Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OP([O-])(O)=O.[K+].C(O)(=O)CCC(O)=O.[OH-].[K+].[O-]S([O-])(=O)=O.[Mg+2].[Na+].[Cl-].CCCCCCCCCCCCCCCC.[CH2:41]([OH:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[CH:41](=[O:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCCCCCO
Agent: O=C(O)CCC(=O)O
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCCCCCCCCCCCC
Product: CCCC/C=C\CCCCCCCCCC=O

Procedure:
Low nitrogen minimal medium (per liter, 2.0 g KH2PO4, 1.18 g succinic acid, 0.1 g NH4SO4, pH adjusted to 7.0 with solid KOH, after autoclaving add 20 ml of sterilized 2% MgSO4) was used in experiments with A. calcoaceticus strain BD413 to induce wax ester formation. High nitrogen minimal medium was the same as the above except that it also contained 1.0 g NH4SO4 per liter. For other purposes such as DNA isolation, A. calcoaceticus was grown and maintained on LB medium (10 g bactotryptone, 5 g bacto-yeast extract and 10 g NaCl per liter, pH 7.0). For chemical feeding experiments in which compounds such as hexadecane, hexadecanol and cis-11-hexadecenal were provided as carbon sources, the above minimal media were used with the addition of 0.3% of the substrate. Hexadecane and hexadecanol were sonicated for approximately 2 minutes in the media to generate a suspension. A. calcoaceticus cultures were typically grown overnight at 30° C. In the case of larger volume cultures(i.e. 50 mls and larger), 3 ml overnight cultures were collected by centrifugation, the cell pellet was washed in new media, recentrifuged and then added to the fresh media, before being incubated at 30° C. overnight. Maintenance and growth of Escherichia coli stains was on LB with appropriate antibiotics. Antibiotics were used in the following concentrations: Ampicillin 100 μg/ml, Chloramphenicol 50 μg/ml, Kanamycin 25 μg/ml, Rifampicin 50 μg/ml and Tetracycline 15 μg/ml.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:5][CH2:4]1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:33](O)=[O:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:33]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)=[O:34]
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CCC2CCNCC2)CC1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cnccn1)N1CCC(CCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To 73 mg of 1-[1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride which was synthesized in Production Example 1, 28 mg of pyrazinecarboxylic acid, 101 μl of triethylamine and 14 mg of 1-hydroxybenzotriazole were added, and the mixture was suspended in 5 ml of chloroform. Then 52 mg of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride was added to the suspension, and the resulting reaction mixture was stirred for 3 hours at room temperature. To the reaction liquid, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added and mixed by shaking, to recover the separated organic layer. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified on silica gel chromatography (chloroform/methanol=10/1) to provide 40 mg of the title compound as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:14]2[CH:15]=[C:16]([C:19](Cl)=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10]1.[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:42]2[N:38]([CH:39]=[C:40]([CH3:47])[C:41]=2[O:45][CH3:46])[CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:42]2[N:38]([C:39]([C:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:12]=[C:11]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[O:10][C:9](=[O:8])[C:14]=4[CH:15]=3)=[O:20])=[C:40]([CH3:47])[C:41]=2[O:45][CH3:46])[CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Reactant: COc1c(C)cn2cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2cc(OCc3ccccc3)ccc12
Reaction time: 2 h
Yield: 71.9 %

