Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].[F-].[Cs+]>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>[NH2:1][C:2]1[C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([Cl:14])[CH:16]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N
Temperature: 80 °C
Yield: 30.2 %

Procedure:
A vial containing a mixture of methyl 3-amino-2,6-dibromoisonicotinate (500 mg, 1.613 mmol), 3-chloro-4-methoxyphenylboronic acid (301 mg, 1.613 mmol), cesium fluoride (588 mg, 3.87 mmol), and tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.097 mmol) was flushed with nitrogen. Dimethoxyethane (8 mL) was added and the reaction was heated at 80° C. for 18 hr. It was then partitioned between EtOAc and water and the organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 25 to 40% methylene chloride) afforded methyl 3-amino-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (181 mg) as a yellow solid. MS (ESI) m/z 373.0 (M+H). 1H NMR (CDCl3) δ ppm 7.79 (1H, s), 7.66 (1H, d, J=2.14 Hz), 7.52 (1H, dd, J=8.55, 2.14 Hz), 7.02 (1H, d, J=8.55 Hz), 5.94 (2H, br. s.), 3.95 (3H, s), 3.92 (3H, s).
Reaction SMILES: C([NH:6][C:7]1[C:8](=[O:31])[NH:9][C:10]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=2)=[N:11][CH:12]=1)(OCC)=O.[OH-].[Na+]>C(O)(=O)C>[NH2:6][C:7]1[C:8](=[O:31])[NH:9][C:10]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:19]=2)=[N:11][CH:12]=1
Reactant: CCOC(=O)Nc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O
Temperature: 120 °C
Yield: 19.8 %

Procedure:
A suspension of 5-carbethoxyamino-2-[3-(3-piperidinomethylphenoxy)propylamino]-4(3H)-pyrimidone (1.70 g; 3.96 mmoles) in 11.3 ml (28.3 meq.) of 10% aqueous NaOH was heated at an oil bath temperature of 120° C. for 20 minutes. The reaction mixture was neutralized with acetic acid and evaporated under reduced pressure. The residue was placed on 250 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using CH2Cl2 /CH3OH/NH4OH (80:20:1) as the eluent. The appropriate fractions containing product were combined, evaporated and treated wih ethanolic hydrochloric acid, and then diluted with ether to give 0.28 g of the title compound as its hydrochloride salt. The NMR spectrum (100 MHz) in d6 dimethyl sulfoxide gave the following resonances δ: 7.14 (m, 4H); 6.94 (s, 1H); 4.0 (m, 4H); 3.32 (t, 2H); 2.84 (m, 4H); 1.94 (m, 2H); 1.66 (m, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:63])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[O:56][CH:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:19](=[O:21])[C:18]2[CH:17]=[CH:16][C:15]([C:11]3[O:10][CH:14]=[N:13][N:12]=3)=[CH:23][CH:22]=2)[CH2:55][CH2:54]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1ccc(-c2nnco2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1ccc(-c2nnco2)cc1
Reaction time: 0.03 h
Yield: 38.4 %

Procedure:
DIPEA (203 mg, 0.27 mL, 1.57 mmol) was added to a stirred solution of 4-[1,3,4]oxadiazol-2-yl-benzoic acid (100 mg, 0.52 mmol) in DMF (2 mL) followed by HOBt (85 mg, 0.63 mmol) and EDCI (121 mg, 0.63 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (192 mg, 0.63 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 88 mg (38.09% yield) of N-{2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-4-[1,3,4]oxadiazol-2-yl-benzamide. LC/MS [M+H]+: 441.13, 95.23%. 1H NMR (300 MHz, DMSO-d6): δ 9.4 (s, 1H), 8.8 (t, 1H), 8.1 (q, 4H), 7.4 (m, 1H), 7.3 (m, 2H), 7.0 (m, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.18 (m, 2H), 1.8-1.5 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].I[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>>[CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: Ic1cccnc1
Product: CC(C)Oc1c(-c2cccnc2)c(=O)c1=O

