was allowed to stir at 0° C. for 15 min and then 1-(chloromethyl)-4-methoxybenzene (5.41 g, 34.6 mmol) was added followed by tetra-N-butylammonium iodide (0.91 g, 2.4 mmol). The reaction mixture was allowed to vigorously stir and warm to rt overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous solution was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-bromo-5-{[(4-methoxybenzyl)oxy]methyl}pyridine (4.40 g, 64%) as a yellow oil. LCMS: (FA) ES+ 308.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:33])[N:10]3[CH2:25][CH:24]([O:26]C(=O)C(C)(C)C)[CH2:23][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=2)=[CH:4][CH:3]=1.[C:34]1([O-:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:33])[N:10]3[CH2:25][CH:24]([OH:26])[CH2:23][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC1Cn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CC(O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 6-(4-fluorophenyl)-7-(2-methane-sulfonyl-pyrimidin-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-2-yl ester, 35, (50 mg, 0.105 mmol) in THF (1 mL) is slowly cannulated into a solution of sodium phenolate in THF (1 mL) at 0° C. The cooling bath is removed and the reaction stirred at room temperature for 1 hour. The reaction is quenched with NH4Cl (sat. aq.) (500 μL). The reaction mixture is concentrated in vacuo and the residue diluted taken up in ethyl acetate (15 mL). The solution is washed with water (20 mL) and a 5% aqueous Na2CO3 (20 mL). The combined aqueous layers are extracted with ethyl acetate (25 mL) and brine (20 mL), dried, filtered and concentrated in vacuo. The crude material is purified over silica (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford 9 mg (21% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=5.2 Hz, 1H), 7.46 (t, J=7.8 Hz, 2H), 7.31-7.27 (m, 3H), 7.19 (d, J=8.2 Hz, 2H), 7.03 (t, J=8.6 Hz, 2H), 6.80 (d, J=5.2 Hz, 1H), 5.41 (br s, 1H), 4.82 (m, 1H), 4.23 (d, J=12.4 Hz, 1H), 3.95-3.85 (m, 2H), 3.76 (dd, J=12.4, 4.4 Hz, 1H); HRMS m/z calcd for C22H18FN4O3 (MH+) 405.1363, found 405.1365.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:25][CH:24]3[O:26][CH:21]([CH2:22][CH2:23]3)[CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:25][CH:24]5[O:26][CH:21]([CH2:22][CH2:23]5)[CH2:20]4)=[N:3][C:2]([C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CC5CCC(C4)O5)c3s2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2cc3nc(-c4ccc([N+](=O)[O-])cc4)nc(N4CC5CCC(C4)O5)c3s2)CC1

Procedure:
In a 100 mL microwave vial was placed 3-(2-chloro-6-((4-methylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (168 mg, 0.426 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (127 mg, 0.512 mmol) in DME (5 ml) to give a yellow solution. Na2CO3 (2M solution in water) (0.853 ml, 1.706 mmol) was added. The mixture was degassed by bubbling N2 through the solution. Pd(PPh3)4 (49.3 mg, 0.043 mmol) was added. The mixture was heated under reflux (oil bath at 95 C). LC MS (RT 2.8, M+H=481) showed complete conversion after 7.5 h. The reaction mixture was diluted with ethyl acetate and washed with a sat. solution of NaHCO3. A precipitate remained that was insoluble in either organic or aqueous phase. LCMS showed that both the precipitate and the organic phase contained product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:24][CH:25]([NH2:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:30][CH:25]([CH3:24])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(C(F)(F)F)c1
Reactant: CC(N)C(C)(C)C
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(C)(=O)=O)cc(C(F)(F)F)c1
Yield: 40 %

Procedure:
3-(3-Methoxy-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.22 g, 0.6 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in EXAMPLE 17, 2) without chromatography gave 100 mg (40%) of the title compound. Mp 110-113° C. 1H NMR (200 MHz, CDCl3): δ=0.87 (s, 9H), 1.01 (d, 3H), 3.08 (m, 1H), 3.10 (s, 3H), 3.87 (s, 3H), 6.81 (br s, 1H), 6.95 (br s, 1H), 6.97 (br s, 1H); Analysis: calc. for C18H24N3O3S: C, 51.54%; H, 5.77%; N, 10.02%; Found: C, 51.77%; H, 6.05%; N, 9.80%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7](N)[C:8]=1[C:9]([OH:11])=[O:10].Cl.N([O-])=[O:15].[Na+]>O>[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:15])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(O)cccc1Cl
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
A stirred suspension of 10.0 grams (0.048 mole) of 6-chloroanthranilic acid hydrochloride and 100 mL of concentrated hydrochloric acid in 200 mL of water was cooled to 5° C., and a solution of 3.5 grams (0.050 mole) of sodium nitrite in 50 mL of water was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was warmed to 90° C. where it was stirred for about 10 minutes. The reaction mixture was cooled to ambient temperature and was filtered. The filter cake was washed with cold heptane and dried to yield 3.7 grams of 6-chlorosalicylic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([OH:20])=O)[C:7]=2[C:6]([CH3:21])=[N:5]1)([CH3:3])[CH3:2].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30]>>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:18]([C:8]1[C:7]2[C:6]([CH3:21])=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)[CH:9]=1)=[O:20]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2cc(-c3cn[nH]c3)cc(C(=O)O)c12
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cn[nH]c3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared from 1-isopropyl-3-methyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylic acid and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.059 g, 0.387 mmol) in the same manner as described for example 80 (step c) wherein the contents were stirred at RT for 5 h. The product was collected as a pale yellow solid (30 mg, 20%). 1H NMR (DMSO-d6, 400 MHz): 1.563 (d, J=6.8 Hz, 6H), 2.207 (s, 3H), 2.455 (s, 3H), 2.556 (s, 3H), 4.616 (d, J=6 Hz, 2H), 4.781-4.798 (m, 1H), 5.899 (s, 1H), 7.236 (s, 1H), 7.488 (s, 1H) 7.522 (s, 1H), 7.797 (d, J=9.6 Hz, 2H). LCMS (ES+) m/z: 419.45.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:8]([O:14][CH3:13])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C[O-]
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c([N+](=O)[O-])ccc(N)c1Cl
Yield: 53.1 %

