Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=O)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CS(=O)(=O)Cl
Product: CCO[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting methanesulfonyl chloride and making non-critical variations provided the title compound as an oil:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.Cl[CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[CH:17]=[N:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[CH:17]=[N:16][N:15]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: CCCn1cnnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnnc1CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
2-mercapto-5-nitropyridine (5.0 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (6.3 g) and potassium carbonate (11 g) was added to N,N-dimethylformamide (100 ml), and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 5-nitro-2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridine (8.0 g) as brown crystals.
Reaction SMILES: [I:1][C:2]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:6](=O)[NH:7][C:8]3([CH2:11][CH2:10]3)[CH2:9][N:4]2[N:3]=1.CSC>C1COCC1>[I:1][C:2]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[CH2:6][NH:7][C:8]3([CH2:11][CH2:10]3)[CH2:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(I)nn2c1C(=O)NC1(CC1)C2
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn2c1CNC1(CC1)C2
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of Intermediate 350B (1.1 g, 3.05 mmol) in THF (10 mL) was added BH3.DMS (0.578 mL, 6.09 mmol, 2M) and the resulting solution was stirred at 40° C. for 18 h. The reaction mixture was cooled to RT, quenched with ethanol (10 mL) and heated to reflux for 1 h. Reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 350C (0.7 g, 66%) as a gummy solid. MS(ES): m/z=348 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([O:16][CH3:17])=[CH:9][C:8]=2[Br:18])=[O:4].[H-].[Na+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.O>CN1CCCC1=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:12]2[C:7](=[C:8]([Br:18])[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(=O)c2cc(OC)cc(Br)c2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.5 %

Procedure:
A brown solution of 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (6.73 g, 21.6 mmol) in 100 mL N-methylpyrolidinone was treated with sodium hydride (60% dispersion in oil, 1.028 g, 25.7 mmol). Gas evolution and warming were observed. The reaction was stirred for 10 minutes at room temperature under nitrogen. Addition of 2-(trimethylsilyl)ethoxymethyl chloride (5.00 mL, 28.3 mmol) resulted in a slightly cloudy, light brown solution. After 2.5 hours at room temperature, the reaction mixture was poured into 800 mL water and stirred for 15 minutes. The resulting cream colored precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the product as a cream colored solid (9.70 g, quantitative yield). 1H NMR (300 MHz, DMSO, d6) δ 7.976 (d, 1 H, Jm=2.7 Hz, ArH7), 7.79 (s, 1 H, C═CH), 7.53 (d, 1 H, Jm=2.7 Hz, ArH5), 5.70 (s, 2 H, OCH2O), 3.99 (s, 6 H, OCH3 and CO2CH3), 3.88 (t, 2 H, J=8.0 Hz, OCH2CH2Si), 0.97 (t, 2 H, J=8.0 Hz, OCH2CH2Si), ), −0.04 (s, 9 H, Si(C H3)3; Mass Spec.: calc. for [C18H24BrNO5Si+H]+ Theor. m/z=442, 444; Obs. 442, 444.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([N:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:26][C:25]([CH:35]=O)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:23]1[C:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:26][C:25]([CH2:35][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: Cc1ccc(-c2cc(CNCCN3CCN(c4ccc([N+](=O)[O-])cc4)CC3)nn2C(C)(C)C)cc1
Yield: 69.4 %

Procedure:
Compound 56 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C:27]1([CH3:36])O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.[OH:50][C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1>O1CCCC1.CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:36][O:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=3)([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:57]2=[O:81])=[CH:82][CH:83]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1(C)O
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.4 %

Procedure:
A solution of 6.6 g of 1,1'-(azodicarbonyl)dipiperidine in 10 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide was added dropwise to a mixture of 6.5 g of 1-t-butoxycarbonyl-2-hydroxy-methylindoline (prepared as described in Preparation 3), 6.5 ml of tributylphosphine, 12.2 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in European Patent Publication No. 549 365A1] and 100 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for about 20 hours. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.70 g of the title compound, melting at 85.4-87.2° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=O)=[N:4][N:3]=1.O=P(Cl)(Cl)Cl>ClCCCl>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][N:10]=[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]3)[N:4]2[N:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nnc(N)[nH]c2=O)CC1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(=O)[nH]c(N)nn32)CC1

