Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[C:15]([NH:20]C=O)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[K+].CCO.CC(O)=O>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=CNc1cccc2c(S(=O)(=O)Nc3nccs3)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(S(=O)(=O)Nc3nccs3)cccc12
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A solution of 5-formylamino-naphthalene-1-sulfonic acid thiazol-2-ylamide (350.0 mg, 1.0 mmol), KOH (168.0 mg, 3.0 mmol), EtOH (1.0 ml) and H2O (0.5 ml) was heated at 60° C. for 6 h. The mixtures was then cooled to 0° C., and neutralized with AcOH (3.0 mmol). The formed precipitate was filtered and dried under vacuum to give 5-amino-naphthalene-1-sulfonic acid thiazol-2-ylamide as a light tan solid (280 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.5 Hz, 1H), 8.11 (dd, J=7.2, 1.0 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.45-7.42 (m, 1H), 7.32-7.28 (m, 1H), 7.19 (d, J=4.6 Hz, 1H), 6.77-6.73 (m, 2H), 5.90 (s, 2H). LC/MS (10-99% CH3CN), M/Z: M+1 obs=306.10; tR=1.12 min.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[F:22])[CH2:5][CH2:4]1>[Pd]>[F:24][C:2]([F:1])([F:25])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[F:22])[CH2:7][CH2:8]1
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
The subtitle compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide with Pd/C and H2 in analogy to example 1f.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2>>[OH:42][C:39]1[CH:40]=[CH:41][C:32]([O:31][CH2:30][C@@H:29]([OH:44])[CH2:28][NH:27][CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[N:3][C:2]4=[O:1])=[CH:13][CH:12]=3)[CH2:15][CH2:16]2)=[C:33]2[C:38]=1[NH:37][C:36](=[O:43])[CH2:35][CH2:34]2
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Product: O=C1CCc2c(OC[C@@H](O)CNC3CCN(c4ccc(C=C5SC(N6CCCCC6)=NC5=O)cc4)CC3)ccc(O)c2N1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and 5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Intermediate 12) according to the procedure of Example 1 as a yellowish solid; mp>120° C. (dec.); 1 H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.43 (t, J=7.9 Hz, 2 H), 2.55-2.90 (m, 9 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.44 (d, J=9.0 Hz, 1 H), 6.59 (d, J=9.0 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.44 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H), 8.82 (s, 1 H); MS (ES) m/z: 303.6 ((M +2H)2+, 100%); 606.1 (MH+, 10%); HRMS Calcd. for C32H40N5O5S (MH+): 606.2750. Found: 606.2711.
Reaction SMILES: O(C([NH:8][C@@:9]1([CH3:16])[C:13]2([CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10]1)=O)C(C)(C)C.F[C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]2[C@@H:29]2[CH2:31][C@@H:30]2[F:32])=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl.CS(C)=O>[NH2:8][C@@:9]1([CH3:16])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:18]2[C:27]([CH3:28])=[C:26]3[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]3[C@@H:29]3[CH2:31][C@@H:30]3[F:32])=[CH:20][CH:19]=2)[CH2:10]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CNCC12CC2
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(N2CC3(CC3)[C@](C)(N)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 75 °C
Reaction time: 120 h

Procedure:
A mixture of (7S)-7-(tert-butoxylcarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (523 mg, 2.31 mmol), 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (538 mg, 1.927 mmol), triethylamine (0.537 mL, 3.85 mmol), and dimethyl sulfoxide (6 mL) was stirred in nitrogen atmosphere in an oil bath at 75° C. for 5 days, and in an oil bath at 85° C. for 2 days. To the reaction mixture was added 10% aqueous solution of citric acid (10 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2) to obtain a pale yellow foam solid. The purified pale yellow foam solid was dissolved in concentrated hydrochloric acid (8 mL) at room temperature, and after transferring the resulting acidic aqueous solution using 6N hydrochloric acid to a separatory funnel, solution was washed with chloroform (50 mL×8). To the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath, and hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3), and lower layer of a mixed solvent chloroform, methanol, and water (chloroform:methanol:water, 7:3:1) (100 mL). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by recrystallization from ethanol-isopropanol system, and the crystals were dried under reduced pressure to obtain 332 mg (2 steps, 42%) of the title compound as a pale yellow powder.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[C:22]([C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([F:43])=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)=[O:33])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:43][C:39]1[CH:38]=[C:37]2[C:42](=[CH:41][CH:40]=1)[N:34]([C:32]([C:22]1[CH:23]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=1)=[O:33])[CH2:35][CH2:36]2
Reactant: CN(c1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1)S(C)(=O)=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1cc(C(=O)N2CCc3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1)S(C)(=O)=O

