Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28].[Br:29]Br.OS([O-])=O.[Na+]>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([Br:29])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Br)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,2-difluoro-7-(trimethylsilyl)benzo[d][1,3]dioxol-4-yl)-5-fluoropicolinate (400 mg, 0.92 mmol) was stirred in 1,2-dichloroethane (5 mL), treated with bromine (1.0 g, 6.5 mmol) and stirred at 20-25° C. for 4 h. The solution was stirred with 10% NaHSO3 solution (30 mL) and extracted with ethyl acetate (35 mL). The organic phase was washed with saturated NaCl (5 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (370 mg, 92%): mp 168-170° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 1H), 5.02 (s, 1H), 3.99 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.23, −137.58; ESIMS m/z 439 ([M+H]+), 437 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[O:32]C(C)(C)O[C:28](=[O:29])[CH:27]=1>>[C:28]([O:24][CH2:23][CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:32]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Product: COc1ccc(-n2nc(CCCOC(=O)CC(C)=O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
5-(4-Chlorophenyl)-3-(3-hydroxypropyl)-1-(4-methoxyphenyl)pyrazole (1.71 g, 0.005 moles) and 2,2,6-trimethyl-1,3-dioxen-4-one (0.71 g, 0.005 moles) were disolved in 100 ml of xylenes. The solution was stirred under reflux for 16 hours. At that time, the solution was cooled to room temperature, and concentrated in vacuo to a yellow oil. The oil was flash chromatographed on silica gel to afford 59 (1.7 g, 80%) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.[OH-].[Na+]>CO>[CH3:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[O:5][CH2:4][C:3]([OH:14])=[O:2]
Reactant: COC(=O)COc1ccc(C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(OCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3,4-dimethyl-phenoxy)-acetic acid methyl ester (7.399 g; 38.099 mmol) in MeOH (100 ml) was treated with aq. 1N NaOH (57 ml; 1.5 eq.), and the resulting mixture was further stirred at rt for 30 min. MeOH was then removed under reduced pressure, water (100 ml) was added followed by aq. 1N HCl (75 ml). Filtration of the precipitated solid, and drying under HV afforded (3,4-dimethyl-phenoxy)-acetic acid as a colorless solid (6.070 g; 88%). LC-MS: tR=0.81 min.; [M+H]+: no ionisation.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.244 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.488 mmol), DIPEA (171 μL, 0.977 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=661.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[CH:6][N:7]=1.[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[NH:8]1[C:5]2=[CH:6][N:7]=[C:2]([NH:18][C:19]3[N:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: N#Cc1cnc(N)cn1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Cl)ncc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cnc(Nc2cc3cc[nH]c3cn2)cn1
Temperature: 150 °C
Yield: 45.4 %

Procedure:
A mixture of tert-butyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.030 g, 0.119 mmol), 5-aminopyrazine-2-carbonitrile (0.017 g, 0.142 mmol), cesium carbonate (0.077 g, 0.237 mmol), Xantphos (0.011 g, 0.019 mmol) and tris(benzylideneacetone)dipalladium (0) (0.009 g, 0.010 mmol) in dioxane (0.8 mL) was degassed by bubbling argon through the mixture for 10 minutes. The sealed reaction vessel was heated to 150° C. for 1 hour in a microwave reactor. The crude mixture was filtered through an SCX-2 acidic resin cartridge, eluting with 2 M ammonia in methanol. The basic filtrate was concentrated and purified by column chromatography to give the title compound (0.018 g, 0.054 mmol, 45%). LC-MS (3) Rt=1.30 min; m/z (ESI+) 237 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([N:13]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:23][CH2:22][N:21]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:20][C:19]2[N:39]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14]1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.[OH-].[Na+]>C(O)C.O>[C:28]([CH2:27][N:24]1[CH2:23][CH2:22][N:21]([CH2:33][C:34]([OH:36])=[O:35])[CH2:20][C:19]2[N:39]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14][N:13]([CH:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:40])=[O:3])[CH2:26][CH2:25]1)([OH:30])=[O:29]
Reactant: CCOC(=O)CCC(C(=O)OCC)N1CCN(CC(=O)OCC)CCN(CC(=O)OCC)Cc2cccc(n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(C(=O)O)N1CCN(CC(=O)O)CCN(CC(=O)O)Cc2cccc(n2)C1
Yield: 60 %

Procedure:
15 mg of the compound obtained in stage 2 (26.5 μmol) are dissolved in 40 μl of ethanol and 53 μl of 5N sodium hydroxide are added dropwise rapidly. The mixture is brought to reflux for 24 h. The reaction medium is diluted 10-fold with water and the pH is then adjusted to 6.5 by adding weakly acidic resin. The resin is filtered off and washed with water. A strongly basic resin is added to the filtrate and then filtered off and washed twice with water. The product is eluted with 50% acetic acid. After evaporation to dryness, the product is obtained in the form of brown crystals. m=8 mg. Yield=60%.
