Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]1C(OC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]C1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:23])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C(Oc1ccccc1)N1C=CC=CC1Cc1ccccc1
Solvent: c1ccccc1
Product: Clc1ccnc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
The crude dihydropyridine intermediate is dissolved in benzene (100 ml) and heated to 65°. A solution of 2,3-dichloro 5,6-dicyanobenzoquinone (5.0 q) in warm benzene (50 ml) is added dropwise with stirring. The reaction mixture is stirred at 65° for one hour and then cooled to room temperature. The mixture is washed with 10% aqueous sodium bicarbonate (two portions of 100 ml each) and water (100 ml), then extracted with 2N hydrochloric acid (two portions of 150 ml each). The combined acid extracts are made alkaline with dilute aqueous sodium hydroxide and extracted with diethyl ether. After drying and concentration, the title compound is obtained as an oil (0.95 g) that can be further purified by chromatography on silica gel (using 4:1 by volume hexane-ethyl acetate as eluent). Structure assignment is confirmed by nmr spectroscopy. nmr (CDCl3): δ (ppm) 4.16 (s, 2H); 7.14-7.40 (m, 7H); 8.46 (d, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[O:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>>[O:31]1[C:35]2([CH2:40][CH2:39][N:38]([CH2:2][CH2:3][O:4][C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]([NH:15][C:16](=[O:30])[C:17]4[CH:22]=[C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:20]=[C:19]([F:29])[CH:18]=4)=[CH:7][CH:6]=3)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: O=C(Nc1ccc(OCCN2CCC3(CC2)OCCO3)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 1,4-dioxa-8-aza-spiro[4.5]decane according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.32 (dd, 1H, J=1.8 and 8.7 Hz), 7.9 (s, 1H), 7.83 (d, 1H, J=7.8 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.53 (m, 2H), 7.31 (s, 1H), 6.99 (d, 1H, J=8.4 Hz), 6.84 (d, 1H, J=8.4 Hz), 6.76 (d, 1H, J=11.7 Hz), 4.31 (t, 2H, J=5.7 Hz), 3.97 (s, 4H), 3.28 (m, 4H), 3.02 (t, 2H, J=6.9 Hz), 2.76 (m, 4H), 1.8 (t, 4H, J=5.7 Hz), 1.62-1.67 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C@@H:7]([NH:31][C:32](=[O:51])[NH:33][C@@H:34]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](ON1C(=O)CCC1=O)=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C@@H:54]([CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:70][C:71]1[N:72]([CH3:76])[CH:73]=[CH:74][N:75]=1)[CH2:63][C:64]1[N:65]([CH3:69])[CH:66]=[CH:67][N:68]=1)[C:55]([OH:57])=[O:56].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:69][N:65]1[CH:66]=[CH:67][N:68]=[C:64]1[CH2:63][N:62]([CH2:70][C:71]1[N:72]([CH3:76])[CH:73]=[CH:74][N:75]=1)[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:54]([C:55]([OH:57])=[O:56])[NH:53][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:30])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:52])[NH:31][C:32](=[O:51])[NH:33][C@H:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:42][CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:49])([CH3:50])[CH3:48]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccnc1CN(CCCC[C@H](NC(=O)CCCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O)Cc1nccn1C
Yield: 17.6 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.356 g, 0.48 mmol), the compound of Compound 13 (0.16 g, 0.48 mmol) and DIPEA (1.0 mL) in DMF (5.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (7S,11S,26S)-26-(4-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-2,2-dimethyl-4,9,17,24-tetraoxo-3-oxa-8,10,16,25-tetraazaheptacosan-27-oic acid (81 mg, 18%). MS (ESI), 481 (M/2+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:20])([F:21])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J17) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) according to the general procedure M. Obtained as a light yellow foam (218 mg).