Procedure:
A solution of methyl trans-4-{[(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]carbamoyl}cyclohexanecarboxylate (2.00 g, 0.00646 mol) in 1,2-dichloroethane (130 mL) was charged with POCl3 (4.2 mL, 0.045 mol) and heated to reflux for 3 h. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and sat. NaHCO3 and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo resulting in 1.43 g, (76% yield) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (q, J=11.79 Hz, 2H), 1.61 (q, J=12.55 Hz, 2H), 1.85-2.11 (m, 4H), 2.38 (t, J=11.87 Hz, 1H), 2.98 (t, J=11.75 Hz, 1H), 3.61 (s, 3H), 6.17 (br. s., 2H), 7.49 (s, 1H) and 10.90 (br. s., 1H); MS (ES+): m/z 292.25 [MH+].
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][S:14]([Cl:17])(=[O:16])=[O:15])=[CH:5][C:4]1([CH3:19])[CH3:18])[CH3:2].C(N1C2C(=CC=[C:29]([O:32]C)C=2)C(CS(O)(=O)=O)=CC1(C)C)C.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:32][CH3:29])[CH:11]=2)[C:6]([CH2:13][S:14]([Cl:17])(=[O:16])=[O:15])=[CH:5][C:4]1([CH3:18])[CH3:19])[CH3:2]
Reactant: CCN1c2cc(OC)ccc2C(CS(=O)(=O)O)=CC1(C)C
Reactant: CCN1c2ccccc2C(CS(=O)(=O)Cl)=CC1(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCN1c2cc(OC)ccc2C(CS(=O)(=O)Cl)=CC1(C)C
Yield: 73 %

Procedure:
(1-Ethyl-7-methoxy-2,2-dimethyl-1,2-dihydroquinol-4-yl)-methanesulfonic acid chloride (16) is prepared similarly to compound (9) from compound (15) and phosphorus pentachloride in dry benzene. The acid chloride that is obtained is immediately used for further reaction.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C@@H:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[N:22]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)[N:24]=3)[CH2:16]1)[CH3:14].C(N(CC)CC)C.[C:55](O)(=[O:59])[C@H:56]([CH3:58])[OH:57].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:25]2[N:24]=[C:23]3[C:28]([N:29]=[C:21]([N:17]4[CH2:18][CH2:19][N:20]([C:55](=[O:59])[C@@H:56]([OH:57])[CH3:58])[C@@H:15]([CH2:13][CH3:14])[CH2:16]4)[N:22]3[CH2:43][C:44]([F:47])([F:46])[F:45])=[C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)=[CH:37][N:38]=1
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)[C@H](C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (80 mg, 0.42 mmol) was added to an N,N-dimethylformamide solution (5 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (136 mg, 0.28 mmol), triethylamine (0.096 ml, 0.69 mmol), L-lactic acid (30 mg, 0.33 mmol), and 1-hydroxybenzotriazole (47 mg, 0.30 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer washed with water and saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:10) to give the title compound (31 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.Br[CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:13][C:14]2[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CO
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(Cl)cc1OC

Procedure:
Using (4-chloro-2-methoxyphenyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(4-chloro-2-methoxybenzyl)oxy]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:28]([C:24]2[C:23]3[CH:31]=[CH:32][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:21][C:22]=3[O:26][C:25]=2[CH3:27])=[O:30])[CH2:41][CH2:40]1
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC6CC6)c(C)oc5c4)c3s2)C1
Yield: 33.1 %

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e (37 mg, 0.08 mmole) by treatment with oxalyl chloride (15 μl, 0.17 mmole) and cyclopropylamine (56 μl, 0.81 mmole) in a manner as previously described for example 16d to give a white solid (13 mg,33%). 1H NMR (DMSO-d6) δ8.57 (1H, d, J=5.1 Hz), 8.19 (1H, s), 8.06 (1H, bs), 7.74 (1H, d, J=6.1 Hz), 7.65 (1H, s), 7.24 (1H, d, J=6.1 Hz), 6.71 (1H, d, J=1.8 Hz), 4.10-3.80 (3H, m), 3.70-3.35 (2H, m), 3.25 (3H, d, J=13.1 Hz), 2.86 (1H, m), 2.59 (3H, s), 2.25-1.95 (2H, m), 0.71 (2H, m), 0.60 (2H, m).
Reaction SMILES: [C:1]([OH:14])(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C([Cl:18])=O>ClCCl>[C:1]([Cl:18])(=[O:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC/C=C/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCC/C=C/C=C/C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2E,4E)-dodeca-2,4-dienoic acid (2.5 g) was dissolved in dichloromethane (25 ml). Oxalyl chloride (2.23 ml) was added and the reaction mixture was stirred at room temperature for 3 h. Solvent and excess oxalyl chloride were removed, and the residue was stripped several times with DCM. The crude acid chloride was used as such in next step.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl.[CH3:23][NH:24][O:25][CH3:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:24]([O:25][CH3:26])[CH3:23])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To a solution of Boc-Glu(OtBu)-OH (15 g) in dichloromethane (150 ml) was added N,O-dimethyl-hydroxylamine hydrochloride (5.3 g) and [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate] (15.87 g) and the pH was adjusted to pH 8-8.5 by adding triethylamine. The reaction mixture was stirred for 16 h at room temperature. The mixture was washed successively with cold 0.3M hydrochloric acid solution, water, 5% aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: dichloromethane/methanol=98/2 v/v %) to yield Boc-Glu(OtBu)-NMeOMe (17.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12]Br)=[CH:10][C:5]=2[O:4][C:3]1=[O:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH3:15])[CH2:28][CH2:27]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cn1c(=O)oc2cc(CCBr)ccc21
Product: COc1ccccc1N1CCN(CCc2ccc3c(c2)oc(=O)n3C)CC1
Yield: 65.1 %