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12])([CH3:3])[CH3:2].C([Li])CCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH:16]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[S:8][C:9]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:10][C:11]=1[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccsc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A mixture of triisopropyl[(3-methylthien-2-yl)methoxy]silane (intermediate 115, 1.42 g) in tetrahydrofuran (20 ml), stirred at −78° C. under nitrogen, was treated with 1.6M butyllithium in hexanes (3.9 ml). The reaction temperature was slowly allowed to rise to 0° C. over 2 hours and then re-cooled to −78° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 ml) was added and the reaction stirred at this temperature for 4 hours and then warmed to 0° C. The reaction was added to a mixture of saturated ammonium chloride and ice. The aqueous mixture was extracted with diethyl ether and the organic solution dried with brine and over sodium sulfate. Evaporation of the solvent afforded the title compound as a white solid
Reaction SMILES: Cl.[OH:2][C@@H:3]([C@H:18]([OH:33])[C@H:19]([OH:32])[C@@H:20]([NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH2:21][OH:22])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:5].[C:34]1([C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N+]=[N-])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C>CO>[OH:2][C@@H:3]([C@H:18]([OH:33])[C@H:19]([OH:32])[C@@H:20]([NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH2:26])[CH2:21][OH:22])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([O:11][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:10])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a solution of (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid hydrochloride (1.84 g) in methanol (40 ml) was added a solution of diphenyldiazomethane (1.45 g) in methanol (20 ml) and the mixture was stirred at room temperature for 4 hours. After addition of acetic acid (0.1 ml), the reaction mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and saturated brine respectively and the ethyl acetate solution was dried over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was purified by silica gel column chromatography. Elution with ethyl acetate-methnaol (2:1) provided the title compound (2.05 g).
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:6]([C:17]#[N:18])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:23](OC(C)C)[N:24]([CH3:26])[CH3:25])(C)C>C1(C)C=CC=CC=1>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:7]1[NH:8][C:4]([C:1](=[O:3])/[CH:2]=[CH:23]/[N:24]([CH3:26])[CH3:25])=[CH:5][C:6]=1[C:17]#[N:18]
Reactant: CC(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Reactant: CC(C)OC(OC(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Temperature: 70 °C
Reaction time: 34 h

Procedure:
To a suspension of 5-acetyl-2-(2,4-dichloro-phenyl)-1H-pyrrole-3-carbonitrile (6.2 g, 22.21 mmol) in 155 mL of toluene was added N,N-dimethylformamide diisopropyl acetal (18.6 mL; 88.85 mmol). The mixture was allowed to stir for 34 hours at 70° C. Then, a further amount of reagent was added (4.6 mL; 22.21 mmol) and the mixture was heated to 80° C. for additional 18 hours under efficient stirring.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (2.198 g, 7.98 mmol), (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (2.15 g, 9.18 mmol) and Hunig's Base (4.18 ml, 23.94 mmol) in DMF (7.9 ml) in a reaction vial was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction solution was added slowly to a stirred ice-water resulting in a light tan precipitate. The suspension was stirred for 30 min. (3S,4S)-Benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate (3.78 g, 7.98 mmol, 100% yield) was collected as a light tan solid via filtration. ESI-MS (analytical LCMS Method A): m/z 473, 475 ([M+H]+). HPLC (analytical HPLC Method A) Rt: 3.808 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Br:8])=[N:5][CH:4]=1.[CH3:9][NH:10][C:11](=[N:14][N+:15]([O-:17])=[O:16])SC.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:8][C:6]1[S:7][C:3]([CH2:2][NH:1][C:11]([NH:10][CH3:9])=[N:14][N+:15]([O-:17])=[O:16])=[CH:4][N:5]=1