Procedure:
0.25 g (0.89 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride, 0.34 g (0.89 mmol) N-[6-chloro-4-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyridin-2-yl]-N-methyl-methanesulphonamide and 0.37 g (2.7 mmol) potassium carbonate were stirred in 3 mL of NMP for 4 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and acetonitrile was eliminated by rotary evaporation. The precipitated substance was suction filtered and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.C1(C[N:26]2[CH:30]=[C:29]([C:31]3S[C:33]([C:37](O)=O)=[C:34](C)[N:35]=3)N=N2)CC1.N1C=CC=C(CN)C=1>>[CH:2]1([CH2:1][N:8]2[CH:12]=[C:11]([C:13]3[S:14][C:15]([C:19]([NH:26][CH2:30][C:29]4[CH:31]=[N:35][CH:34]=[CH:33][CH:37]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[N:10]=[N:9]2)[CH2:7][CH2:6]1
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(CC3CC3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(CC3CC3)nn2)sc1C(=O)NCc1cccnc1
Yield: 57 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 57% yield: mp 140-141° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.73-8.48 (m, 2H), 8.24 (s, 1H), 7.76-7.66 (m, 1H), 7.39-7.19 (m, 1H), 6.71 (br s, 1H), 4.62 (d, J=5.3 Hz, 2H), 4.26 (d, J=7.2 Hz, 2H), 2.72 (s, 3H), 1.39-1.23 (m, 1H), 0.81-0.66 (m, 2H), 0.53-0.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.9, 158.3, 157.3, 149.2, 148.9, 143.9, 142.5, 135.8, 133.8, 124.1, 121.2, 55.5, 41.6, 17.3, 10.8, 4.4; MS (ES+) m/z 355.3 (M+1).
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[K+].[CH3:23][C:24]1([CH3:32])[CH2:29][C:28](=[O:30])[O:27][C:26](=[O:31])[CH2:25]1.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH3:23][C:24]([CH3:32])([CH2:29][C:28](=[O:30])[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][C:26]([OH:31])=[O:27]
Reactant: CCCCCCCCCCCc1cc2ccccc2[nH]1
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCc1cc2ccccc2n1C(=O)CC(C)(C)CC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 2-undecyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture 4,4-dimethyl-dihydro-pyran-2,6-dione was added and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:17][C:16]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)[N:12]([C:13](=[O:35])[N:14]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:15]2=[O:26])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([CH2:8][N:9]1[CH2:17][C:16]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)[N:12]([C:13](=[O:35])[N:14]([C:27]3[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:15]2=[O:26])[CH2:11][CH2:10]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 48 h

Procedure:
To a solution of 4-(tert-butoxycarbonylmethyl)-6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.080 g) in CH2Cl2 (10 mL) was added TFA (0.10 mL). Additional TFA (0.5 mL) was added after 3 and 22 hours. After stirring for 48 hours, the mixture was concentrated and purified by chromatography (Silica gel: 8% MeOH/CH2Cl2, Chromatotron) afforded the titled compound. (0.083 g). MS (m/z) 526 (MH+). mp 236.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (64.5 mg, 0.131 mmol) in N,N-dimethylormamide (2.5 ml) was added sodium hydride (6 mg, 0.158 mmol), 60% dispersion in mineral oil, then acetic acid 2-bromo-ethyl ester (17 μl, 0.158 mmol). The reaction stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched the following day with water and diluted with ethyl acetate. The organic layer was washed twice with water, then brine. After the organic layer was dried over magnesium sulfate the solvent was distilled off under reduced pressure to give the title compound, 132 mg (100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:10]2[NH:11][C:12](=[O:15])[CH2:13][O:14][C:9]=2[CH:8]=1)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[CH:17]=[CH:16][C:10]2[NH:11][C:12](=[O:15])[CH2:13][O:14][C:9]=2[CH:8]=1
Reactant: O=C1COc2cc(C(=O)CCCBr)ccc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1COc2cc(CCCCBr)ccc2N1
Yield: 80 %

