Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].Cl.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=O>CO>[CH3:23][C:24]([CH2:25][CH2:26][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)(C)CC=O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
Aspartame (7.86 g) and methanol (100 ml) were charged to a hydrogenation vessel. The pH was adjusted to 1.3 with 5 ml of 1 N hydrochloric acid, followed by the addition of 3,3-dimethylbutyraldehyde (2.60 g). The vessel was pressure purged with nitrogen (4×), and 0.34 g of 4% palladium on carbon (containing 50% water) was added. After pressure purging the reactor with nitrogen (4×), followed by hydrogen (4×), the mixture was hydrogenated at 50 psig for 12 hours at room temperature. After completion of the reaction, the vessel was pressure purged with nitrogen (4×). The catalyst was removed from the reaction mixture by filtration through powdered cellulose. Methanol (20 ml) was used to rinse the reaction vessel and the filter cake. The filtrate and wash were combined, and methanol was evaporated under reduced pressure. The solution was reduced to 50 ml total volume, and 25 g of deionized water was added. Methanol was again evaporated from the solution under reduced pressure until the methanol content was 25-30%. The crystallized solid was isolated by filtration and washed with 20 ml deionized water. The wet product was dried under vacuum at 40° C. to give 6.5 g neotame (>98% by HPLC).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH3:9])(=[O:4])=[O:3]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methanesulfonyl chloride (13.2 mL, 170 mmol) was added to a 0° C. solution of tert-butyl [(2S)-1-hydroxypropan-2-yl]carbamate (28.4 g, 162 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (350 mL), and the reaction mixture was allowed to stir for 30 minutes. After aqueous ammonium chloride solution was added to the reaction mixture, the aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting sticky white solid was slurried with diethyl ether (100 mL), stirred for 10 minutes, and filtered to afford the product as a white solid. Yield: 28.8 g, 114 mmol, 70%. The filtrate was concentrated under reduced pressure and recrystallized from diethyl ether (the hot mixture was filtered through Celite before crystallization) to provide additional product as a white solid. Yield: 11.66 g, 45.63 mmol, combined yield 98%. 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=7.0 Hz, 3H), 1.45 (s, 9H), 3.04 (s, 3H), 3.91-4.04 (br m, 1H), 4.16 (dd, half of ABX pattern, J=10.1, 4.2 Hz, 1H), 4.19-4.28 (br m, 1H), 4.62 (br s, 1H).
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)NC1C=C(C(O)=O)C(NC2C=CC=C(Cl)C=2)=CC=1C(O)=O.C1(C)C=CC(NC2C=C(C(O)=O)C(NC3C=CC(C)=CC=3)=CC=2C(O)=O)=CC=1>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=C(O)c1cc(Nc2cccc(Cl)c2)c(C(=O)O)cc1Nc1cccc(Cl)c1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C

Procedure:
450 parts of polyphosphoric acid containing 85.0% P2O5 are metered into a stirred vessel. Then 135 parts of 2,5-dianilinoterephthalic acid, 11.25 parts of 2,5-di(3-chloroanilino) terephthalic acid and 3.75 parts of 2,5-di(4-toluidino)terephthalic acid are introduced at 125° C. with stirring and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is subsequently metered with stirring over 2 minutes (CG: 50%/min) into 1607.5 parts of 80% strength phosphoric acid at 135° C., during which it is hydrolyzed. During this hydrolysis the temperature rises to 150° C. The phosphoric acid concentration after the hydrolysis is 87.5%. Then 1209.2 parts of 40% strength phosphoric acid are added dropwise and the suspension is cooled to 120° C. The phosphoric acid concentration thereafter is 70%. The mixture is stirred at 120° C. for 1 hour. Subsequently the mixed crystal pigment is filtered off with suction at 110° C., washed with 70% strength phosphoric acid until the runoff is colorless, washed to neutrality with water, and dried at 80° C. This gives 131.9 parts of mixed crystal pigment (Pigment Violet 19, γIV phase). In the AM lacquer, transparent and strongly colored coatings of deep hue are obtained. The rheology is evaluated as 3 and the viscosity is 4.2 s. The gloss measurement gives a value of 58.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:15]([C:22]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=CC=CC=1NC1C=C(C(O)=O)C(NC2C=CC=CC=2Cl)=CC=1C(O)=O>>[CH:38]1[CH:39]=[C:40]2[C:31]([C:29]3[C:28]([NH:34][C:35]2=[CH:36][CH:37]=1)=[CH:27][C:23]1[C:24]([C:21]2[C:16]([NH:15][C:22]=1[CH:30]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:25])=[O:32]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=C(O)c1cc(Nc2ccccc2Cl)c(C(=O)O)cc1Nc1ccccc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C

