Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:15][O:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>O1CCCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:15]([O:16][CH3:17])[C:45](=[O:47])[CH3:46])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1
Reactant: CCCC1(NOC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1(N(OC)C(C)=O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of Example 9 (15 mg, 0.029 mmol) in tetrahydrofuran (200 μL) was added N,N-diisopropylethylamine (11 μL, 0.062 mmol) and acetyl chloride (5 μL, 0.070 mmol) and stirring was continued overnight. The solution was concentrated and taken up in H2O (1 mL) and 1N NaOH (0.5 mL). This solution was stirred at room temperature for 2 hours and 1N HCl was added slowly until the solution became acidic. This aqueous solution was extracted with ethyl acetate (3×2 mL), the organic extracts combined, dried over Na2SO4, the drying agent filtered off, the solvent removed in vacuo, and the crude product was purified by column chromatography on silica gel (5% methanol/chloroform) to give the title compound as a colorless solid: 1H NMR (d6-DMSO) δ 13.81 (s, 1H), 10.18 (s, 1H), 8.10, 8.07 (d, 1H), 7.71-7.45 (m, 7H), 4.07 (s, 3H), 3.06 (s, 3H), 2.03 (br s, 3H), 1.30-1.05 (br s, 1H), 1.24 (br s, 2H), 0.75-0.50 (br s, 1H), 0.74-0.65 (t, 3H); MS (ESI) m/z 563 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].Cl.CN.ON1C2C=CC=CC=2N=N1.[CH2:49]([N:51]=[C:52]=NCCCN(C)C)C>ClCCl.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:51]([CH3:52])[CH3:49])=[O:33])=[CH:34][CH:35]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(C(=O)O)cc2)s1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(C(=O)N(C)C)cc2)s1

Procedure:
To a solution of 4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}benzoic acid (50 mg) in 0.5 ml of dichloromethane were added methylamine hydrochloride (10.7 mg), 1-hydroxybenzotriazole (20.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (55.3 μl), then, the mixture was stirred for 3. hrs. at 25° C. The reaction mixture was diluted with 10 ml of chloroform and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under vaccum. The residue was triturated with ethyl acetate and diisopropylether, and collected by filtration to give tert-butyl {4-[2-(2-(acetylamino)-5-{4-[(dimethylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate as a pale yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Br:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][NH2:40])([CH3:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][NH:40][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Br:22])=[CH:20][N:19]=2)([CH3:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 100.1 %

Procedure:
A stirred mixture of 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (400 mg, 0.979 mmol), 4-(2-aminoethyl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (474 mg, 1.96 mmol) and diisopropylethylamine (253 mg, 1.96 mmol) in 1,4-dioxane (10 mL) is heated at 90° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with 3% 2 M NH3/MeOH in dichloromethane, to give 602 mg of 4-{2-[5-bromo-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-4-methylpiperidine-1-carboxylic acid tert-butyl ester. It is then subject to deprotection by dissolving the material (132 mg, 0.220 mmol) in MeOH (10 mL) and dichloromethane (5 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 1.5 hours, then concentrated to give the title compound as a yellow solid (126 mg, 100% yield). ES+(m/z) 514 (79Br) and 516 (81Br) [M(free base)+H].
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[CH:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[C:33][C:2]3[CH:16]=[CH:15][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC1CCN(Cc2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: COC1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-methoxypiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 25 mg (13% of theory); melting point: 145° C.-146° C.; C28H27ClN2O2 (M=458.99); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461; Rf value: 0.4 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:3][CH:4]=[C:5]2[C:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=1)([OH:14])=[O:13]
Reactant: CN1CCC(=O)CC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Yield: 71 %

