Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])=[C:9]([CH:18](OCC)[O:19]CC)[N:8]([CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:6]=2[N:7]=1.O>CC(O)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])=[C:9]([CH:18]=[O:19])[N:8]([CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:6]=2[N:7]=1
Reactant: CCOC(OCC)c1c(-c2ccccc2C)c2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1-c1c(C=O)n(CCNC(=O)OC(C)(C)C)c2nc(Cl)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate (0.85 g, 1.74 mmole) in AcOH (10 mL) was added water (1.5 mL), stir at room temperature for 16 hrs. The crude reaction was then concentrated under vacuum. After addition of ethyl acetate (50 mL) the organic layer was washed with satd. NaHCO3. The organic layer was dried with magnesium sulfate and then concentrated under vacuum to afford the crude intermediate, tert-butyl N-[2-[2-chloro-6-formyl-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate. To this crude intermediate in DMF (5 mL) was added oxone (1.3 g). After stirring for 2.5 hrs, water (20 mL) and ethyl acetate (100 mL) was added. The organic layer was separated, dried and then concentrated under vacuum to afford the crude product which was columned over silica gel using hexane/ethyl acetate (0-50%) to afford 7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (0.112 g). LCMS (ESI) 431 (M+H).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([O:18]CC)=O)=[C:4]12.[CH:21]1([C:24](=[N:26]O)[NH2:25])[CH2:23][CH2:22]1.C(Cl)Cl>C(O)C>[CH:21]1([C:24]2[N:26]=[C:16]([C:15]3[N:14]=[CH:13][N:5]4[C:6]5[CH:12]=[CH:11][S:10][C:7]=5[C:8](=[O:9])[N:3]([CH3:2])[C:4]=34)[O:18][N:25]=2)[CH2:23][CH2:22]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)c1ncn2c3ccsc3c(=O)n(C)c12
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(=O)c2sccc2n2cnc(-c3nc(C4CC4)no3)c12
Temperature: 25 °C

Procedure:
Sodium (50 mg) was dissolved in dry ethanol (20 ml). Ethyl 4,5-dihydro-4-methyl-5-oxo-imidazo[1,5-a]thieno[2,3-e]-pyrimidine-3-carboxylate (0,55 g, 2 mmole), cyclopropanecarboxamide oxime (0,5 g, 5 mmole), and 5 g crushed mol. sieves 4 Å were added. The mixture was refluxed for 6 hours, then cooled to room temperature, where methylene chloride was added (30 ml). The mol. sieves were filtered off and the filtrate was reduced to 5 ml by evaporation in vacuo. Addition of water (25 ml) afforded a crystalline precipitate of the title compound which was collected by filtration. M.p. 215°-21° C. (Compound 8).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3](CC(O)=O)([C:5]([OH:7])=[O:6])[OH:4].O1B([C@@H](NC(=O)CNC(=O)C2C=C(Cl)C=CC=2Cl)CC(C)C)OB([C@@H](NC(=O)CNC(=O)C2C=C(Cl)C=CC=2Cl)CC(C)C)O[B:15]1[C@@H](NC(=O)CNC(=O)C1C=C(Cl)C=CC=1Cl)CC(C)C>CCOC(C)=O>[O:12]=[C:1]1[O:13][BH:15][O:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)c1cc(Cl)ccc1Cl)B1OB([C@H](CC(C)C)NC(=O)CNC(=O)c2cc(Cl)ccc2Cl)OB([C@H](CC(C)C)NC(=O)CNC(=O)c2cc(Cl)ccc2Cl)O1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: O=C1CC(C(=O)O)OBO1
Reaction time: 3 h