Procedure:
380 parts of polyphosphoric acid, containing 85.0% P2O5, are introduced into a pressure vessel. Then 68.5 parts of 2,5-dianilinoterephthalic acid and 7.6 parts of 2,5-di(2-chloro-anilino)terephthalic acid are introduced with stirring at from 80 to 90° C. and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then introduced into a second pressure vessel where it is hydrolyzed under pressure and with stirring with a mixture of 1711 parts of 30% phosphoric acid at 140° C. During this hydrolysis the temperature rises to 155° C. The mixture is stirred at 155° C. for 0.5 hour. Then it is cooled to 60° C. and the mixed crystal crude pigment is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=C(C=CC=1C)NC1C=C(C(O)=O)C(NC2C=CC(C)=C(OC)C=2)=CC=1C(O)=O>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: COc1cc(Nc2cc(C(=O)O)c(Nc3ccc(C)c(OC)c3)cc2C(=O)O)ccc1C
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C

Procedure:
450 parts of polyphosphoric acid containing 85.0% P2O5 are metered into a stirred vessel. Then 135 parts of 2,5-dianilinoterephthalic acid and 15 parts of 2,5-di(3-methoxy-4methylanilino) terephthalic acid are introduced at 125° C. with stirring and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is subsequently metered with stirring over 2 minutes (CG: 50%/min) into 1607.5 parts of 80% strength phosphoric acid at 135° C., during which it is hydrolyzed. During this hydrolysis the temperature rises to 150° C. The phosphoric acid concentration after the hydrolysis is 87.5%. Then 1209.2 parts of 40% strength phosphoric acid are added dropwise and the suspension is cooled to 120 ° C. The phosphoric acid concentration thereafter is 70%. The mixture is stirred at 120° C. for 1 hour. Subsequently the mixed crystal pigment is filtered off with suction at 110° C., washed with 70% strength phosphoric add until the runoff is colorless, washed to neutrality with water, and dried at 80° C. This gives 132.5 parts of mixed crystal pigment (Pigment Violet 19, γII phase with small amounts of γIV phase). In the AM lacquer, transparent and strongly colored coatings of deep hue are obtained. The rheology is evaluated as 3 and the viscosity is 4.2 s . The gloss measurement gives a value of 49.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.[Fe].[Cl-].[Na+]>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: [Fe]
Agent: O=P(O)(O)O
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
To 270 g of polyphosphoric acid (117.4% phosphoric acid) heated at 80°-95° C. was added 0.25 g (4.3 mmole) of sodium chloride followed by 50 g (0.144 mole) of 2,5-dianilinoterephthalic acid having an iron content of less than 100 ppm. The mixture was heated at 120°-125° C. for four hours. After the viscous solution was cooled to 90°-95° C., the acid strength was adjusted to 107% by the dropwise addition of 75% phosphoric acid. The resultant melt was stirred for 20 minutes and then slowly poured into a mixture of 360 g of methanol and 40 g of water (i.e., 90% aqueous methanol) at 35° C. The temperature of the resultant slurry was allowed to rise during the addition to about 64° C., with the temperature being controlled during addition by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour and diluted with 600 g of water. After the resultant slurry was stirred for 30 minutes, the solid component was collected by filtration and washed with water until acid-free. The resultant presscake was reslurried in 1000 g of aqueous sodium hydroxide, then heated at about 85° C. The slurry was cooled, filtered, and washed with water until free of alkali, then reslurried in water and treated with aqueous sodium hydroxide containing naphthenic acid. The resultant slurry was heated at about 140°-145° C. in a closed system (e.g., a pressure reactor), cooled, acidified to pH 4.5-5.0 with phosphoric acid, and stirred. The solid component was collected by filtration and washed with water. The wet cake can be oven dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give about 40 g of quinacridone as a brilliant violet solid.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C1C=CC2[C@]3(C)[C@@H](CCC=2C=1)[C@@](CN)(C)CCC3)C.[OH-].[K+]>O.C(O)(=O)C>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(CN)CCC[C@]21C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 0 °C
Yield: 96 %

