Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.CCOCC>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][N:26]=[N+:27]=[N-:28])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1[C@H](CN=[N+]=[N-])C[C@H]2C[C@H]21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of (1R,3S,5R)-3-(toluene-4-sulfonyloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.400 g, 1.08 mmol) and NaN3 (0.420 g, 6.47 mmol) in dry DMSO (8 mL) was stirred at 65° C. overnight. After cooling, the mixture was diluted with Et2O and washed with water (×3) and brine (×2). The organics were dried (phase separator) and concentrated in vaccuo to give the title compound as a colorless oil. MS (LC-MS): 239.0 [M+H]+; tR (HPLC conditions k): 3.78 min. The material thus obtained was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:29](OC(C)(C)C)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl>[F:15][C:12]([F:13])([F:14])[C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]2[CH:16]=[N:29][NH:1][C:2]=2[CH:11]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (1 equiv.) in chloroform (13 mL per 1 mmol), potassium acetate (1.05 equiv.) and acetic anhydride (2 equiv.) were added and reaction mixture stirred at room temperature for 12 h. After this time, tert-butyl nitrite (4 equiv.) and 18-crown-6 (0.35 equiv.) were added and reaction stirred again at 65° C. for 3 h. On completion, the reaction mixture was cooled to room temperature, diluted with chloroform (500 mL) and washed with sat. sodium bicarbonate solution. the organic layer was dried over sodium sulfate and concentrated to afford title the compound (yield 90-95%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[O:25]=[C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:32]([C:31]5[C:26](=[O:25])[N:27]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:28]=[CH:29][CH:30]=5)=[O:33])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: O=C(O)c1cccn(-c2ccccc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)c1cccn(-c2ccccc2)c1=O
Yield: 71 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.460 mmol), N,N-dimethylacetamide (3.0 mL), 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (138 mg, 0.644 mmol), HATU (262 mg, 0.689 mmol) and N,N-diisopropylethylamine (120 μL, 0.689 mmol) and in the same manner as in Example 10, the title compound (171 mg, 71%) was obtained as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:20]([N:28]1[CH:34]=[CH:33][N:32]=[CH:31][CH2:30][N:29]1[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>CCOCC>[C:20]([N:28]1[CH2:34][CH2:33][N:32]([CH2:11][CH2:10][CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][N:29]1[C:35](=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(c1ccccc1)N1C=CN=CCN1C(=O)c1ccccc1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4,4-bis(4-fluorophenyl)butyl bromide (2.08 g), 1,2-dibenzoyl-1H-1,2,5-triazepine (2.0 g), powdered anhydrous sodium carbonate (2.71 g) and N,N-dimethylformamide (20 ml, dried over 4A molecular sieves) was stirred at room temperature under a nitrogen atmosphere for three days. The mixture was filtered and the filtrate was evaporated under oil pump vacuum to an oil. The oil was chromatographed on a column of silica gel; elution with ethyl acetate-dichloromethane (2:3) giving a major product. The hydrochloride salt of the titled compound was formed in ether from this material; wt. 2.0 g (52%), mp=216°-218°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].Cl.[N:12]1([CH2:17][CH:18]([N:20]2[C:33]3[CH:32]=[C:31]([C:34](Cl)=[O:35])[CH:30]=[CH:29][C:28]=3[S:27][C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:34]([C:31]1[CH:30]=[CH:29][C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH:18]([CH3:19])[CH2:17][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:33]=2[CH:32]=1)=[O:35]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Reactant: COc1ccccc1CN
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
2-Methoxybenzylamine (26.1 cc) is added dropwise at a temperature of 10° C. and with stirring to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (13.2 g in methylene chloride (125 cc). Stirring is continued for 15 minutes at 10° C. and 16 hours at 20° C. The reaction mixture is washed with distilled water (3×100 cc) and the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column (height: 64 cm; diameter: 3 cm) of silica gel (0.06-0.2 mm), eluting with ethyl acetate (2 liters) and collecting 200-cc fractions. Fractions 3 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-(2-methoxybenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (9.3 g) in the form of a white crystalline solid, m.p. 127° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)c1
Yield: 62 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,4-dimethoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 207 mg, 62%) which was obtained as a white solid. MS: m/e=364.2 [M+H]+.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[N:9][CH:8]=1
Reactant: OCc1ccc(O)cn1
Reactant: Fc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: OCc1ccc(OCc2cccc(F)c2)cn1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A mixture of 6-hydroxymethyl-pyridin-3-ol hydrochloride (1:1) (6.29 g, 38.9 mmol), 3-fluorobenzyl bromide (8.1 g, 42.8 mmol), potassium carbonate (10.76 g, 77.9 mmol) and 2-butanone (200 ml) was heated to 80° C. for 5 h. After cooling, water was added, and the mixture extracted with ethyl acetate. After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, CH2Cl2—MeOH 95:5) to give the title compound as a brown solid (6.12 g, 67%). MS: m/e=234.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:14]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To an ice cooled solution of 2-chloro-3-trifluoromethylbenzaldehyde (1 g, 4.8 mmol) in THF (16 mL) was added methylmagnesium bromide (3M in THF, 1.8 mL, 5.3 mmol). The reaction was allowed to warm to rt and stirred overnight. Saturated aqueous NH4Cl was added, and the mixture was extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford the desired product as a clear oil (1.1 g, 98%). 1H NMR (500 MHz, CDCl3) δ 7.86-7.82 (m, 1H), 7.62 (dd, J=7.8, 1.5 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 5.40 (q, J=6.4 Hz, 1H), 2.14 (s, 1H), 1.50 (d, J=6.4 Hz, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[O:23]1[CH2:24][CH:21]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2COC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC(C2COC2)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-hydroxy-1-(hydroxymethyl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (7.62 g, 0.029 mol) in anhydrous THF (100 mL) at 0° C., a solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min, then a solution of toluenesulfonyl chloride (5.26 g, 0.028 mol) in anhydrous THF (50 mL) was added by canula. The thick reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. A solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise and the reaction mixture heated at 60° C. for 2 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, pentane:EtOAc; gradient from 100:0 to 20:80) to afford 4-oxetan-3-ylpiperidine-1-carboxylic acid tert-butyl ester as a white solid (5.33 g, 75%). TFA (10 mL) was added to a solution of 4-oxetan-3-yl-piperidine-1-carboxylic acid tert-butyl ester (7.1 g, 0.029 mol) in DCM (100 mL) and the mixture stirred at ambient temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (50 g), the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10 to 85:15 to 80:20) to afford 4-Oxetan-3-ylpiperidine as a colourless oil which solidified on standing (2.05 g, 49%). 1H NMR (CDCl3, 300 MHz) δ 4.75 (dd, J=7.9, 6.0 Hz, 2 H); 4.52-4.42 (m, 2 H); 3.14-3.04 (m, 2 H); 2.81-2.67 (m, 1 H); 2.61 (td, J=12.2, 2.6 Hz, 2 H); 1.85-1.68 (m, 1 H); 1.60 (m, 2 H) and 1.02 (qd, J=12.2, 4.0 Hz, 2 H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([OH:19])(=[O:18])[CH:12]=[CH:13][CH2:14][C:15]([OH:17])=[O:16]>OS(O)(=O)=O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH:13]([CH2:12][C:11]([OH:19])=[O:18])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)C=CCC(=O)O
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: O=C(O)CC(CC(=O)O)Sc1nc2ccccc2s1
Yield: 87 %