Procedure:
To a solution of citric acid (10.1 g, 52.6 mmol) in EtOAc (300 mL) with an internal temperature of about 74° C. was added a solution of N,N′,N″-{boroxin-2,4,6-triyltris[[(1R)-3-methylbutane-1,1-diyl]imino(2-oxoethane-2,1-diyl)]}tris(2,5-dichlorobenzamide) (20.0 g, 19.5 mmol) in EtOAc (60 mL). The solution was cooled slowly (about 0.33° C./min) until the internal temperature was about 60° C. and the mixture was stirred for 3 h. The resulting slurry was cooled slowly (rate of about 0.12° C./min) until the internal temperature was about 25° C. and the mixture was stirred overnight. The resulting precipitate was collected by filtration to yield 4-(R,S)-(carboxymethyl)-2-OR)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid Form 2 as a crystalline solid (26.7 g, 98%). 1H NMR (500 MHz, DMSO-d6, δ 110° C.): 10.08 (s, 1H), 8.69 (s, 1H), 7.61 (s, 1H), 7.52 (d, J=1.3 Hz, 2H), 4.26 (d, J=5.5 Hz, 2H), 2.70 (q, J=14.5 Hz, 4H), 2.70 (bs, 1H), 1.72 (sept, J=6.5 Hz, 1H), 1.42 (ddd, J=5.2 Hz, J=8.6 Hz, J=13.9 Hz, 1H), 1.28 (ddd, J=5.3, J=9.4 Hz, J=14.3 Hz, 1H), 0.91 (dd, J=3.3 Hz, J=6.6 Hz, 6H). 13C NMR (100 MHz, DMSO-d6, δ 100° C.): 21.65, 23.34, 25.09, 38.39, 38.98, 42.07, 76.25, 128.97, 129.14, 130.94, 131.48, 131.73, 137.05, 165.44, 170.23, 175.74, 177.43. MS (m/z) in CH3CN: [M+Na] calculated for C20H23BCl2N2NaO9, 539.1. found, 539.1.
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+]>O>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
10 parts sodium stearate and 100 gelatin peptide were dissolved in 140 parts warm water, after which the pH was adjusted to 9.0; a stearic acid-gelatin peptide reactant was obtained by heating 30 minutes at 120° C. Shampoo was prepared using this reactant, according to the recipe indicated in Table 6 below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:13].N1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>ClCCl>[Br:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12](=[O:13])[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:32]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1NC(=O)CBr
Reaction time: 3 h

Procedure:
To a solution of (2-Amino-5-trifluoromethyl-phenyl)-(5-chloro-2-methoxy-phenyl)-methanone (IV)(14.13 g, 42.9 mmol, 1 eq) in Dichloromethane (120 mL) at 0° C. was added pyridine (4.65 mL, 57.5 mmol, 1.34 eq), then Bromoacetyl bromide (4.98 mL, 57.2 mmol, 1.33 eq). After 3 h, the reaction was quenched with Sodium bicarbonate (aq) and extracted three times into Dichloromethane. The combined organic layers were dried over Magnesium sulfate, filtered and concentrated in vacuo. The product was used without further purification. 1H NMR (300 MHz, CDCl3) δ 12.18 (s, 1H), 8.88 (d, J=8.9 Hz, 1H), 7.82 (dd, J=1.9, 8.9 Hz, 1H), 7.71 (d, J=1.9 Hz, 1H), 7.51 (dd, J=2.6, 8.9 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 4.08 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:15])[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:22][CH2:23][N:24]=3)[C:10]([NH:13][C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)=[N:11][C:12]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(OCCOCCNC(=O)OC(C)(C)C)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-[2-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)ethoxy]ethyl}carbamate (Step 3, 3.6 g, 6.8 mmol) was diluted in a mixture of trifluoroacetic acid (18 mL) and dichloromethane (70 mL). The mixture was stirred at rt overnight, then was concentrated in vacuo. The resultant orange oil was redissolved in dichloromethane and treated with an excess of triethylamine. After stirring at rt for 0.5 h, the solvent was evaporated under reduced pressure and the residue triturated with ethyl acetate. The title compound was isolated by vacuum filtration and dried in the vacuum oven. This material was contaminated with a small amount of triethylamine, but was suitable for use in the next step as is. HPLC MS RT=1.09 min, MH+=425.2. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.01 (2H, m), 3.69 (2H, t), 3.89 (2H, m), 4.02 (3H, s), 4.26 (2H, m), 4.44 (2H, m), 4.57 (2H, m), 7.49 (1H, d), 7.76 (1H, m), 8.05 (1H, d), 8.72 (1H, m), 8.89 (1H, m), 9.44 (1H, m).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A solution of freshly distilled (b.p. 82° C., 2 torr) benzothiazole (10 g, 0.074 mole) in 250 ml tetrahydrofuran was cooled under nitrogen to -78° C. and stirred at this temperature for 15 minutes. To this was added dropwise over 15 minutes 29.6 ml (0.074 mole) 2.5M n-butyllithium, stirring continued for 25 minutes, and 8.6 ml (0.111 mole) dimethylformamide was added and the reaction mixture stirred for an hour. The mixture was allowed to warm to room temperature, 200 g ice was added and the solvent evaporated in vacuo. The aqueous residue was extracted with 5×100 ml ethyl acetate, the extracts dried (MgSO4), concentrated to a small volume and chromatographed on a silica gel column, eluting with 96:4 chloroform/ethyl acetate to yield 8.4 g of the desired aldehyde, m.p. 74.5°-75° C. 1H--NMR(CDCl3)ppm (delta): 7.54 (m, 2H), 7.97 (m, 1H), 8.21 (m, 1H), 10.1 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:5][OH:6])[NH2:4].C(=O)(O)[O-].[Na+].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1>CC(C)=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=2)[O:6][N:5]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(CCl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: ClCc1noc(-c2ccc(Cl)cc2)n1