Reaction SMILES: C([O:4][CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH:18]=[CH:19][C:20]([O:22]CC)=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11])(=O)C.[OH-].[Na+].C(O)C>O>[OH:4][CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH:18]=[CH:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCCCCC(CCCN(Cc1cccc(C=CC(=O)OCC)c1)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(Cc1cccc(C=CC(=O)O)c1)S(C)(=O)=O
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution composed of ethyl m-[N-(4-acetoxynonyl)methanesulfonamidomethyl]cinnamate (4.1 g., 0.0088 mole), sodium hydroxide (1.05 g., 0.026 mole), water (15 ml.), and ethanol (75 ml.) is kept at room temperature 20 hours. The reaction mixture is added to water, extracted with ether, and the aqueous layer acidified. After extraction with ethyl acetate and drying overanhydrous magnesium sulfate, the ethyl acetate is removed by evaporation in vacuo. This gives, after crystallization from 1-chlorobutane, m-[N-(4-hydroxynonyl)methanesulfonamidomethyl]cinnamic acid, 2.6 g. (74% yield), m.p. 105° C. Anal. Calcd. for C20H31NO5S: C, 60.42; H, 7.86; N, 3.52 Found: C, 60.69; H, 8.43; N, 3.51
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([NH:24][CH2:25][CH2:26][CH:27]=C)=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOC[CH2:30]1.CO>O>[CH2:25]([N:24]([CH3:30])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:3])=[O:5])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:26]=[CH2:27]
Reactant: C=CCCNc1ncccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Reactant: C1COCCO1
Solvent: O
Solvent: CO
Product: C=CCN(C)c1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 38 h
Yield: 100 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(allyl-methyl-amino)-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (339, 280 mg, 0.74 mmol) is charged with 1,4-dioxane (2 mL) and MeOH (2 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1 mL) is added followed by the LiOH monohydrate (78 mg, 1.86 mmol). After 38 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 15 days, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.26 g, 100%).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][C:8]1[S:9][C:10]([CH:14]=[O:15])=[C:11]([Br:13])[N:12]=1>O>[Br:7][C:8]1[S:9][C:10]([C:14]([OH:2])=[O:15])=[C:11]([Br:13])[N:12]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1sc(Br)nc1Br
Agent: [K+]
Solvent: O
Product: O=C(O)c1sc(Br)nc1Br

Procedure:
Solid potassium permanganate (2.19 g, 13.85 mmol) was added portionwise to a hot suspension of 2,4-dibromo-thiazole-5-carbaldehyde (2.5 g, 9.23 mmol) in water (20 ml). The progress of the reaction was monitored by HPLC. More potassium permanganate was added until all of the aldehyde was consumed. The dark suspension was filtered while hot. The filtrate was cooled and acidified with conc. hydrochloric acid to pH=2 to 3. The resulting precipitate was filtered off to afford a white solid as the desired product. The filtrate was lyophilized and methanol was added to dissolve the remaining acid product. The suspension was filtered and the filtrate was concentrated in vacuo. Two crops were combined to give 2,4-dibromo-thiazole-5-carboxylic acid 1.8 g (68%). 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H).