Procedure:
A solution of 2,3-dichloro-4-nitroaniline (25 g) and sodium methoxide (25 g) in methanol (250 ml) is stirred and heated at reflux under a nitrogen atmosphere for 5.5 hours. The reaction mixture is poured into water (1.5 l), the precipitated yellow solid is collected and dried. This material is purified by chromatography on silica gel using 1:1 hexane/ether eluent. The eluents are collected and evaporated to dryness to afford 13 g of title compound, m.p. 118°-123° C.
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][C:7](=[O:9])[CH3:8]>C(O)(=O)C>[Cl:1][C:12]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:3])[CH:13]=1
Reactant: ClCl
Reactant: CC(=O)Nc1ccccc1F
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1F
Reaction time: 4 h

Procedure:
Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during 1 hour, at 25°-27° C, with icewater cooling. While stirring for 4 hours at 25°-27° C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2,000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C to yield 119 parts of 4'-chloro-2 '-fluoroacetanilide as white crystals melting at 152°-155° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:11][O:12][CH2:13][C:14]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:15]
Reactant: COCC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)COC(=O)COC

Procedure:
71 ml of ethyl 4-chloro-3-oxo-butyrate are reacted with 89.5 g of methoxyacetic acid and 132 ml of triethylamine in 1 l of toluene by the procedure described in Example 4. The product is purified by bulb tube distillation.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH2:16]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:13])[CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)=CC(=O)Nc1ccccc1CN
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)=CC(=O)Nc1ccccc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The product of Example 1 (612 mg, 3.0 mmol) was placed in a 25 mL round bottom flask and dissolved in methanol (6 mL). To this solution was added benzaldehyde (0.32 mL, 3.0 mmol) and the mixture was stirred at room temperature for 1 hr. After this time sodium borohydride (170 mg, 4.5 mmol) was added slowly over 10 minutes, and the mixture was allowed to stir for an additional 20 minutes. 15 mL of 1N NaOH was then added to quench the reaction, and the mixture was transferred to a separatory funnel with ethyl acetate. An additional 25 mL of ethyl acetate was added and the organic layer was washed successively with 1N NaOH (3×15 mL), brine (1×15 mL), and then dried over magnesium sulfate, filtered, and evaporated. The product was purified by flash column chromatography with ethyl acetate-hexane (3:7 then 1:1) to yield 3-methyl-but-2-enoic acid [2-(benzylamino-methyl)-phenyl]-amide (839 mg, 95% yield) of a yellow oil. 1H NMR (250 MHz, CDCl3) 10.44 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.39-6.84 (m, 8H), 5.64-5.56 (m, 1H), 3.78 (s, 2H), 3.70 (s, 2H), 2.15 (s, 3H), 1.82 (s, 3H). The amine was then converted to the HCl salt with an excess of 1N HCl in ether to be used in further transformations.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][C:8]1[CH:12]([CH:13]2[CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:11][C:10](=[O:21])[C:9]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30].CCN(CC)CC>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:20][O:19][N:16]1[CH2:17][CH2:18][CH:13]([CH:12]2[C:8]([O:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:9]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:10](=[O:21])[NH:11]2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)Cl
Reactant: CON1CCC(C2NC(=O)C(c3c(C)cc(C)cc3C)=C2O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)NC1C1CCN(OC)CC1
Reaction time: 0.25 h

Procedure:
Ethyl chloroformate (216 mg, 2 mmol) was added dropwise to a mixture of 4-hydroxy-5-(1-methoxy-piperidin-4-yl)-3-(2,4,6-trimethyl-phenyl)-1,5-dihydro-pyrrol-2-one (400 mg, 1.2 mmol), Et3N (606 mg, 6 mmol) and DMAP (60 mg, 0.5 mmol) in acetone (20 ml). The mixture was stirred for 15 min and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel. Yield: 260 mg of carbonic acid ethyl ester 2-(1-methoxy-piperidin-4-yl)-5-oxo-4-(2,4,6-trimethyl-phenyl)-2,5-dihydro-1H-pyrrol-3-yl ester (title compound P1.12) as a solid, mp 154-155° C.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:14]([OH:17])[C:15]#[CH:16].C(NC(C)C)(C)C>C(#N)C.[Cu]I>[N:7]1([CH2:6][C:5]2[CH:12]=[CH:13][C:2]([C:16]#[C:15][CH2:14][OH:17])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C#CCO
Reactant: Brc1ccc(CN2CCCC2)cc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: OCC#Cc1ccc(CN2CCCC2)cc1
Temperature: 60 °C

Procedure:
A mixture of 4.8 g (20.0 mmol) 1-(4-bromo-benzyl)-pyrrolidine, 1.75 mL (30.0 mmol) propargylalcohol, 2.31 g (2.0 mmol) tetrakis-triphenylphosphane-palladium, 381 mg (2.0 mmol) CuI and 7.07 mL diisopropylamine in 100 mL acetonitrile is heated for 14 h at 60° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).