Procedure:
To a solution of 5.8 gm (90 mMol) potassium hydroxide in 50 mL methanol were added 4.83 gm (30 mMol) indole 5-carboxylic acid followed by 7.4 mL (60 mMol) 1-methyl-4-piperidone and the resulting solution was heated at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the resulting oil dissolved in 200 mL water. The solution was gradually neutralized by addition of 18 mL 5N hydrochloric acid. The precipitate which formed was isolated by filtration and washed with water to provide 6.09 gm after drying. This solid was dissolved in 100 mL 0.5N sodium hydroxide, filtered and the filtrate treated with 50 mL 1N hydrochloric acid. The solid which formed was filtered and dried under reduced pressure to provide 5.46 gm (71%) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH2:8][CH2:7][O:6][CH2:5]2.C([Li])CCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:26]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH2:8][CH2:7][O:6][CH2:5]2)[CH2:27][CH2:28][CH3:29]
Reactant: Ic1cc2n(c1)CCOC2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2n(c1)CCOC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) mixture of 7-iodo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (300 mg, 1.205 mmol) and THF (10 mL) was added n-butyllithium (0.530 mL, 1.325 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 60 minutes, after which tributylchlorostannane (0.392 mL, 1.445 mmol) was added. The reaction mixture was stirred at −78° C. 60 minutes, then warmed to room temperature and stirred for 1 hour. The reaction was quenched with brine (10 mL) and extracted with EtOAc (2×25 mL). The organic phase was separated, dried over sodium sulfate, concentrated, and purified via flash column chromatography to give the title compound as an oil, which was used without further purification (300 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:21](C)=O.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][N:11]([CH3:21])[CH2:10][C@H:9]1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CO[C@@H]1CNCC[C@H]1NC(=O)OC(C)(C)C
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Tert-butyl((3R,4R)-3-methoxy-piperidin-4-yl)-carbamate (2.88 g) is dissolved with formaldehyde (1.79 mL, 37% solution in H2O) and acetic acid (100 μL) in DMF. Then Na(OAc)3BH (12.59 g) is added. After 20 h the reaction mixture is combined with aqueous NaHCO3 solution (saturated with NaCl) and extracted 5 times with EtOAc. The combined organic phase is dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. The residue is used in the next reaction step without any further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:20][C:21]([OH:23])=[O:22])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1
Reactant: CN(CC(=O)OC(C)(C)C)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CN(CC(=O)O)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrazinyl]amino}acetate (0.20 g, 0.52 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added thereto. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.15 g, 87%) as pale yellow crystals
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[C:9]([NH2:22])[N:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C

Procedure:
To an ice cooled stirring solution of 2-[(2-cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6.53 g) in chloroform (75 ml), was added N-bromosuccinimide (4.02 g). The reaction mixture was allowed to warm to room temperature and after 16 h treated with water and extracted twice with DCM. The combined extracts were washed with dilute sodium metabisulphite then dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as an orange foam, yield 7.96 gm.
Reaction SMILES: C[Mg]Br.[CH2:4](N(CC)CC)C.[CH3:11][C:12]1[CH:13]=[C:14]([N:18]2[N:22]=[N:21][C:20]([C:23]([O:25]CC)=O)=[N:19]2)[CH:15]=[CH:16][CH:17]=1.Cl>C1(C)C=CC=CC=1.O>[CH3:11][C:12]1[CH:13]=[C:14]([N:18]2[N:22]=[N:21][C:20]([C:23](=[O:25])[CH3:4])=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1nnn(-c2cccc(C)c2)n1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1nnn(-c2cccc(C)c2)n1
Temperature: -10 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Methylmagnesium bromide (1070 mL, 1.50 mol, 1.4 M in tetrahydrofuran/toluene) in triethylamine (520 mL, 3.74 mol) was added via an addition funnel to a stirred solution of ethyl 2-(3-methylphenyl)-2H-tetrazole-5-carboxylate in dry toluene (1000 mL) at −10° C. for 5 hours. The mixture was continued to stir at −10° C. overnight. A cooled (+3° C.) solution of hydrochloric acid (37%, 500 mL) and water (500 mL) was added over 2 hours 20 minutes. The layers were separated and the organic layer was washed with water (500 mL) and brine (2×250 mL). The aqueous layer was extracted with toluene (3×500 mL) and the toluene was washed with brine (2×250 mL). The combined organic extracts were concentrated and purified on silica using dichloromethane as eluent. The concentrated product residue was triturated with petroleum ether, filtrated and dried under reduced pressure at room temperature to give the title product (90.86 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: COc1ccc(OC)c(C=CCCl)c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(OC)c(C=CCN2CCc3nc(N)sc3CC2)c1
Yield: 4 %