Reaction SMILES: ClCCl.C([O:6][C:7](=[O:37])[CH:8]([NH:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH:11]=1)C.[Cl:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:40]=1[C:41](Cl)=[O:42].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:34]([O:33][C:31]([NH:30][CH:8]([CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:41](=[O:42])[C:40]3[C:39]([Cl:38])=[CH:47][CH:46]=[CH:45][C:44]=3[Cl:48])=[CH:26][CH:27]=2)[CH:11]=1)[C:7]([OH:6])=[O:37])=[O:32])[CH:35]=[CH2:36]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(N)cc2)no1)C(=O)OCC
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
A dichloromethane (1 mL) solution 2-allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester (80 mg, 0.170 mmol) was cooled to 0° C. and 2,6-dichlorobenzoylchloride (39 mg, 0.187 mmol) was added. The mixture was stirred for 15 minutes then pyridine (28 μL, 0.34 mmol) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1M sodium hydroxide and brine. The organic portion was dried over magnesium sulfate and concentrated to give the title compound (84 mg, 78%). MS (Cl) m/z 635.3 (M+1), 632.5 (M−1) C. 2-Allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)propionic acid ethyl ester
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=S)[NH:11][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: NNC(=S)NCCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(NCCc2ccccc2)n[nH]c1C
Temperature: 25 °C

Procedure:
A stirred slurry of 33.1 g (0.17 mole) of 4-phenylethyl-3-thiosemicarbazide in 500 mL of absolute ethanol under nitrogen atmosphere was treated with 29 g (0.17 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for ~72 hr, heated to reflux to dissolve most materials, and filtered hot. The filtrate was concentrated in vacuo to give a reddish oil, 71 g. The residue was chromatographed on 800 g Florosil® and eluted first with benzene to remove a yellow band (sulfur) followed by an acetone/benzene gradient which gave two main fractions. These two fractions were combined, and concentrated to give a yellow oil which solidified. Recrystallization (twice) from ligroin gave a fluffy white crystalline product, with small spots of green-yellow color, 12.1 g, mp 138°-139° C.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30].C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[C:29]([C:31]1[CH:36]=[C:35]([C:2]2[CH:16]=[C:15]([CH2:17][NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1Br
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
t-butyl 2-(2-bromo-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (7) (64 mg, 0.135 mm ol, 1 eq), 3-cyanophenylboronic acid (30 mg, 0.20 mmol, 1.5 eq), K2CO3 (75 mg, 0.54 mmol, 4 eq), Pd(PPh3)4 (2.3 mg, 0.001 mmol, 0.01 eq) and 4 mL of dioxane/H2O (4:1) were heated to 140° C. for 1 h in a microwave. The mixture was then cooled to room temperature, filtered, concentrated in vacuo, and purified by preparative TLC to give 51 mg (76%) of t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (8).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:28]=[CH:27][C:19]3[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=3[CH:17]=2)=[CH:12][C:11]=1[NH:29][CH:30]([CH3:32])[CH3:31]>CS(C)=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:28]=[CH:27][C:19]3[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=3[CH:17]=2)=[CH:12][C:11]=1[NH:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cnc(OCCN(C)C)c(NC(C)C)c3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
2-(dimethylamino)ethanol (140.2 mg, 1.573 mmol) was dissolved in DMSO (1.5 ml) and sodium hydride (85.8 mg, 60% in mineral oil, 2.15 mmol) was added. The reaction was stirred under nitrogen at room temperature for almost 2 hours, and then N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (102.5 mg, 0.2840 mmol) was added. The flask was put in a preheated oil bath (105° C.) and stirred under nitrogen (a reflux condenser was added after about 5 minutes). After 90 minutes, the reaction was cooled to room temperature and quenched with water. The reaction was extracted with 10:1 DCM/MeOH, but the product is water soluble, so the organic and aqueous phases were combined, concentrated, and filtered through a pad of Celite® (diatomaceous earth), which was washed with DCM and MeOH. This filtrate was concentrated and purified on a silica gel column (20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N ammonia in MeOH) to afford N-(6-(6-(2-(dimethylamino)ethoxy)-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (39.4 mg, 34% yield). MS (ESI pos. ion) m/z: 414. Calculated exact mass for C21H27N5O2S 413.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[OH2:14].[OH-].[K+]>CS(C)=O>[CH3:13][N:11]1[CH:12]=[C:8]([C:7]2[C:2](=[O:14])[NH:3][CH:4]=[CH:5][N:6]=2)[CH:9]=[N:10]1
Reactant: Cn1cc(-c2nccnc2Cl)cn1