Procedure:
In a 500-cm3 ground-necked flask surmounted by a condenser, and placed in an oil bath, 40.8 g (0.15 mol) of 7-(4-bromoBUTYRYL)2,3-dihydro 3-oxo 1,4-benzoxazine described in European Patent Application EP 0223674 are dissolved in 90 cm3 of trifluoroacetic acid with magnetic stirring and while the temperature is stabilized at 60° C. 52.7 cm3 (0.33 mol) of triethylsilane are introduced dropwise via a dropping funnel. After the addition, the heating is stopped and the mixture is then left stirring vigorously for 30 hours. The reaction medium is hydrolyzed by pouring it into ice-cold water, and the precipitate obtained is drained and washed with water until the filtrate is neutral and then with hexane. The product is dried and recrystallized in absolute ethanol. Yield: 80%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@@H:27](O)[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F-].[F:39]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C1COCC1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([F:39])[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C[C@H](C[C@H]1CC[C@@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A mixture of benzyl (S)-2-(t-butoxycarbonylamino)-3-(cis-4-hydroxycyclohexyl)-propyl(methyl)carbamate (1 g, 2.38 mmol), base Et3N (5 mL, 28 mmol), a fluoride source NEt3(HF)3 (1.9 mL, 9.52 mmol) and perfluorobutanesulfonyl fluoride (2.1 mL, 9.52 mmol) were stirred in THF (24 mL, 1 mmol/10 mL) in a capped vial or flask at 50° C. until LC revealed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL), dried over MgSO4, and evaporated. The residue was then purified by preparative HPLC to give benzyl (S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)propyl-(methyl)carbamate (200 mg, 20%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[N:20]=[CH:19]4)=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])C.Cl>CC(O)=O>[CH3:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([CH2:15][C:12]3[N:10]4[N:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: C=C(OCC)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1

Procedure:
A solution of 6-(1-ethoxy-vinyl)-3-(1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine (50 mg, 0.15 mmol) and HCl (0.15 mL, 0.15 mmol) in AcOH (10 mL) was heated at 50° C. for 3 h. The solvent was removed under reduced pressure. The residue was diluted with water and pH of solution was adjusted to around 8 with saturated NaHCO3 solution, then was extracted with DCM three times. Organic layers were combined, dried over Na2SO4 and concentrated. The crude product was used in the next step without purification (45 mg, 75%, 76% purity). LCMS (method A): [MH]+=306, tR=5.03 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C@@H:16]2[CH2:22][C:21]([F:24])([F:23])[CH2:20][CH2:19][NH:18][C:17]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:15]([C@@H:16]2[CH2:22][C:21]([F:24])([F:23])[CH2:20][CH2:19][NH:18][C:17]2=[O:25])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:27])=[O:28])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCC(F)(F)C[C@H]1N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 91.8 %

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.105 g, 0.2 mmol) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:1) and stirred overnight. After extraction with aqueous sodium bicarbonate solution the organic layer was dried (MgSO4) and evaporated to yield 80 mg (94%) of 4-chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-piperidin-4-ylmethyl-benzenesulfonamide;
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C@H:4]([C@H:9]([OH:11])[CH3:10])[C:5]([O:7]C)=[O:6].O.O.[OH-].[Li+].CO>C1COCC1>[CH3:1][CH:2]([CH3:12])[CH2:3][C@H:4]([C@H:9]([OH:11])[CH3:10])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)[C@H](CC(C)C)[C@@H](C)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.6 %

