Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:13])[CH3:12].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:13][CH2:11][CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CCN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCNC(C)c1ccc(Cl)nc1
Reaction time: 8 h
Yield: 80 %

Procedure:
6-chloro-3-acetylpyridine (1.03 g, 0.3 mmol) and a 30% ethylamine-methanol solution (1.0 mL) were mixed with 8 mL of chloroform, and the mixture was subjected to refluxing. After 8 hours, 1 mL of 30% ethylamine-methanol solution was added and stirring was continued for 12 hours at the same temperature. The chloroform was distilled off and the residue was dissolved in 10 mL of methanol, then ice-cooled. Sodium borohydride (1 g) was added a little at a time, and the system was stirred overnight. The methanol was distilled off, and the residue was extracted with acetonitrile. The extract was then concentrated under reduced pressure. Acetonitrile extraction and concentration under reduced pressure were each repeated another two times, following which the residue was dissolved in chloroform, washed with 1% aqueous NaOH, and the chloroform phase was dried over solid KOH. The chloroform was distilled off under reduced pressure, giving 790 mg of crude N-[1-(6-chloro-3-pyridyl)ethyl]-N-ethylamine product (purity, 80%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccncc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccncc3)ccn2c1=O
Yield: 70 %

Procedure:
Methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and pyridin-4-yl-boronic acid (253 mg, 2.05 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (400 mg, 69%). ESI-MS m/z: 373 (M+K)+, 357 (M+Na)+, 335 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[C:18]([O:25]C)=[C:17]([CH3:27])[C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:19]1[C:18](=[O:25])[C:17]([CH3:27])=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(C)c(Cc2ccc(C=CC(=O)O)cc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
The compound (589 mg, 1.58 mmol) obtained in Step 1 was dissolved in a mixture of acetonitrile (30 ml) and water (10 ml), to which was added CAN (1.38 g, 2.52 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ether. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by a silica gel column chromatography (5% methanol-methylene chloride) to yield the title compound (452 mg, 1.32 mmol, yield 84%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([N+:36]([O-:38])=[O:37])=[CH:6][C:7]([C:20](=[O:35])[NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][N:28]3[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[C:8](CCNCCOS(C)(=O)=O)[CH:9]=1>C1COCC1>[NH2:3][C:4]1[C:5]([N+:36]([O-:38])=[O:37])=[CH:6][C:7]2[C:20](=[O:35])[N:21]([C:22]3[CH:30]=[C:29]4[C:25]([CH:26]=[N:27][N:28]4[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:24][CH:23]=3)[CH2:7][CH2:20][N:21]([CH2:22][CH3:23])[C:8]=2[CH:9]=1
Reactant: CS(=O)(=O)OCCNCCc1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cnn(S(C)(=O)=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc3cnn(S(C)(=O)=O)c3c2)C(=O)c2cc([N+](=O)[O-])c(N)cc21
Yield: 192.3 %

Procedure:
NaH (60%, 266 mg, 6.7 mol) was added to a solution of crude methanesulfonic acid 2-{[5-amino-2-(1-methanesulfonyl-1H-indazol-6-ylcarbamoyl)-4-nitrophenyl]ethylamino}ethyl ester (2.6 mmol) in THF (10 mL) at room temperature. The solution was stirred at reflux for 3 h. The solvent was removed under reduced pressure, and the residue was taken up in EtOAc and washed with water (10 mL). The organic layer was separated, dried over MgSO4, and the solvent was removed under reduced pressure to afford 8-amino-1-ethyl-4-(1-methanesulfonyl-1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (1.1 g, 2.5 mmol).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[NH2:30][C:31]1[C:32]([C:38]([OH:40])=O)=[N:33][C:34]([Br:37])=[CH:35][N:36]=1.[C:41]([NH:49][NH2:50])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.O>[NH2:30][C:31]1[C:32]([C:38]([NH:50][NH:49][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:48])=[O:40])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.5 %