Procedure:
100 parts of 2,5-dianilinoterephthalic acid are added with stirring at 100°-120° C. to 450 parts of polyphosphoric acid (P2O5 content 85.5%), the mixture is stirred at said temperature until the reaction has ended (which takes about 2 hours) and is then poured onto 1,350 parts of ice-water, and the hydrolysis suspension attains a temperature of 15°-20° C. After the hydrolysis has ended the precipitated crude quinacridone is filtered off and is washed with water until free of acid. The water-moist approximately 20-22% strength crude quinacridone thus obtained is suspended in 600 parts of water. A solution of 1.2 parts of dehydroabietylamine, 10.6 parts of water and 0.24 part of acetic acid is then added dropwise, and the mixture is stirred for 30 minutes. 150 parts of 10% strength aqueous potassium hydroxide solution are then added, and the mixture is bulked with water to a total of 1,500 parts. The suspension is then refluxed with stirring for 10 hours and is then filtered at 70°-80° C., and the filter cake is washed with water until neutral. The water-moist approximately 18-22% strength quinacridone thus isolated is suspended in 600 parts of 80% strength isobutanol, and the suspension is then stirred at 145°-150° C. in a sealed vessel for 5 hours. The isobutanol is then distilled off with steam, and the pigment is then filtered off, is washed with water and is dried at 80° C. The pigment yield is at least 96%.
Reaction SMILES: [NH2:1][C@H](C(O)=O)C.C([O-])=O.[Na+].OP([O-])([O-])=O.[Na+].[Na+].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.[CH2:78]([O:85][C@@H:86]1[C:91](=O)[CH2:90][CH2:89][O:88][CH2:87]1)[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH2:78]([O:85][C@@H:86]1[C@@H:91]([NH2:1])[CH2:90][CH2:89][O:88][CH2:87]1)[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C1CCOC[C@@H]1OCc1ccccc1
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: N[C@H]1CCOC[C@@H]1OCc1ccccc1
Reaction time: 15 h

Procedure:
To a solution of L-Alanine (200 g, 2.24 mol), sodium formate (76.0 g, 1.12 mmol), and sodium phosphate dibasic (28.7 g, 202 mmol) in 2.25 L of water adjusted to pH 7.5 was added NAD (2.2 g, 3.21 mmol), pyridoxal-5-phosphate (2.2 g, 8.90 mmol), LDH (0.45 g, 0.22 mol), FDH (4.5 g, 0.20 mol), and TA P1G5 (4.5 g, 0.22 mol). After all the components were completely dissolved, (3S)-3-(benzyloxy)tetrahydro-4H-pyran-4-one (45 g, 0.22 mol) was added and the pH was adjusted to pH 7.25 with 6 NHCl and aged at 30° C. After 15 h, potassium carbonate (700 g, 5.06 mol) was added slowly, followed by ethyl acetate (2.2 L). The mixture was filtered through a bed of Solka Floc and the cake was washed with ethyl acetate (250 mL). The combined filtrates were separated and the aqueous layer was extracted a second time with ethyl acetate (2 L). The combined organic extracts were concentrated in vacuo to provide crude (3R,4S)-3-(benzyloxy)tetrahydro-2H-pyran-4-amine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:21]=[O:22])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 22.84 g (95.0 mmol) of 3-bromobiphenyl in 280 ml of dry tetrahydrofuran was added 61 ml (99.8 mmol) of n-butyllithium (1.64 mol/liter, n-hexane solution) at −70 ° C. under an atmosphere of nitrogen. The mixture was stirred at the same temperature for 1 hour, and to this was added dropwise 36.55 g (0.50 mol) of N,N-dimethylformamide. The resultant mixture was stirred overnight, while being slowly warmed to room temperature. To the reaction solution was added 400 ml of about 5% aqueous hydrochloric acid, and the mixture was stirred for 2 hours at room temperature. The mixture was extracted with tert-butyl methyl ether, and the organic layer was washed with an about 5% aqueous solution of sodium bicarbonate and water, then dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with n-hexane, then n-hexane:ethyl acetate=15:1) to obtain 13.95 g (76.56 mmol) of 3-phenylbenzaldehyde.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[C:8]#[C:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#CCN1CCCC1
Agent: Cl
Product: C(#C[C@H]1CCCN1)CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.6 %

Procedure:
(R)-t-Butyl 2-[3-(1-pyrrolidinyl)-1-propynyl]-1-pyrrolidinecarboxylate (11.06 g, 0.039 mol) was dissolved in methanolic HCl (200 mL) and stirred at room temperature for 2 hr. The reaction was evaporated under house and high vacuum to give a beige solid which was recrystallized from methanol:ether to give 9.5 g of product. The analytical sample was recrystallized from methanol:ether; m.p. 214°-216° C. [α]D +21° (c 0.55, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(O)C.[OH-].[Li+]>O>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Yield: 52.3 %