Procedure:
Prepared from 2,5-dimethoxy-cinnamyl chloride (prepared at -b 5° C. for 10 minutes) and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 4% of theory, Melting point: 112°-115° C. (ether).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH2:28][C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32](O)=[O:33])[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH2:28][C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:42][CH2:41][CH:40]([O:43][CH3:44])[O:39][CH3:38])=[O:33])[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: COC(CN)OC
Reactant: O=C(O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(CNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
906 mg (4.73 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) are added to a solution of 1.24 g (3.64 mmol) of 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]benzoic acid (prepared in accordance with WO 2008/017361), 382 mg (3.64 mmol) of aminoacetaldehyde dimethyl acetal and 557 mg (3.64 mmol) of 1-hydroxybenzotriazole hydrate (HOBt) in 14 ml of DMF, and the mixture is stirred overnight at room temperature. Water is added to the reaction mixture. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-N-(2,2-dimethoxyethyl)benzamide as colourless crystals; ESI 430.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C=O)CC1
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(2-(hydroxymethyl)phenyl)piperidine-1-carboxylate (216 mg, 0.74 mmol, 1 eq.) and Dess Martin periodinane (377 mg, 1.2 eq., 0.89 mmol) were stirred in DCM (7 mL) for 1 h. HPLC and LCMS showed completion of the reaction. Sodium thiosulfate was then added and the biphasic mixture was stirred for 10 min, then the mixture was diluted with EtOAc (50 mL), the biphasic mixture was separated, the organics were dried (MgSO4), conc in vacuo and purified by ISCO chromatography (8 g SiO2, 0 to 15% EtOAc in Hexanes). Remaining DMP side product was observed so the residue was taken up in DCM, the insolubles filtered off, the filtrate concentrated and purified by ISCO chromatography (12 g SiO2, 0 to 10% EtOAc in Hexanes) to give, after concentration, 229 mg of tert-butyl 4-(2-formylphenyl)piperidine-1-carboxylate as a clear oil (still contains some DMP side product) which was used in the next step without further purification. LC/MS ES+1-Boc: 190.08.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])#[N:3]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CC(C)N=C=O
Agent: [Cl-]
Product: CC(C)NC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and isopropyl isocyanate in 100% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (d, J=6.5 Hz, 6H), 1.91 (m, 3H), 2.13 (m, 1H), 3.17 (m, 1H), 3.79 (m, 1H), 4.19 (m, 2H), 4.32 (d, J=8.8 Hz, 1H), 5.91 (d, J=8.1 Hz, 1H), 7.89 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([N+:19]([O-:21])=[O:20])=[C:2]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c([N+](=O)[O-])cc2c1=O
Temperature: 120 °C
Yield: 54 %

Procedure:
A mixture of 9.3 g (0.03 mole) of 7-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid and 12.9 g (0.15 mole) of piperazine in 60 ml of dimethylsulphoxide is warmed at 120° C. for 15 minutes. After a short time, a precipitate separates out of the hot solution. The mixture is concentrated under a high vacuum, the residue is stirred with 30 ml of water and the mixture is heated again at 95° C. for 30 minutes. The mixture is adjusted to pH 8 with 2N hydrochloric acid and the precipitate is filtered off with suction and washed with water and methanol. 5.8 g (54% of theory) of 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 296° to 298° C. are isolated.
Reaction SMILES: [CH:1]([S:4][C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH:1]([S:4]([C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)=[O:30])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
2-[6-(Isopropylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.09 g, 0.29 mmol) was dissolved in chloroform (50 ml). A solution of 3-chloroperbenzoic acid (ca. 77%, 0.064 g, 0.29 mmol) in chloroform (10 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (0.056 g, 59%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.C(NC(C)C)(C)C.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32]>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.[Cu]I.C1COCC1>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: C#CC(C)(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.250 g, 0.718 mmol), Pd(PPh3)4 (0.083 g, 0.072 mmol), and copper(i) iodide (0.014 g, 0.072 mmol), was treated with 1 mL THF followed by diisopropylamine (1.535 mL, 10.77 mmol). The solution was degassed with argon and 3,3-dimethylbut-1-yne (0.295 g, 3.59 mmol) was added and the vial heated to 80° C. overnight. The reaction mixture was purified directly by column chromatography yielding (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol.
Reaction SMILES: C([S:4][C:5]1[C:6]([Cl:24])=[CH:7][C:8]([F:23])=[C:9]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH:10]=1)(=O)C.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Cl:24][C:6]1[C:5]([SH:4])=[CH:10][C:9]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)=[C:8]([F:23])[CH:7]=1
Reactant: CC(=O)Sc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2cc(S)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
2.8 g (7.7 mmol) of 3-(5-acetylthio-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 30 ml of methanol, 8.5 ml (8.5 mmol) of a 1N sodium hydroxide aqueous solution was dropwise added thereto under cooling with ice. After stirring at room temperature for 1 hour, the mixture was poured into water and acidified with citric acid and extracted with ethyl acetate. After washing with water and a saturated sodium chloride aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 2.4 g (yield: 93%) of the desired product. Melting point: 141-142° C.