Procedure:
TBTU (22.09 g, 68.80 mmol) and triethylamine (4.642 g, 6.394 mL, 45.87 mmol) were added to a suspension of 3-amino-6-bromo-pyrazine-2-carboxylic acid (10 g, 45.87 mmol) and benzohydrazide (7.494 g, 55.04 mmol) in DMF (100.0 mL) and the resulting solution stirred at ambient temperature for 48 hours and then poured into water (400 mL) with vigorous stirring. This was allowed to stir for 30 minutes, filtered and washed with water. The moist solid was dissolved in hot EtOAc, dried (MgSO4), filtered and concentrated in vacuo and the resultant solid dried under vacuum to give the desired product (11.34 g, 73% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.51 (2H, m), 7.61 (1H, m), 7.69 (2H, br s), 7.92 (2H, m), 8.44 (1H, s), 10.48 (1H, br s), 10.54 (1H, br s) ppm; MS (ES+) 338.01.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cccc(C(=O)c2ccc(O)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
Under argon, 4-hydroxyphenyl 3-methylphenyl ketone (307 mg) obtained in Example 132 and 4-dimethylaminopyridine (194 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (324 mg) was added, and the admixture was then refluxed with heat for 23 hours. The reaction mixture was treated in the same manner as described in Example 122 to obtain 262 mg of the title compound (yield: 45%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:21])=[CH:15]/[C:16](OCC)=[O:17])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:3][CH:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:21])=[CH:15]/[CH2:16][OH:17])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:1]
Reactant: CCOC(=O)/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc2c(c1)CCCN2C(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
1.0 g of ethyl (E)-3-[1-(1-methylethy)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenoate prepared in Example 1 was dissolved in 20 ml of tetrahydrofuran. The obtained solution was cooled to −70° C., followed by the gradual addition of 7.0 ml (10.5 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene. The obtained mixture was stirred for 2 hours, followed by the addition of an aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum to give 650 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[N:17]=[C:16]([NH:18]C(=O)OC(C)(C)C)[CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C:16]1[N:17]=[C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:7]2)[CH:13]=[CH:14][CH:15]=1
Reactant: C=CC(=O)N[C@H]1CCCN(c2cccc(NC(=O)OC(C)(C)C)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(N)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of 114d (880 mg, 2.53 mmol) and TFA (2.0 mL) in DCM (10.0 mL) was stirred at rt overnight. The mixture was concentrated and diluted with EA (30 mL), neutralized with 1M NaOH. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE/EA=1/1) to give (S)—N-(1-(6-aminopyridin-2-yl)piperidin-3-yl)acrylamide 114e (440 mg, 70%) as yellow oil. MS-ESI: [M+H]+ 247.2
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:17]=[C:18]([C:31]2[C:32]([OH:38])=[CH:33][CH:34]=[C:35]([F:37])[CH:36]=2)[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:39]([O:44]C(C)(C)C)(=[O:43])[C@@H:40]([CH3:42])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C@@H:40]([CH3:42])[C:39]([OH:44])=[O:43])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxylate (0.19 ml) was added to a solution of the product of example 2 part (iii) (250 mg), tert-butyl(R)-(+)-lactate (141 mg) and triphenylphosphine (252 mg) in tetrahydrofuran (10 ml) at 0° C. After 20 minutes the ice bath was removed and the reaction stirred at room temperature overnight. The reaction mixture was then adsorbed onto silica and purified using flash column chromatography (eluent 10% ethylacetate/hexane) to give the subtitle compound as an oil, yield 140 mg.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].CO.Cl>O.CO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1oc(Sc2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 89 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), thiophenol (0.54 ml), sodium methoxide-methanol solution (28% 2.00 g) and methanol (15 ml) was stirred under reflux for 16 hours. Water was added to the reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-phenylthio-5-oxazolepropionic acid (1.60 g, 89%). This was recrystallized from methanol to give colorless needles. mp 156-157° C.
Reaction SMILES: [C:1]1(/[C:7](=[N:9]/[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.O.[H][H]>CC(C)=O>[C:1]1([CH:7]([NH:9][NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C/C(=N\NC(=O)c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(NNC(=O)c1ccccc1)c1ccccc1