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: NCc1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Br)s1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A mixture of 0.39 g of 5-(aminomethyl)-2-bromothiazole, 0.30 g of 1,2-dimethyl-3-nitroisothiourea, 0.58 g of cuprous bromide, 0.55 g of anhydrous potassium carbonate and 4 ml of dry acetonitrile was stirred in an oil bath of 60° C. for 45 minutes. The reaction mixture was purified by a column chromatography [developing solvent: dichloromethane-methanol (10:1)] to obtain 1-(2-bromo-5-thiazolylmethyl)-3-methyl-2-nitro-guanidine (Compound No. 39), as white solid.
Reaction SMILES: [Na].[CH2:2]=[C:3]1[CH2:6][CH:5]([C:7](=[O:9])[CH3:8])[CH2:4]1.[O-]CC.[Na+].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:2]=[C:3]1[CH2:6][CH:5]([C:7](=[O:9])[CH2:8][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=C1CC(C(C)=O)C1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: C=C1CC(C(=O)CC(=O)C(=O)OCC)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium (1.15 g, 49.9 mmol) was dissolved in dry EtOH (30 mL, denaturated with 5% diethylether). Compound 8a (5.5 g, 49.9 mmol, crude) was dissolved in dry EtOH (45 mL) and the above prepared sodium ethoxide solution was added. This mixture was stirred at rt for 15 min and then diethyl oxalate (6.8 mL, 49.9 mmol) was added dropwise. The reaction mixture was placed in a pre-heated (to 67° C.) oil bath and stirred at this temperature for 4.5 h. The mixture was left at rt overnight. The solvent was removed, EA (100 mL) and 1 M HCl (70 mL) were added and organic phase was separated. The aq. phase was re-extracted with EA (50 mL). The combined organic phases were washed with water, brine and dried over anh. Na2SO4. The solvent was removed under reduced pressure and the residue was purified on silica using hexanes/MTBE 9:1 as eluent giving pure product 8b. Yield: 6.29 g, 56% over two steps. 1H-NMR (CDCl3), δ (ppm): 6.36 (s, 1H), 4.85-4.80 (m, 2H), 4.34 (q, J=8.0 Hz, 2H), 3.35-3.25 (m, 1H), 3.05-2.85 (m, 4H), 1.36 (t, J=8.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([CH2:27]OC)OC>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>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][C:24]=3[CH3:27])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=2)[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: COCCOC
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+]
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A mixture of 200 mg (0.666 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in the previous step), 136 mg (0.999 mmol) and 77.0 mg (0.0666 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar was added 4.0 mL of degassed dimethoxyethane (DME) and 400 μL (0.799 mmol) of 2.0 M aq Na2CO3. The mixture was heated with stirring under Ar at 80° C. for 14 h. The cooled (RT) mixture was concentrated and chromatographed on a 10-g silica SPE column with 1-5% MeOH in dichloromethane-hexane (1:1). The product fractions were treated with 80 mg of decolorizing carbon, filtered, concentrated, and then rechromatographed on a similar column with 1-3% EtOH-dichloromethane to afford 265 mg of the title compound as a yellow resin (75% purity by 1H-NMR as a mixture with triphenylphosphine) that was used in the following reaction without further purification: Mass spectrum (ESI, m/z): Calcd. for C11H21N3O3, 312.2 (M+H). found 312.2.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]2)=[CH:5][C:4]=1[F:20].[OH:23][CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=2)[S:28][CH:29]=1>>[OH:23][CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:3]3[CH:8]=[CH:7][C:6]([N:9]4[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]4)=[CH:5][C:4]=3[F:20])=[CH:34][CH:35]=2)[S:28][CH:29]=1