Procedure:
16.8 g of 2-mercaptobenzothiazole are suspended in 50 ml of 70% H2SO4, and 13.7 g of glutaconic acid are added at 45°-50° in the course of 30 minutes, with stirring. The reaction mixture is stirred for a further 1.5 hours at 45°-50° and the product is isolated as described in Example 5. 26 g (88% of theory) of 3-(benzothiazol-2-ylthio)-glutaric acid, of melting point 153°-154°, are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([Mg]Br)[CH3:16].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH2:15][CH3:16])=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2cccc(F)c2)s1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1cnc(-c2cccc(F)c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.320 g, 1.545 mmol) in THF (12 mL) was added 3.0 M solution of ethyl magnesium bromide in diethyl ether (1.28 mL, 3.86 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stir for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and water (5 mL), extracted with ethyl acetate (50 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude compound was purified by Biotage Isolera® One chromatograph (using 15% ethyl acetate and hexane) to afford 1-(2-(3-fluorophenyl)thiazol-5-yl)propan-1-ol (0.18 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.68 (d, 3H), 7.40 (q, 1H), 7.11 (t, 1H); 4.93 (t, 1H), 4.11 (q, 1H), 1.90-1.87 (m, 2H), 1.01 (t, 3H); LC-MS m/z calcd for [M+H]+ 238.06. found 238.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19](=O)[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19](=[S:32])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent (0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours and concentrated to a residue which is purified over silica to provide 0.350 g (83%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70 (d, J=7.2 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.Cl.O1CCOCC1>CO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[O:5][CH2:4]2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)OCC(=Cc1ccc(F)cc1)C2=O

Procedure:
The title compound was prepared from methyl 4-oxochroman-7-carboxylate (Koch, K., and Biggers, M. S. J. Org. Chem. 1994, 59, 1216-1218) and 4-fluorobenzaldehyde according to Method A2 using methanol and 4 N Hydrogen chloride/dioxane. Off-white solid (76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 5.48 (s, 1H), 7.35 (t, J=8.59 Hz, 2H), 7.50-7.61 (m, 3H), 7.66 (d, J=7.25 Hz, 1H), 7.80 (s, 1H), 8.01 (d, J=8.06 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.BrCCBr.CN([CH:18]=[O:19])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1)[CH:18]=[O:19]
Reactant: COc1cccc(Cl)c1Cl
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1cc(Cl)cc(C=O)c1
Temperature: -10 °C
Yield: 44.9 %