Procedure:
A flask is charged successively with 5 g (22.62 mmol) of methyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Azasynth), 50 mL of 95% ethanol, 50 mL of water and 1.63 g (67.92 mmol) of lithium hydroxide. The reaction mixture is refluxed for 30 minutes and then left to return to room temperature. The solution is concentrated under reduced pressure and then diluted in 200 mL of water. The aqueous phase is extracted with 3×60 mL of ethyl acetate, then acidified with 32% hydrochloric acid until the pH is between 2 and 3. The precipitate formed is filtered, rinsed with 50 mL of ethyl acetate and then dried under vacuum for 6 h. 2.45 g of a white solid is obtained (52%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.[CH3:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:16]([C:18](O)=[O:19])[N:17]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:18]([C:16]1[N:17]=[C:13]([CH3:12])[S:14][C:15]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:19]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: COC(=O)CC1CCCCN1
Product: COC(=O)CC1CCCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Yield: 60.2 %

Procedure:
The title compound (2.1 g) was prepared from piperidin-2-yl-acetic acid methyl ester (3.4 g) and 2methyl-5-(4-fluorophenyl)-thiazole-4-carboxylic acid (2.20 g) according to the method of description 20.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:23]
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Agent: [Pd]
Solvent: CCO
Product: O=c1cc(O)ccn1Cc1cccc(F)c1
Reaction time: 1.5 h
Yield: 72.4 %

Procedure:
To a solution of 4-benzyloxy-1-(3-fluorobenzyl)-1H-pyridin-2-one (1.79 g, 5.8 mmol) in EtOH (50 mL) was added 10% Pd/C (0.4 g), and reaction mixture was stirred under a hydrogen atmosphere for 1.5 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (0.92 g, 72%): 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=6 Hz, 1H), 7.40-7.30 (m, 1H), 7.10-6.95 (m, 3H), 6.07 (dd, J=6, 3 Hz, 1H), 5.85 (d, J=3 Hz, 1H), 5.11 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCCCC.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.C(O)(=O)C>O1CCCC1.O>[CH3:1][N:2]1[C:6]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=[CH:5][CH:4]=[N:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cccn1
Agent: [Li]CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C

Procedure:
N-Methylpyrazole (6.0 kg, 1 mol eq, limiting reagent) was charged, followed by anhydrous tetrahydrofuran (84 L, 14 rel vol) and the reaction mixture was cooled to −10° C. n-Hexyllithium (2.3 M solution in hexanes, 23.6 kg, 1.05 mol eq) was charged keeping the temperature below −5° C., followed by a line rinse of iso-hexane (1.2 L, 0.2 rel vol). The reaction mixture was stirred at below −5° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.9 kg, 1.1 mol eq) was diluted with anhydrous tetrahydrofuran (6.0 L, 1 rel vol) and was charged to the reaction keeping the temperature below 0° C. A line rinse with anhydrous tetrahydrofuran (3.0 L, 0.5 rel vol) was charged and the reaction mixture was stirred for around 30 minutes. The reaction was warmed to 25° C. A solution of glacial acetic acid (6.6 kg, 1.5 mol eq) in water (36 L, 6 rel vol) was charged to the reaction over about 30 minutes. The reaction mixture was stirred for around 30 minutes. The phases were separated and the organic layer retained. Change of solvent to acetonitrile by distillation afforded the title compound as a solution in acetonitrile. The solution yield of the title compound was determined by GC assay; 1H NMR (d6-DMSO): δ 1.31 (s, 12H), 3.98 (s, 3H), 6.62 (d, 1H, J=1.9 Hz), 7.45 (d, 1H, J=2.1 Hz) ppm.
Reaction SMILES: C([Si](C)(C)OC(CCCCCCCC(O)=O)CCCCCCCC(O)=O)(C)(C)C.[Si]([O:37][CH:38]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65]([O:67][CH2:68]/[CH:69]=[CH:70]\[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])=[O:66])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:47])(C(C)(C)C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[OH:37][CH:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:47])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65]([O:67][CH2:68]/[CH:69]=[CH:70]\[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])=[O:66]
Reactant: CCCCCC/C=C\COC(=O)CCCCCCCC(CCCCCCCC(=O)OC/C=C\CCCCCC)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC(CCCCCCCC(=O)O)CCCCCCCC(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCC/C=C\COC(=O)CCCCCCCC(O)CCCCCCCC(=O)OC/C=C\CCCCCC
Temperature: 70 °C
Yield: 55.8 %

Procedure:
To a solution of compound 7 (2.0 g, 12.8 mmol) in toluene (40 mL) and CH2Cl2 (18 mL) and was added 8 (3.96 g, 11.8 mmol). The mixture was heated at 70° C. overnight. Column chromatography gave pure compound 9 (1.40 g, 6.59 mmol, 51%) as a colorless oil.