Procedure:
10 ml (71.8 mmol) of triethylamine and 15 g (52.7 mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride are added portionwise, at ambient temperature and under nitrogen, to the solution of 12.8 g (47.9 mmol) of 6-(benzyloxy)-1-methoxy-2-methylindolizine in 160 ml of dichloromethane. The reaction medium is stirred for 2 hours and is then filtered. The solid obtained is washed with dichloromethane and then with diisopropyl ether and dried. 17.8 g (83%) of an orange powder are obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+].CCOCC.[C:26](OC(C)=O)([CH3:29])([CH3:28])[CH3:27]>>[C:1]1([CH2:7][C:8]([O:10][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
A solution of 2-phenylacetic acid (12 g, 88 mmol) in t-BuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid (70% redistilled, 0.212 mL, 3.53 mmol) and stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O. Gas evolution was observed. The resulting layers were separated and the organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give Intermediate S-3D (11.6 g, 68% yield): 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=4)[CH2:17]3)[C:13]2=[O:32])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[O:32]=[C:13]1[C:14]2([CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][N:23]=3)[CH2:17]2)[CH2:15][CH2:16][N:12]1[CH:9]1[CH2:10][CH2:11][N:6]([C:2]([O:4][CH3:5])=[O:3])[CH2:7][CH2:8]1
Reactant: O=C1N(C2CCNCC2)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(N2CCC3(CCCN(c4ccc(C(F)(F)F)cn4)C3)C2=O)CC1
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of 2-piperidin-4-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one (18.3 mg, 0.0000478 mol) and N,N-diisopropylethylamine (27 μL, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 0.5 h. The volatiles were removed in-vacuo and the product was purified by prep-HPLC. LC-MS: 441.2 (M+H)+.
Reaction SMILES: N1C(=O)C2NC=NC=2NC1=O.N1C=C2C(N=CN2)=NC=1.[OH-].[Na+:22].[C:23]([C:25]1[CH:26]=[C:27]([C:36]2[S:40][C:39]([C:41]([OH:43])=[O:42])=[C:38]([F:44])[CH:37]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH:33]([CH3:35])[CH3:34])#[N:24]>C(O)C>[C:23]([C:25]1[CH:26]=[C:27]([C:36]2[S:40][C:39]([C:41]([O-:43])=[O:42])=[C:38]([F:44])[CH:37]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH:33]([CH3:35])[CH3:34])#[N:24].[Na+:22]
Reactant: CC(C)COc1ccc(-c2cc(F)c(C(=O)O)s2)cc1C#N
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)COc1ccc(-c2cc(F)c(C(=O)[O-])s2)cc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Using (3-cyano-4-isobutoxyphenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate, methyl 4-bromo-5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate was obtained in accordance with the method of Preparation Example 1(1). To an ethanol (60 ml) suspension of 1.75 g of the compound was added 1.00 g of 10% palladium-carbon, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere at normal pressure. After insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain 0.39 g of methyl 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate. (2) The compound was dissolved in 15 ml of THF, and 2.5 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 60° C. for 5 hours. After cooling to room temperature, 2.5 ml of 1M hydrochloric acid and water were added thereto, followed by extraction with ethyl acetate. The resulting organic layer was dried and concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate and hexane to obtain 252 mg of 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylic acid. (3) Then, 215 mg of sodium hydroxide was added to an ethanol (60 ml) solution of 1.81 g of 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylic acid, followed by stirring at 80° C. overnight. After the reaction solution was cooled to room temperature, the precipitate was collected by filtration to obtain 1.60 g of sodium 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 108 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:14](OC)=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH:14]([C:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: COC(=O)C1(C)CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1(C)C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (3.5 g, 14.3 mmol) in toluene at −78° C. was added DIBAL-H (17.6 mL, 30 mmol, 1.7 M) dropwise, while maintaining the reaction temperature below −65° C. The reaction was stirred at −78° C. for 2 hr and then quenched with methanol (10 mL). The mixture was then diluted with ethyl acetate (50 mL), saturated NH4Cl was added and the mixture was stirred vigorously for 20 min at room temperature. The two phases were then separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organics were then washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 3 g of the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](Cl)(=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[O:22]=[C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCCN1CCNCC1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)N1CCN(CCO)CC1