Procedure:
In a 120 mL high-pressure autoclave were charged (E)-N′-(1-phenylethylidene)benzohydrazide (119 mg) [mw. 238.28, 0.5 mmol], [Rh(cod) (S,S)-ptbp-skewphos)]OTf (5.1 mg) [mw. 1025.08, 5.0 μmol, s/c 100], and methanesulfonic acid (0.5 mg) [mw. 96.11, 5.0 μmol, 0.01 eq.]. The system was substituted with argon 7 times. 10 mL Schlenk flask was substituted with argon, pure water (9 mg) [mw. 18.02, 0.5 mmol, 1.0 eq.] and dehydrated acetone for organic synthesis (5 mL) were added, and the solution was fed into an autoclave by argon pressure supply. The system was substituted with hydrogen gas, and the mixture was stirred with hydrogen gas pressurization at 1.0 MPa for 2 hr. The system was depressurized, and analyzed by high performance liquid chromatography to find that the starting material, (E)-N′-(1-phenylethylidene)benzohydrazide, remained by 43%, and the resultant product, N′-(1-phenylethyl)benzohydrazide was produced by 45%, and the decomposed product, acetophenone, was produced by 7%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:11][CH2:12][C@H:13]([NH:18][CH2:19][C@@H:20]([OH:42])[C@@H:21]([NH:31]C(=O)OCC1C=CC=CC=1)[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH2:10].O.[OH-].[Ba+2].[OH-]>COCCOC.O>[CH2:8]([O:11][CH2:12][C@H:13]([NH:18][CH2:19][C@@H:20]([OH:42])[C@@H:21]([NH2:31])[CH2:22][C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:14][CH:15]([CH3:16])[CH3:17])[CH:9]=[CH2:10]
Reactant: C=CCOC[C@@H](CC(C)C)NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC[C@@H](CC(C)C)NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
Step AO (2): To a solution of benzyl (2S,3R)-4-((R)-1-(allyloxy)-4-methylpentan-2-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate trifluoroacetate salt (560 mg, 1.19 mmol) in DME (9.0 mL) and water (6.0 mL) was added barium hydroxide monohydrate (1.35 g, 7.11 mmol). The reaction mixture was stirred at 110° C. in a high pressure vial for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by reverse phase chromatography to give (2R,3S)-1-((R)-1-(allyloxy)-4-methylpentan-2-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol double trifluoroacetate salt (243 mg, 57%) as a colorless oil. LC-MS (M+H)+=357.09.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=1F)(=[O:12])=[O:11])(C)C.[OH:30][C:31]1[CH:32]=[C:33]([CH:43]=[C:44]([O:46][C@@H:47]([CH3:60])[CH2:48][O:49][Si](C(C)C)(C(C)C)C(C)C)[CH:45]=1)[C:34]([NH:36][C:37]1[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[O:12]=[S:10]1(=[O:11])[C:13]2[CH:14]=[CH:15][C:16]([O:30][C:31]3[CH:32]=[C:33]([CH:43]=[C:44]([O:46][C@@H:47]([CH3:60])[CH2:48][OH:49])[CH:45]=3)[C:34]([NH:36][C:37]3[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=3)=[O:35])=[CH:17][C:18]=2[O:6][CH2:7][CH2:8][N:9]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCN(Cc2ccccc2)S3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 150 °C
Yield: 117.8 %

Procedure:
N-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,4-difluoro-N-(phenylmethyl)benzenesulfonamide (291 mg, 0.66 mmol) was added to 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(s)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (296 mg, 0.66 mmol) and potassium carbonate (183 mg, 1.31 mmol) in dry DMA (4 mL). The mixture was heated in a Smith Creator microwave at 150° C. for 45 mins. Water (25 mL) was added to the reaction mixture and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 80-90% ethyl acetate in isohexane, afforded the title compound as a colourless oil (450 mg). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.16-2.19 (m, 1H), 3.53 (t, 2H), 3.68-3.71 (m, 2H), 3.74 (s, 3H), 4.14 (t, 2H), 4.18 (s, 2H), 4.50 (ddd, 1H), 6.70 (d, 1H), 6.72 (d, 1H), 6.75 (t, 1H), 6.78 (dd, 1H), 7.09 (t, 1H), 7.22 (ddd, 1H), 7.24-7.26 (m, 1H), 7.28-7.29 (m, 5H), 7.78 (d, 1H), 8.45 (s, 1H). m/z 579 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH3:31])[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:31][O:30][C:23]1[CH:22]=[C:21]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH2:3][CH2:2]2)[CH:26]=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
tert-Butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (1.842 g, 6.84 mmol) was added to a stirring mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.17 g, 6.84 mmol) and K2CO3 (2.83 g, 20.51 mmol) in acetonitrile (15 mL) and the reaction mixture was stirred at 90° C. for 15 h. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (hexanes/EtOAc) to give the title product (2.5 g, 87%). m/z 421.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[N:5][N:6]=1.Cl[CH2:9][CH:10]=O.C(=O)(O)[O-].[Na+]>O>[Br:7][C:4]1[S:3][C:2]2=[N:1][CH:9]=[CH:10][N:6]2[N:5]=1
Reactant: O=CCCl
Reactant: Nc1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1nn2ccnc2s1
Reaction time: 10 h