Procedure:
A solution of 2-chloroacetamidoxime (0.5 g) and sodium bicarbonate (0.78 g) in 10 mL of anhydrous acetone was treated with 4-chlorobenzoyl chloride (0.58 mL) at room temperature for 2 hours, concentrated in vacuo, dissolved in water and extracted with ethyl acetate. The organic layers were combined, dried with MgSO4 and concentrated to a semi-solid. This material was redissolved in toluene (50 mL). refluxed under nitrogen for 15 hours, cooled and absorbed on to silica gel. Chromatography using ethyl acetate:hexane (1:9) gave the pure title product as a light yellow solid, mp 79-80° C. Mass spectrum m/e: 228 (M+), 1H NMR (250 MHz, CDCl3) δ 8.1 (d, 2H), 7.5 (d, 2H), 4.7 (s, 2H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][N:15]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCOCCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 94.7 %

Procedure:
A mixture of methyl thiosalicylate (7.4 g, 43.8 mmol), tert-butyl 3-[3-[2-cyano-4-pyridyl]propoxy]propanoate (14.0 g, 48.2 mmol), triethylamine (7.1 g, 70.2 mmol) and toluene (37 ml) was refluxed under nitrogen atmosphere for 24 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a column chromatography and eluted with ethyl acetate-hexane (3:2, v/v) to give the titled compound (17.7 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:11][CH:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:13](=[O:14])[CH:12]([Cl:11])[CH3:16])=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)c1cscc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cscc1NC(=O)C(C)Cl
Temperature: -15 °C
Yield: 82 %

Procedure:
To a suspension of 4-amino-thiophene-3-carboxylic acid methyl ester (2.0g) in dichloromethane (25 mL) was added 2-chloropropionyl chloride (1.13 mL). The reaction mixture was then cooled down to −15° C. and a solution of triethylamine (3.2 mL) in dichloromethane (5 mL) was slowly added over 30 minutes. After such time the reaction mixture was allowed to warm up to room temperature, and the solution was washed twice with water, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a light yellow solid (2.1g, 82%). MS (EI): 247.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1C(O)=O.B.[O:14]1CCC[CH2:15]1.CO>O1CCCC1>[O:1]1[C:5]2[C:6]([CH2:15][OH:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C(O)C1Cc2ccccc2O1
Agent: B
Solvent: CO
Product: OCc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-Dihydrobenzofuran carboxylic acid (5.047 g, 30.77 mmol) in tetrahydrofuran at −10° C. was treated dropwise with a solution of 1.0 M borane-tetrahydrofuran (20 mL 20 mmol). The temperature was allowed to warm to room temperature overnight, and was then treated with additional 1.0 M borane-tetrahydrofuran (10 mL 10 mmol), and stirred at room temperature for 2 hours. The mixture was cooled to 5° C., slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2×), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:ethyl acetate, 3:2) to provide the title compound. MS (DCI/NH3) M/Z 168 (M+NH4)+; 1H NMR (CDCl3) δ 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1H), 7.08 (dd, 1H), 7.14 (dd, 1H).
Reaction SMILES: C([O-])([O-])=O.[Ca+2:5].[C:6]([OH:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([OH:16])=[O:15])([C:10]([OH:12])=[O:11])[OH:9]>O>[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[Ca+2:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reaction time: 15 h