Procedure:
In a manner similar to Example 9, Step 1, 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione (1.90 g, 4.43 mmol), 3-iodopyridine (1.00 g, 4.87 mmol), benzylchlorobis(triphenylphosphine)palladium (II) (0.201 g, 0.267 mmol), and cuprous iodide (0.076 g, 0.399 mmol) were reacted together to give the title compound which was of sufficient purity to use in the next step: 1H NMR (DMSO-d6) δ9.07(m,1H), 8.75(m,1H), 8.20(br d,1H), 7.65(m,1H), 5.50(sept,1H), 1.50(d,6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]3[N:16]([CH3:20])[C:17](=[O:19])[NH:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:21](=O)[CH2:22][CH2:23][CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C.C(OCC)(=O)C>[CH2:21]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10]1[C:15]2[N:16]([CH3:20])[C:17](=[O:19])[NH:18][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:22][CH2:23][CH3:24]
Reactant: COc1ccc(Nc2cccc3[nH]c(=O)n(C)c23)cc1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCN(c1ccc(OC)cc1)c1cccc2[nH]c(=O)n(C)c12
Temperature: 70 °C
Yield: 581.4 %

Procedure:
A mixture of 0.100 g (0.37 mmol) of 7-[(4-methoxyphenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 0.13 mL (1.5 mmol) of butyraldehyde in 15 mL of dichloroethane was treated with four drops of glacial acetic acid and 0.31 g (1.5 mmol) of sodium triacetoxyborohydride. The mixture was heated to 70° C. for five days. The mixture was diluted with ethyl acetate and was washed successively with saturated sodium bicarbonate and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude oil was purified by flash chromatography eluting with a 97% dichloromethane/methanol mixture to give 0.70 g (45%) of the title compound as a yellow sticky semi-solid that was used without further purification.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1>>[CH2:4]([O:3][CH2:2][N:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[N:14][C:15]1=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: ClCOCc1ccccc1
Product: O=c1ncc(Br)cn1COCc1ccccc1
Reaction time: 20 h
Yield: 29 %

Procedure:
was prepared as described in Example 3 from benzyl chloromethyl ether (see Preparation 1a and 1b) (4 mmol) and 5-bromopyrimidin-2-one by allowing the reaction to proceed for 20 hours at room temperature; yield 29% (0.34 g), m.p. 169° C. 1H NMR (CDCl3): δ4.65 (CH2Ph), 5.30 (CH2O), 7.18 (Ph), 7.78 and 8.40 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm-1 (CO).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][C:10]#[N:11].[Na].[CH3:14][S:15](O)(=[O:17])=[O:16].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O.[Cu](I)I.O>[CH3:14][S:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][C:10]#[N:11])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)O
Reactant: N#CCC(=O)c1ccccc1Br
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccccc1C(=O)CC#N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-bromophenyl)-3-oxopropanenitrile (15 g, 66.94 mmol) in DMSO (267 mL) were added sodium salt of methanesulfonic acid (13.6 g, 138.89 mmol), copper iodide (6.3 g, 33.47 mmol), L-proline (3.8 g, 33.47 mmol) and sodium hydroxide (1.3 g, 33.47 mmol) at 25° C. The reaction mixture was stirred for 1 h at 60° C. Water was added to the reaction mixture at 25° C. and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0-45% EtOAc in hexane to give 3-(2-(methylsulfonyl)phenyl)-3-oxopropanenitrile: 1H NMR (400 MHz, CHLOROFORM-d): δ 3.183 (S, 3H), 4.041 (s, 2H), 7.468 (dd, 1H, J=1.2 Hz, J=7.6 Hz), 7.699-7.798 (m, 2H), 8.084 (dd, 1H, J=1.2 Hz, J=7.6 Hz); LC-MS (ESI) m/z 224.0 [M+H]+.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:33])[C@H:15]([CH3:32])[C@@H:16]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1)C1C=CC=CC=1.C(O)C.[Li+].[BH4-]>C1COCC1.C(OCC)C.[OH-].[Na+]>[Si:25]([O:24][C@@H:16]([C@H:17]1[CH2:21][O:20][C:19]([CH3:22])([CH3:23])[O:18]1)[C@@H:15]([CH3:32])[CH2:14][OH:33])([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:26])[CH3:27]
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-4-benzyl-3-((2R,3R)-3-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropanoyl)oxazolidin-2-one (1.0 equiv.) and ethanol (3.0 equiv.) in THF (0.09 M) was added LiBH4 (1.0 equiv.) at −40° C. The reaction mixture was allowed to warm up to rt slowly and stirred at that temperature for 12 hours. The solution was cooled back to −40° C. and additional LiBH4 (0.3 equiv.) was added. After warming back up to rt and stirring for 2 hours the solution was then diluted with diethyl ether and 1N NaOH) was added. The resulting mixture was extracted with ethyl acetate, the organic layer was separated, washed with NaCl(sat.), dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel column chromatography (10-30% EtOAc/n-heptanes) yielding (2S,3R)-3-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol in (75%). LC/MS=247.1 (M+H-ketal-H2O), Rt=0.64 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH3:20])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-:24])C.[K+].O=O.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:20](=[O:24])[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2[nH]cc(C)c2c1OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]ccc(=O)c2c1OCc1ccccc1
Yield: 10.6 %