Procedure:
To a mixture of dichloroanisole (60 mmol, 10.62 g), Mg (66 mmol, 1.60 g) and THF (30 ml) was added 1,2-dibromoethane (6 mmol, 1.13 g). The mixture was stirred until bubbles of gas started to evolve (2-3 min), and then heated to reflux for 2.5 h. The resulting dark brown mixture was cooled to −10° C. on an acetone-ice bath and DMF (90 mmol, 7 ml) was added slowly. After 20 min the ice-bath was removed, the mixture was stirred for 3 h and subsequently quenched with NHrCl (10% w/w in water, 100 ml). The product mixture was extracted with DCM (4×50 ml), the organic phase washed with water, then brine and dried (MgSO4). Filtration and evaporation under reduced pressure gave a red liquid residue, which was purified by means of flash chromatography (silica, pentane/ether gradient. 5-30%) to provide the title compound (4.60 g, 45%) as a clear liquid. 1H NMR (DMSO, 300 MHz) δ 3.84 (s, 3H), 7.16 (s, 1H), 7.25 (s, 1H), 7.43 (s, 1H) and 9.92 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[C:17](Cl)([CH3:19])=[O:18]>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:11][CH2:12][N:13]([C:17](=[O:18])[CH3:19])[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: CC(=O)Cl
Reactant: Brc1ccc2ncn(C3CCNCC3)c2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cnc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-1-(piperidin-4-yl)-1H-benzo[d]imidazole (50 mg, 0.178 mmol) in DCM (5 mL) in pyridine (5 mL) cooled by an ice-bath was added AcCl (14 mg, 0.178 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvents were removed by concentration and the residue used for next step without further purification.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]2.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[C:25](O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]4)[N:20]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33]
Reactant: CCOc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OCC)c(Cl)c4)n3)ccc21
Yield: 20.6 %

Procedure:
Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (265 mg, 0.96 mmol) and 3-Chloro-4-(ethyloxy)benzoic acid (D7) (192 mg, 0.96 mmol) were stirred together in DMF (5 ml) at 80° C. and EDAC (203 mg) and HOBt (142 mg) were added. When the reaction was judged to be complete (analysis by LCMS) it was cooled and the reaction mixture was partitioned between EtOAc and aq. sodium bicarbonate solution. The organic layer was separated and washed with water, dried and evaporated and triturated with ethanol to give the crude product. Purification by flash chromatography (EtOAc/hexane 1:3 to 1:1) to afforded the title compound (87 mg) as a white solid. MS (ES): C22H2135ClN4O4 requires 440 found (MH+) 441.
Reaction SMILES: [CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[C:25]([O:28]CC)(=[O:27])C>CCCCCC.Cl>[CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:25]([OH:28])=[O:27])=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)OCCCS2
Reactant: CCOC(C)=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCCCS2
Temperature: 0 °C
Yield: 81 %

Procedure:
To 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene (16.2 g, 97 mmol) in 250 mL of dry hexane was added tetramethylethylene diamine (16 mL, 106 mmol). The solution was cooled to 0° C. and n-butyllitium (1.6 M solution in hexane, 73 mL, 116.8 mmol) was slowly added with stirring. A tan-colored precipitate slowly started to form and some gas evolution occured. The suspension was stirred at rt for 18 h, after which CO2 gas was bubbled though it for 20 min. An exothermic reaction occured. The mixture was diluted with 300 mL ethyl acetate and 4 N HCl. After all solids dissolved, the organic layer was washed with 1 N HCl. The acid was extracted into the water layer using sat. NaHCO3. The aqueous layer was washed with ethyl acetate and treated with 10 N HCl to pH 1. Extraction with ethyl acetate (2×250 mL), drying over Na2SO4 and concentration yielded the compound as a tan solid (16.5 g, 81%). MS [M−H]− 209.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH2:22][CH2:23][NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>CN(C=O)C>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([N:24]2[CH2:23][CH2:22][C:15]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=3[NH:13][C:6]2=[O:7])[CH2:26][CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
35.0 g (216 mmol) N,N-carbonyldiimidazole were added to 23.9 g (70.3 mmol) [2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine in 175 mL DMF and the mixture was stirred for 2 h at 100° C. The reaction mixture was poured onto approx. 1 kg of ice water and stirred overnight. The precipitated product was suction filtered, washed with 100 mL water and dried at 45° C. in the CAD. The residue was stirred with 150 mL DIPE and suction filtered. The solid product was washed with 50 mL DIPE. After drying in the CAD at 35° C., 21.6 g of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].OS([O-])=O.[Na+].[C-:18]#[N:19].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[C:18]#[N:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(O)C#N)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To 3,4-dimethoxybenzaldehyde (1.66 g, 10 mmol) in ethyl acetate (20 mL) was added NaHSO3 (5.2 g, 50 mmol) in water (20 mL), followed by potassium cyanide (3.26 g, 50 mmol) in water (20 mL). The mixture was stirred overnight at rt, then warmed to 50° C. for 6 h. The reaction was cooled to rt, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-50% ethyl acetate/hexanes) to provide 6A (1.25 g, 65%) and starting material, 3,4-dimethoxybenzaldehyde (0.52 mg). 6A: LC-MS: 176.22 (M−H2O)+.