Reactant: OCc1csc(-c2ccc(Br)cc2)n1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(-c4nc(CO)cs4)cc3)c(F)c2)CO1

Procedure:
With the exception of using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material and 4-(4-hydroxymethylthiazol-2-yl)-bromobenzene, the same procedure as in Example 1 was conducted to prepare the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (177 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) by refluxing in xylene according to the general procedure M. Obtained as a brown solid (269 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O[Li].O>CO.O>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Cl)cccc2s1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Cl)cccc2s1
Yield: 99.6 %

Procedure:
Stir a mixture of methyl 4-chlorobenzo[b]thiophene-2-carboxylate (1.0 g, 4.44 mmol) and LiOH—H2O (0.56 g, 13.3 mmol) in MeOH (30 mL) and water (10 mL) at room temperature overnight. Concentrate the reaction mixture under vacuum and then dilute the residue with ice water (20 mL). Acidify the aqueous mixture with conc. HCl solution to pH=1. Extract the resultant mixture with EtOAc (15 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and evaporate under vacuum to afford 4-chlorobenzo[b]thiophene-2-carboxylic acid as a white solid (0.94 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: OB(O)c1ccc(Cl)nc1
Product: O=Cc1cnc2ccc(-c3ccc(Cl)nc3)cn12
Yield: 44 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 6-chloropyridin-3-ylboronic acid. Yield: 44%; 1H NMR (DMSO-d6; 300 MHz): δ 10.02 (s, 1H), 9.76 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.93 (bs, 2H), 7.79 (d, 1H, J=9 Hz), 7.52 (d, 1H, J=8.1 Hz); MS: m/z 258(M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7][CH2:8][C:9](=[O:13])[NH:10][C:11]=2[N:12]=1>C(Cl)Cl.C1COCC1.O=[Mn]=O>[O:13]=[C:9]1[CH2:8][S:7][C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[N:12][C:11]=2[NH:10]1
Reactant: O=C1CSc2ccc(CO)nc2N1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of 6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (330 mg, 1.68 mmole) in CH2Cl2 (30 mL) and THF (30 mL) was treated with MnO2 (730 mg, 8.40 mmole), and the mixture was stirred at RT. Additional MnO2 was added after 1 hr (730 mg, 8.40 mmole) and after 16 hr (300 mg, 3.45 mmole). After a total of 20 hr the mixture was filtered through kieselguhr and the filtrate was concentrated to dryness. The reside was triturated with 1:1 EtOAc/hexanes, collected, and dried to afford the title compound (180 mg, 55%) as a solid: MS (APCI−) m/e 195 (M−H)−.
Reaction SMILES: Cl.[Si]([O:9][CH:10]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH:13]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:14]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[C:16](=[O:17])[CH:13]([CH2:12][CH2:11][CH:10]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[OH:9])[CH:14]2[C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1cccc(C#N)c1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Reaction time: 12 h

Procedure:
10 ml of 1N hydrochloric acid are added to 7.8 g of 3-[3-[3-(tert-butyldimethyl-silanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]benzonitrile (13) in 200 ml of methanol, and the mixture is stirred for 12 h. Aqueous sodium bicarbonate solution is added to the reaction mixture, which is then extracted with methylene chloride. The organic phase is dried over magnesium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate/heptane=1/3%→1/1). This gives 14: C25H20F2N2O2 (418.45) MS (ESI) 401 (M+H—H2O)