Procedure:
4-Benzyloxy-5-methoxy-3-methylindole (3.5 g) was dissolved in dimethylformamide (40 ml), and potassium t-butoxide (3.3 g) was added to the mixture. The resulting mixture was stirred at room temperature under a stream of oxygen for 5 days, poured into water and extraction with ethyl acetate was conducted. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 80 g). Elution with a mixed solvent of chloroform (92 parts) and methanol (8 parts) gave 5-benzyloxy-6-methoxy-4(1H)-quinolone (compound 4; 390 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]>[Ni].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CCN1CCN(Cc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.6 %

Procedure:
A suspension of 1-ethyl-4-(4-nitro-benzyl)-piperazine (7.2 g, 29.14 mmol) and Raney Nickel (1.5 g) in MeOH (100 mL) is stirred for 6 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford 6.3 g of the title compound as a yellow solid: ESI-MS: 220.1 [MH]+; TLC: Rf=0.08 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][S:15]([CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:21][CH2:22]1
Reactant: CS(=O)(=O)CCC1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (2.02 g, 10.9 mmol) and 4-[2-(methylsulfonyl)ethyl]piperidine (2.48 g, 13.0 mmol) in DMSO (75 mL) was added K2CO3 (5.26 g, 38.1 mmol). The mixture was stirred at 100° C. for 2 days. The mixture was diluted with EtOAc, washed with H2O (4×), and rotovapped down. The crude residue was taken up in DCM and dried (MgSO4), filtered, and concentrated. Purification by flash chromatography provided the title compound of Step D (3.26 g, 9.14 mmol, 84%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (q, J=11.0 Hz, 2H), 1.52 (br. s., 1H), 1.60-1.72 (m, 2H), 1.78 (d, J=12.1 Hz, 2H), 2.17 (s, 3H), 2.67 (t, J=11.6 Hz, 2H), 2.95 (s, 3H), 3.07-3.21 (m, 2H), 3.21-3.35 (m, 2H), 3.88 (s, 3H), 6.66 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:2]1[CH2:3][CH:4]2[CH2:23][CH2:24][CH:1]1[CH:6]=[C:5]2[C:7]1[N:12]=[C:11]2[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C:10]2=[CH:9][CH:8]=1)(=[O:36])[CH3:35]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC2CCC1C=C2c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-5, 25 mg, 0.08 mmol, 1.0 equiv) was added to anhydrous DCM (0.80 mL). To this solution was added DIPEA (40 μL, 0.23 mmol, 3.0 equiv) and acetyl chloride (11 μL, 0.15 mmol, 2.0 equiv) and the resulting mixture was allowed to stir at room temperature for 10 min. Following this duration, LCMS showed consumption of starting material. Saturated NaHCO3 (3 mL) and ethyl acetate (3 mL) were then added and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×3 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 3-1 as a white solid. MS m/z (M+H): calculated=369.2285; observed=369.2284.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:10]=1[N+:21]([O-])=O.[NH4+].[OH-].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:10]=1[NH2:21]
Reactant: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
[4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.20 g, 0.56 mmol was dissolved in dioxane (8 mL) and H2O (8 mL), followed by conc. NH4OH (0.3 mL) and Na2S2O4 (0.79 g, 4.53 mmol) and stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with H2O, brine, dried (Na2SO4), filtered, and concentrated in vacuo to produce 0.13 g (72%) of 4-(2,4-dichloro-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 326.2 [(M+H)+, 90].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=3)[C:14](=[O:24])[O:13][N:12]=2)=[N:8][O:9][N:10]=1.Cl[S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[Br:23][C:18]1[CH:17]=[C:16]([N:15]2[C:14](=[O:24])[O:13][N:12]=[C:11]2[C:7]2[C:6]([NH:5][CH2:4][CH2:3][NH:2][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:27])=[O:28])=[N:10][O:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
A 22 L flask was charged with 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (661 g, 1.57 mol) and 8.5 L dichloromethane. After cooling to −15° C. with an ice/salt bath, the solution of tert-butyl [chlorosulfonyl]carbamate (prepared as above) was added at a rate so that the temperature did not exceed −10° C. (addition time 7 min). After stirring for 10 min, triethylamine (1085 mL, 7.78 mol) was added at a rate so that the temperature did not exceed −5° C. (addition time 10 min). The cold bath was removed, the reaction was allowed to warm to 10° C., split into two portions, and neutralized with 10% conc HCl (4.5 L each portion). Each portion was transferred to a 50 L separatory funnel and diluted with ethyl acetate to completely dissolve the white solid (˜25 L). The layers were separated, and the organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford an off-white solid. The solid was triturated with MTBE (2×1.5 L) and dried to a constant weight to afford a white solid. A total of 4113 g starting material was processed in this manner (5409 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.08 (dd, J=6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J=8.6 Hz, 1 H), 6.58 (t, J=5.7 Hz, 1 H), 3.38 (dd, J=12.7, 6.2 Hz, 2 H), 3.10 (dd, J=12.1, 5.9 Hz, 2 H), 1.41 (s, 9 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[N:8]=[CH:7]2)([O-])=O>[Ni].CCOC(C)=O>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.50 g Raney nickel are added to a solution of 3.50 g (13.4 mmol) 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole in 50 mL EtOAc and the reaction mixture is stirred for 20 h at RT at 1.4 bar H2. After filtration the solvent is eliminated i.vac. The product is further reacted without any more purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]#[N:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.O>O1CCCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)[C:4]#[N:5])(=[O:18])=[O:17]
Reactant: Cc1ccc(C=CC(C#N)=NO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C=CC(C#N)=NOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 64.3 %