Procedure:
5.2 g of 1-(2-hydroxyethyl)piperazine and 8.8 g of dodecanoyl chloride was reacted following the procedure under Example 3. This provided 8.7 g of product, m.p. 38°-40° C.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([NH:45][C@H:46]([C:48]([NH:50][C@H:51]([C@H:56]([CH2:58][C:59]([O:61][CH3:62])=[O:60])[OH:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:49])[CH3:47])=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([NH:45][C@H:46]([C:48]([NH:50][C@H:51]([C@H:56]([CH2:58][C:59]([O:61][CH3:62])=[O:60])[OH:57])[CH2:52][CH:53]([CH3:54])[CH3:55])=[O:49])[CH3:47])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 52 mg of BOC-Phe-His-OH, 60 mg of H-Leu-Val-Ala-Sta-OCH3.HCl, 18 mg of HOBT, 0.24 ml of ethyldiisopropylamine and 34 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (30 g of silica gel 60, 40-63 μm, system N8). Rf(N9)=0.38.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1C=CC=CC=1.[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[CH3:17][O:18][CH2:19][C:20]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])=[O:21]
Reactant: COCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of Meldrum's acid (30 g, 0.208 mol) in dichloromethane (420 mL) was added pyridine (33.7 mL, 0.416 mol) over 3 minutes in an ice-methanol bath under nitrogen atmosphere (−9° C.). To this mixture was added dropwise a solution of methoxyacetyl chloride (24.8 g) in dichloromethane (180 mL) over 1 hour period at the temperature. After addition, the reaction mixture was stirred at the temperature for 1 hour and at ambient temperature for 2 hours. The mixture was quenched with 1N hydrochoric acid (600 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as dark orange oil (38.1 g, 84.7%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.C(N(CC)CC)C.[CH2:29]([O:36][CH2:37][CH2:38][C@H:39]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:40]([NH:42][N:43]1[CH:47]=[CH:46][C:45]([Br:48])=[C:44]1[C:49](=[O:59])[NH:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=1)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:29]([O:36][CH2:37][CH2:38][C@H:39]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:40]1[N:50]([C:51]2[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=2)[C:49](=[O:59])[C:44]2=[C:45]([Br:48])[CH:46]=[CH:47][N:43]2[N:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(Br)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Triphenylphosphine (1.29 g, 4.92 mmol) was dissolved in 21 mL anhydrous dichloromethane. Bromine (253 μl, 4.94 mmol) was added dropwise under argon atmosphere and the reaction was stirred at room temperature for 30 min. Triethylamine (1.96 mL, 4 mmol) and (S)-tert-butyl (4-(benzyloxy)-1-((3-bromo-2-((3,5-difluorophenyl)carbamoyl)-1H-pyrrol-1-yl)amino)-1-oxobutan-2-yl)carbamate (2.15 g, 3.52 mmol) were added and the reaction mixture was heated at 60° C. for 2 h. The mixture was poured into 75 mL 4% aqueous solution sodium bicarbonate and extracted with dichlorometane. The organics were dried over sodium sulphate, filtered and evaporated. The residue was re-dissolved in 19 mL tetrahydrofuran and 2 mL dichloromethane and, under argon conditions, sodium methanethiolate was added and the reaction was stirred at room temperature for 1 h. The mixture was poured into 4% aqueous solution sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulphate, filtered and concentrated. The residue was purified using Isolera® Purification System (0% to 20%, hexane-ethyl acetate) to obtain 1.66 g (74% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=23)=[CH:5][CH:4]=1)#[N:2].[OH-:28].[K+].Cl>C(O)(C)(C)C.O>[C:15]([C:14]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:28])=[CH:8][CH:7]=2)=[C:10]2[CH:27]=[N:26][NH:25][C:11]2=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[F:24])#[N:16]
Reactant: N#Cc1ccc(-c2c(C#N)c(-c3ccc(O)cc3F)nc3[nH]ncc23)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1c(-c2ccc(O)cc2F)nc2[nH]ncc2c1-c1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 0.06 g (0.17 mmol) of 4-(4-cyanophenyl)-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 0.08 g (1.40 mmol) of potassium hydroxide in 6 ml of tert-butanol is refluxed for 4 h. The mixture is then cooled to room temperature, diluted with water, acidified with 1N HCl, and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated. The solid obtained is then purified by chromatography on silica (methanol gradient in dichloromethane: 0 to 10%) to yield 0.019 g (30%) of 4-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)benzamide in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[NH:12][C:11]3=[O:16])[C:9](=[O:17])[NH:8][C:5]2=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[CH2:24]([N:12]1[C:13](=[O:15])[CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][C:9]2=[O:17])[C:11]1=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccc(Cl)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of the crude 5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 9 (800 mg, 3.19 mmol) in anhydrous N,N-dimethylformamide (6 ml) was treated with potassium tert-butoxide (377 mg, 3.19 mmol). After stirring at ambient temperature for 40 min, benzyl bromide (0.38 ml, 3.19 mmol) was added. The mixture was stirred for 2 hours and left to stand overnight. The resultant mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione which was purified by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 75%) of ethyl acetate. This gave 789 mg (73%) of a yellow solid.
Reaction SMILES: [CH2:1]1C[O:4][CH2:3][CH2:2]1.C(Cl)(=O)C=C.[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.O>C(OCC)(=O)C>[CH:12]1([NH:11][C:3](=[O:4])[CH:2]=[CH2:1])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: C1CCOC1
Reactant: NC1CCc2ccccc21
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)NC1CCc2ccccc21
Reaction time: 0.33 h

Procedure:
A THF (10 mL) solution of acrylic acid chloride (2.04 g) was added dropwise to a THF (30 mL) solution of 1-aminoindane (3.00 g) and TEA (2.28 g) under ice-cooling, and the reaction solution was agitated for 20 minutes at the temperature. Water and ethyl acetate were added to this reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2.23 g of the title compound was obtained by adding ether to the residue and filtering insoluble matter.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[CH3:24]I>C1COCC1>[CH3:24][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[C:8]([CH:7]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CI
Reactant: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ncc[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)OCC)cc(-c2nccn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 422.1 %

Procedure:
A solution of diethyl 5-(1H-imidazol-2-yl)isophthalate (0.0689 g, 0.239 mmol, 1 eq) in anhydrous THF (2 ml) was added dropwise to a stirred suspension of NaH (60% dispersion in oil, 0.0105 g, 0.263 mmol, 1.1 eq) in anhydrous THF (3 ml) at 0° C. under Ar. After 1 h the reaction was warmed to room temperature. After 1 h the reaction was cooled to 0° C. and MeI (0.016 ml, 0.037 g, 0.263 mmol, 1.1 eq) was added dropwise. The reaction was stirred at 0° C. to room temperature overnight. The reaction was quenched with water and diluted with EtOAc. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.305 g (0.1.1 mmol, 42% yield) of diethyl 5-(1-methyl-1H-imidazol-2-yl)isophthalate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reaction time: 18 h
Yield: 79.7 %

Procedure:
To tert-butyl 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate (782 mg, 1.86 mmol, Eq: 1.00) in DCM (20 ml) was added TFA (2.12 g, 1.43 ml, 18.6 mmol, Eq: 10). The reaction mixture stirred under nitrogen for 18 h. Concentrated in vacuo to give 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (474 mg, 80%). LC/MS-ESI observed [M+H]+ 320.