Procedure:
To a suspension of 2-amino-5-bromo-1,3,4-thiadiazole (1.65 g, 9.15 mmol) in water (27 mL) was added a water solution of chloroacetaldehyde (50% wt, 1.7 mL). The mixture was stirred at reflux. After 10 hours, a second addition of chloroacetaldehyde (1.5 eq, 1.7 mL) was done and stirring was continued until disappearance of starting material (20 hours). After cooling, the reaction mixture was neutralized with sodium bicarbonate (sat. aq. solution) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried over sodium sulphate and the solvent evaporated under vacuum. The crude product was triturated with diethyl ether to yield 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole as a white solid. The mother liquor was purified by flash chromatography (Biotage™, ethyl acetate:hexane, 3:7 to 7:3) to yield another batch of compound (20% global yield) as a white solid.
Reaction SMILES: [ClH:1].Cl.Cl.N1C=C(CN2C3C=CC(C4C=NC=CC=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.Cl.BrC1C=CC2N(CC3N=CNC=3)C[C@@H](CC3C=CC=CC=3)N(S(C)(=O)=O)CC=2C=1.[C:70]([C:72]1[CH:73]=[CH:74][C:75]2[N:81]([CH2:82][C:83]3[N:84]=[CH:85][N:86](C(OC(C)(C)C)=O)[CH:87]=3)[CH2:80][C@@H:79]([CH2:95][C:96]3[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=3)[N:78]([S:102]([CH3:105])(=[O:104])=[O:103])[CH2:77][C:76]=2[CH:106]=1)#[N:71]>>[ClH:1].[NH:86]1[CH:87]=[C:83]([CH2:82][N:81]2[C:75]3[CH:74]=[CH:73][C:72]([C:70]#[N:71])=[CH:106][C:76]=3[CH2:77][N:78]([S:102]([CH3:105])(=[O:103])=[O:104])[CH:79]([CH2:95][C:96]3[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=3)[CH2:80]2)[N:84]=[CH:85]1
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Agent: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Agent: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Product: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1

Procedure:
Example 320 was prepared as a yellow solid from Compound B of Example 75 as described in the following sequence: Compound C of Example 224, Compound A of Example 225, and Compound B of Example 225.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[OH:40][C:37]1[CH:38]=[CH:39][C:34]([C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:35][CH:36]=1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Yield: 67.9 %

Procedure:
Preparation of example 153 from the title compound of Example 7 (hydrochloride) (42 mg, 0.134 mmol), (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (54 mg, 0.202 mmol), triethylamine (0.056 mL, 0.402 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (77 mg, 0.202 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Additional (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (27 mg, 0.10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were added after 24 hours to drive the reaction to completion. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (48 mg, 0.091 mmol) as a yellow powder in 68% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH3:27]>CN(C=O)C>[CH2:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1)[CH2:26][CH3:27]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 75 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a mixture of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.2 g, 8 mmol) in anhydrous DMF (20 ml) was added potassium carbonate (2.43 g, 17 mmol) followed by propyl iodide (4.42 g, 26 mmol). The mixture was stirred at 75° C. for 16 hours, then evaporated under reduced pressure. The residue was taken up with EtOAc (50 ml) and washed with water and brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure to afford the titled compound as a solid (2.2 g, 88%) used in the next step without further purification. TLC—Chloroform/methanol (9/1): Rf=0.75. 1H-NMR (CDCl3, 400 MHz) δ 1.04 (3H, t), 1.50 (9H, s), 1.81 (2H, m), 2.76 (2H, m), 3.62 (2H, m), 3.91 (2H, m), 4.54 (2H, s), 6.65 (1H, s), 6.74 (1H, d), 7.04 (1H, d).