Procedure:
To sixty grams of bright casing solution contained in a beaker and given continuous agitation with a magnetic stir bar, there were added 1.34 grams of Ca(OH)2 powder, 15 grams of CaCO3 powder, and 22.0 grams of citric acid dissolved in 60 ml of water. Upon completion of effervescence, the mixture was filtered through a Whatman grade 54 filter paper. The resultant clear solution had a pH of 3.47 and a solids content of about 19.3%. If allowed to stand quiescent for 15 hours, it formed a precipitate of calcium citrate, Ca3 (C6H5O7)2.4H2O.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH:31]=[CH:30][N:29]=[N:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: c1c[nH]nn1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-n2ccnn2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 24.5 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1H-1,2,3-triazole (197 mg, 2.84 mmol) and potassium carbonate (47 mg, 0.34 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20, 56 mg, 25%) which was obtained as a white solid. MS: m/e 401.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6](Cl)[CH:5]=[C:4]([CH3:11])[N:3]=1.O.[NH2:13][NH2:14]>ClCCCl>[Cl:1][C:2]1[C:7]2[CH:8]=[N:13][NH:14][C:6]=2[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: NN
Reactant: Cc1cc(Cl)c(C=O)c(Cl)n1
Solvent: O
Solvent: ClCCCl
Product: Cc1cc2[nH]ncc2c(Cl)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-6-methylpyridine-3-carbaldehyde (12 g, 63 mmol) in 1,2-dichloroethane (200 mL) was added hydrazine monohydrate (9.52 g, 0.190 mol), and the reaction mixture was heated at 80° C. for 18 hours. After removal of solvents in vacuo, the residue was suspended in water (150 mL) and stirred for 30 minutes. The resulting precipitate was collected by filtration and washed with petroleum ether (2×250 mL), then was suspended in chloroform (150 mL), stirred for 30 minutes and filtered. The chloroform suspension was repeated twice to afford the product as a white solid. Yield: 6.7 g, 40 mmol, 63%. LCMS m/z 168.1 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 13.70 (br s, 1H), 8.21 (s, 1H), 7.38 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[H-].[Na+].I[CH3:17]>C1COCC1>[C:9]([O:8][C:7](=[O:13])[NH:6][C@H:4]1[CH2:3][C@@H:2]([O:1][CH3:17])[CH2:5]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 192.1 %

Procedure:
tert-Butyl (cis-3-hydroxycyclobutyl)carbamate (0.8 g, 4.3 mmol) was dissolved in dry THF (25 mL) under a nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution, sodium hydride (60% dispersion in oil, 0.17 g, 4.3 mmol) was added portion wise (evolution of H2 observed). The mixture was stirred at RT for 30 min. then iodomethane (0.40 mL, 1.5 mmol) added dropwise and the resulting yellow suspension stirred at rt for 16 h. The reaction mixture was quenched with saturated aqueous solution of NH4Cl (20 mL) and partitioned between saturated aqueous solution of NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-70% EtOAc in cyclohexane) to afford the title compound as a white solid (0.58 g, 66%). 1H NMR (CDCl3, 300 MHz): δ 4.66 (1H, br, NH), 3.71-3.62 (1H, m), 3.61-3.50 (1H, m), 2.71 (3H, s), 2.76-1.62 (2H, m), 1.78-1.62 (2H, m), 1.41 (9H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]1=[O:19])([O-])=O.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]1=[O:19]
Reactant: O=C1OC(c2ccccc2)CCN1Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1CN1CCC(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
3-(2-Nitrobenzyl)-6-phenyl-[1,3]-oxazinan-2-one (1.59 g, 5.10 mmol), iron powder (1.42 g, 25.4 mmol), ammonium chloride (0.14 g, 2.62 mmol) were suspended in ethanol (30 ml) and water (15 ml) and heated to reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and 3-(2-aminobenzyl)-6-phenyl-[1,3]-oxazinan-2-one (1.43 g) was obtained by evaporating the solvent under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(O)(c1cccc(-c2ccc(Cl)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccc(Cl)cc2)c1)c1c[nH]cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(4′-Chloro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (0.71 g) and pyridine hydrochloride (0.25 g) were dissolved in methanol (20 ml), and the mixture was stirred at 60° C. for 2 h. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was concentrated. Water and ethyl acetate were added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chomatography (eluent, dichloromethane:methanol=40:1). Recrystallization from hexane-ethyl acetate gave the title compound (0.31 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:6]=1)=[O:4].[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)OC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 3 h

Procedure:
To a solution of 1.7 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester in 10 ml water/THF 1:1, 4 ml of a 1M aqueous NaOH were added at RT and the mixture was stirred for 3 h with LCMS reaction control. Then the reaction mixture was acidified to pH 3 with half concentrated HCl and extracted with DCM (3×50 ml). The organic phase was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was subjected to the next reaction step without further purification.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:25][C:17]=2[CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].C([SiH](CC)CC)C>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[C:27](=[O:28])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[CH:18][C:17]=3[CH2:25]2)=[CH:35][CH:34]=1.[C:39]([OH:41])([C:38]([F:43])([F:42])[F:37])=[O:40]
Reactant: O=C1c2c(cc3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(cc3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 283b (11 mg) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 285, TFA salt, (3.9 mg) as a yellow solid: 1H NMR (CDCl3) δ 9.1 (d, 1H), 8.3 (d, 1H), 7.6 (m, 1H), 7.35 (s, 1H), 7.33 (m, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.4(s, 2H); MS: 309 (M+1).