Procedure:
By following the procedure indicated in Example 1, but starting from 5.12 g of 3-methyl-6-(2-bromoethyl)-benzoxazolinone and 4.82 g of 1-(2-methoxyphenyl)-piperazine, 4.78 g of the title product having a melting point of 137°-137.5° C. were obtained after crystallisation from cyclohexane.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>O1CCOCC1.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>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2ccccn2)C1
Temperature: 130 °C

Procedure:
To a solution of 1,1-dimethylethyl 3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (200 mg, 0.660 mmol, commercially available) in 1,4-dioxane (2 mL), 2-(tributylstannanyl)pyridine (364 mg, 0.990 mmol) was added and mixture was degassed with a stream of argon for few minutes. Pd(Ph3P)4 (38.1 mg, 0.033 mmol) was then added followed by copper(I) iodide (39.2 mg, 0.206 mmol) and the mixture was submitted to microwave irradiation heating at 130° C. for 25 minutes until the reaction was complete by LCMS. Volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel (Snap 11 g NH column) eluting with a gradient from 0 to 100% ethyl acetate in iso-hexane (10CV) and then with 100% ethyl acetate (7CV). A colourless oil was obtained. The product was still impure and so was further purified by chromatography on silica gel (Si 5 g) eluting with a 80% ethyl acetate in iso hexane (5CV) and then with 10% MeOH in DCM (5 CV) then by chromatography on silica gel (Si column 5 g) eluting first with ethyl acetate (4CV) and then with 10% MeOH in DCM (6CV). Colourless oil was obtained of the desired product in 115 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH:31]([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH:31]([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Reactant: CC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 65.5 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-hydroxy-propyl)-amide (56 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (75 mg), 1-amino-2-propanol (15 mg), HBTU (83 mg), and DIEA (48 uL). LC/MS: m/z 466.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.36 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.89-3.77 (m, 1H), 3.64 (s, 3H), 3.27-3.16 (m, 2H), 1.10 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:28]2)=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])C1
Yield: 90 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzophenone (1.0 eq), 3-(N-Boc-amino) piperidine (1.1 eq), and TEA (2.0 eq) in NMP yielding tert-butyl 1-(4-benzoyl-2-nitro phenyl)piperidin-3-ylcarbamate (90%). LCMS (m/z): 426.2 (MH+); LC Rt=3.49 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CN2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.3 %

Procedure:
Trifluoroacetic acid (75 ml, 974 mmol) was added to a solution 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g, 130 mmol) in chloroform (75 ml). The reaction mixture was stirred for 1 h at room temperature and then made basic with a sodium hydroxide solution. The product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 1-(3,4-dichlorobenzyl)piperazine (35.8 g) as a solid.
Reaction SMILES: CN(C)C=O.CS(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.O.O.[CH3:22][N:23]([CH3:27])[C:24](=[S:26])[S-:25].[Na+]>O>[CH3:22][N:23]([CH3:27])[C:24](=[S:25])[S:26][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:17])[F:18]
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: CN(C)C(=S)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCSC(=S)N(C)C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To 100 ml of N,N-dimethylformamide, 4.56 g (20 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 4.70 g (26 mmol) of sodium dimethyldithiocarbamate dihydrate were dissolved, followed by stirring at 100° C. for 3 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 2.60 g (yield: 51%) of 6,6-difluoro-5-methyl-5-hexenyl N,N-dimethyldithiocarbamate.