Procedure:
2-Hydroxyimino-4-p-tolyl-but-3-enenitrile (1.9 g; 0.01 mol) is dissolved in 15 ml of anhydrous tetrahydrofuran, and cooled to 0° C. Methanesulfonyl chloride (0.93 ml, 0.012 mol) is added at once, followed by triethylamine (2.1 ml, 0.015 mol) dropwise over 20 min, keeping the temperature of the mixture below 5° C. The mixture is then stirred at 5-10° C. for 3.5 hours, and poured into 200 ml of iced water. The suspension is extracted with ethyl acetate, the organic extract is washed neutral with water, then with brine, and dried over magnesium sulfate. Rotary evaporation of the solvent and recrystallization from 50 ml of ethanol yields 2-methanesulfonyloxyimino-4-p-tolyl-but-3-enenitrile (1.7 g; 64%) as off-white crystals, mp 134-135° C. with one part melting at 145° C. 1H-NMR reveals the presence of two isomers (probably E/Z around the imino double bond).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1>[Pd].CCO>[NH:11]1[CH2:10][CH:9]([O:8][C:3]2[CH:2]=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CC(Oc2nccnc2Cl)C1
Agent: [Pd]
Solvent: CCO
Product: c1cnc(OC2CNC2)cn1
Reaction time: 0.5 h
Yield: 180.8 %

Procedure:
To a nitrogen-purged round bottomed flask was added benzyl 3-(3-chloropyrazin-2-yloxy)azetidine-1-carboxylate (see PREPARATION P20.1; 0.400 g, 0.688 mmol) and Pd/C (0.10 g, 0.094 mmol) and EtOH (10 mL). Hydrogen gas was bubbled through the solution for 1 minute, then a balloon of hydrogen gas was placed atop the round bottomed flask. After 30 minutes, the balloon was removed and the round bottomed flask sealed with a rubber septum. After 16 hours, the reaction was filtered through CELITE® and the cake was washed liberally with EtOAc. The filtrate was concentrated in vacuo to give crude 2-(azetidin-3-yloxy)pyrazine (0.188 g, 181% yield), as a off-white solid. The product was carried forward in the next step without further purification. MS (ESI) m/z 152.1 (MH+).