Procedure:
Methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoate (7.99 g, 46 mmol) in 50 mL of THF is treated with 50 mL of water containing 3.9 g (92 mmol) of lithium hydroxide monohydrate. The reaction flask is treated with 5.0 mL of MeOH and allowed to stir for 17 h at 25° C. The mixture is partitioned between water and ether followed by separation of the aqueous layer. The aqueous solution is brought to pH 3 with 6 N aqueous hydrochloric acid and the mixture is extracted with ether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to afford 6.6 g (90%) of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14](O)=[N:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([Cl:20])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cn1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2nc3cc(Br)cnc3[nH]2)cn1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-ol (300 mg, 1.03 mmol) was added to phosphorous oxychloride (6 ml) and the mixture was stirred at 110° C. for 4 h. The excess phosphorous oxychloride was evaporated off and the remaining oil was purified by flash chromatography using ethyl acetate/heptane as eluent. The title compound was isolated as a yellow solid (139 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12]Cl.CI>C1COCC1>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][C:3]2[O:10][CH2:11][CH2:12][C:4]=2[CH:5]=1
Reactant: COc1ccc(OCCCl)c(Br)c1
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
To a solution of 2-bromo-1-(2-chloroethoxy)-4-methoxybenzene (1.38 g, 5.22 mmol) in THF was added 190 mg (7.82 mmol) of Mg and MeI (3 mL). The mixture was sonicated for 2 h and stirred at room temperature for additional 20 h. The reaction was quenched with 3N HCl (50 mL) and extracted with 1:1 hexane/ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (3:1 hexane/ethyl acetate) of the residue gave 0.66 g (85%) of the title compound as a colorless liquid: 1H NMR (400 MHz, CDCl3) d 6.80 (d, 1H), 6.70 (d, 1H), 6.65 (dd, 1H), 4.53 (t, 2H), 3.75 (s, 3H), 3.18 (t, 3H).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([CH3:18])([CH3:17])[C:12](=[NH:16])OCC)[CH:10]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH2:28]2)=[N:24][C:25]=1N>C(O)C>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:12]2[NH:16][C:25]3=[N:24][C:23]([N:27]4[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:34])[CH2:28]4)=[CH:22][CH:21]=[C:20]3[N:19]=2)([CH3:17])[CH3:18])[CH:10]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C(C)(C)n1cc(Cl)cn1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1)n1cc(Cl)cn1
Yield: 25 %

Procedure:
Acetic acid (2.9 mL, 48.58 mmol) and ethyl 2-(4-chloro-1H-pyrazol-1-yl)-2-methylpropanimidate (Intermediate 54) were added to a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone in ethanol, prepared in the previous step. The reaction mixture was heated at reflux for 18 h. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified via column chromatography (100-200 mesh silica gel, 5% methanol in ethyl acetate) to afford the title compound (530 mg, 25% yield over 2 steps). 1H NMR (500 MHz, CDCl3) δ 1.53-1.65 (m, 1H) 1.74-2.00 (m, 7H) 2.10 (s, 6H) 2.58-2.70 (m, 1H) 2.88-2.93 (m, 1H) 3.01-3.09 (m, 1H) 3.40-3.50 (m, 3H) 3.55-3.63 (m, 1H) 4.22 (d, 1H) 4.43 (d, 1H) 6.63 (d, 1H) 7.57 (d, 2H) 7.79 (d, 1H) 10.08 (br s, 1H). MS (ES+APCI) (M+H) 442.2; LCMS retention time 2.216 min (Method N1).
Reaction SMILES: [C:1]([NH:11][NH2:12])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[O:10])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)NNC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.25 mol of anisohydrazide is dissolved in 300 ml of pyridine. At room temperature, 0.25 mol of butyryl chloride is added dropwise, and the mixture is stirred for a further 11/2 hours. The mixture is subsequently poured into 1.5 1 of ice/water, and the crystals are filtered off with suction and washed with water. The N-(4-methoxybenzoyl)-N'-butyrylhydrazine obtained is recrystallized from toluene. 0.1 mol of this compound and 0.1 mol of Lawesson's reagent are refluxed for 10 hours in 200 ml of THF. 2/3 of the solvent are removed by distillation, the residue is poured into 500 ml of water and 50 ml of 32% sodium hydroxide solution, and the precipitate is filtered off with suction and recrystallized from ethanol/activated charcoal, to give 2-(p-methoxyphenyl)-5-propyl-1,3,4-thiadiazole, m.p. 54°, C 0°.