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1cc(-c2ncc[nH]c2=O)cn1
Temperature: 80 °C

Procedure:
To 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (200 mg, 1.03 mmol) from Step 1 of this Example in DMSO (1.5 mL) and water (1.5 mL) was added KOH (890 mg, 15.4 mmol) and the mixture was heated at 80° C. for 3 h. The mixture was cooled and partitioned between EtOAc and 4 N HCl. The aqueous layer was concentrated under reduced pressure and then a mixture of MeOH and EtOH was added and the suspension was filtered through Celite. The filtrate was concentrated under reduced pressure and then Et2O was added and the mixture again concentrated under reduced pressure. The residue was triturated with DCM and filtered to afford crude 3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one (300 mg, quantitative) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.18 (s, 1H), 7.24-7.39 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (4.5 g, 18.44 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (11.01 g, 55.33 mmol) in dichloroethane (50 mL), acetic acid (6.64 g, 110.6 mmol) was added and reaction stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (11.72 g, 55.28 mmol) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired compound (5.2 g, 66.24%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[N:3]=1.F[C:24]1C=CC=C[N:25]=1.[CH3:30]N1C(=O)CCC1>>[CH3:30][C:22]1[CH:21]=[C:20]([C:24]#[N:25])[CH:19]=[N:18][C:17]=1[N:14]1[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=2)[CH2:16][CH2:15]1
Reactant: Fc1ccccn1
Reactant: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Reactant: CN1CCCC1=O
Product: Cc1cccc(C#CC=C2CCN(c3ncc(C#N)cc3C)CC2)n1
Yield: 81.3 %

Procedure:
The title compound was prepared following the procedure described for the compound of Example 59, but substituting N,N-dimethylacetamide for NMP and substituting 5-cyano-2-fluoro-3-methylpyridine for 2-fluoropyridine. Purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with EtOAc—Petroleum Ether 2:8. Yellowish solid. Yield: 81.3%.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15](OC)=[N:14]3)=[CH:10][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:28].[NH4+:29]>>[ClH:28].[C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[NH:14][C:15](=[NH:29])[CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:10][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1=NC(Cc2cc(-c3ccccc3)nn2-c2ccccc2)CCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Product: Cl
Product: N=C1CCCCC(Cc2cc(-c3ccccc3)nn2-c2ccccc2)N1

Procedure:
The title material of Example 147 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][O:13][C@@H:14]1[CH2:17][C@H:16]([NH2:18])[CH2:15]1.CCN(C(C)C)C(C)C>CC#N.[Pd]>[F:8][C:6]1[CH:7]=[C:2]([NH:18][C@H:16]2[CH2:17][C@@H:14]([O:13][CH3:12])[CH2:15]2)[C:3]([NH2:9])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CO[C@H]1C[C@@H](N)C1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CO[C@H]1C[C@@H](Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 134.7 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.18 mL, 1.6 mmol) in CH3CN (3 mL) were added cis-3-methoxycyclobutylamine (0.17 g, 1.6 mmol) and DIPEA (0.28 mL, 1.6 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The resulting residue was carried to the next step without any further purification (0.39 g, quantitative). To a solution of the product thus obtained (1.6 mmol) in EtOAc (15 mL) was added Pd/C (350 mg) and the reaction mixture stirred at RT for 18 h under a hydrogen atmosphere. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as a dark oil (0.453 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.67-6.06 (1H, m), 6.35-6.17 (2H, m), 3.75-3.63 (1H, m), 3.61-3.25 (3H, br s), 3.22 (3H, s), 3.12-2.93 (1H, m), 2.90-2.78 (2H, m), 1.85-1.60 (2H, m).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[N:13]1([CH2:19][CH2:20][O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([N:28]3[C:33](=[O:34])[C:32]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:38][CH:37]=4)=[C:31]([CH2:50][CH2:51][CH3:52])[N:30]4[N:53]=[CH:54][N:55]=[C:29]34)[CH2:24][CH2:23]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[N:13]1([CH2:19][CH2:20][O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([N:28]3[C:33](=[O:34])[C:32]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]5[NH:3][C:4](=[O:7])[O:5][N:49]=5)=[CH:38][CH:37]=4)=[C:31]([CH2:50][CH2:51][CH3:52])[N:30]4[N:53]=[CH:54][N:55]=[C:29]34)[CH2:24][CH2:23]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCN3CCOCC3)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCCN3CCOCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-morpholin-4-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.1 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was adjusted to pH 7 with 1 N hydrochloric acid and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 59%).