Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:21][C:22](=[O:25])[NH:23][OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCOCC>[CH2:12]([O:21][C:22](=[O:25])[NH:23][O:24][C:8](=[O:10])[CH3:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCOC(=O)NO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCOC(=O)NOC(C)=O
Reaction time: 2 h

Procedure:
25 Parts of triethylamine are added over 30 minutes to a stirred solution of 19.6 parts of acetyl chloride and 50.6 parts of nonyl-N-hydroxycarbamate in 500 parts of ether at 0°-5° C. keeping the pH of the mixture in the range pH3 to pH6. The reaction is stirred for a further 2 hours at 0°-5° C. followed by 24 hours at 25° C. and is then filtered to remove amine hydrochloride. The filtrates are washed with water, dried, filtered and evaporated to constant weight at 30° C. under reduced pressure to give 61 parts of nonyl-N-(acetoxy)carbamate as a pale yellow oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13](O)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1.[CH3:28][C:29]1([CH3:37])[O:36][C:34](=[O:35])[CH2:33][C:31](=[O:32])[O:30]1>ClCCl>[CH3:28][C:29]1([CH3:37])[O:36][C:34](=[O:35])[CH:33]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:31](=[O:32])[O:30]1
Reactant: CCCCCCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (71.7 g, 0.442 mol) was added portionwise to a stirred solution of heptanoic acid (0.402 mol) in 300 mL of dry dichloromethane. The resulting mixture was stirred at room temperature for 2 hours. A solution of pyridine (35.8 mL, 0.442 mol) and Meldrum's acid (63.7 g, 0.442 mol) in 150 mL of dry dichloromethane were added over a period of 2 hours to the reaction mixture. The reaction mixture was stirred for 16 hours, quenched with 400 mL of 2 N HCl (bubbling), separated, washed sequentially with 2×400 mL 2 N HCl, brine (400 mL), dried (MgSO4), and the solvent was removed in vacuo to give the title compound as aviscous oil. The crude product was used in the next step after spectral characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)=[O:16]
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)Nc1cccc2ccc(O)cc12

Procedure:
The coupling component used in this Example was prepared by chloroacetylating 8-amino-2-naphthol in glacial acetic acid with chloroacetic acid chloride by using sodium acetate as an acid binding agent, to obtain 8-chloroacetylamino-2-naphthol, dissolving isolated 8-chloroacetylamino-2-naphthol in acetone, and then blowing gaseous trimethylamine into the solution.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[F:36][C:37]([F:44])([F:43])[CH:38]([OH:42])[C:39](O)=[O:40]>>[F:34][C:32]([F:33])([F:35])[CH2:31][NH:30][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:18]2[N:15]3[N:16]=[CH:17][C:12]([C:10]4[CH:9]=[N:8][N:7]([CH:4]5[CH2:5][CH2:6][N:1]([C:39](=[O:40])[CH:38]([OH:42])[C:37]([F:44])([F:43])[F:36])[CH2:2][CH2:3]5)[CH:11]=4)=[CH:13][C:14]3=[N:20][CH:19]=2)[CH:22]=1)=[O:29]
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)C(O)C(F)(F)F)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 3,3,3-trifluoro-2-hydroxypropanoic acid (Lancaster, Cat. No. L07742). LCMS (M+H)+: m/z=611.2.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate (compound 76.2, 1.34 g, 3.75 mmol) in tetrahydrofuran (20 mL). Tetrabutylammonium fluoride (1.95 g, 7.47 mmol) was added and the resulting solution was stirred for 10 min at room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound as a brown oil (1.0 g, crude).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CC1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 97.7 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethyl amide (0.142 g, 0.485 mmol) and (+/−)-4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.156 g, 0.533 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (260 mg, 97%) (following SiO2 chromatography, eluting with 0-3% MeOH/dichloromethane). MS (ESI) m/z 549.3 (M+H)+
Reaction SMILES: [NH3:1].CO[C:4](=[O:38])[CH:5]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:11][CH:10]=1>CO>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH:5]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C:4](=[O:38])[NH2:1])=[CH:10][CH:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 63 %

Procedure:
Ammonia (7 M in methanol, 20 mL) was added to a solution of N-Boc methyl ester 31(718 mg, 1.40 mmol) in methanol (5 mL) and the mixture was stirred at room temperature in a sealed tube for 40 h. The mixture was concentrated by rotary evaporation and purified by flash silica gel column chromatography using methanol/dichloromethane (1:30, 1:20, v/v) to give the desired amide 32 as a white solid (436 mg, 63% yield). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.48-1.68 (m, 4H), 2.09-2.32 (m, 2H), 2.48-2.61 (m, 2H), 3.08-3.25 (m, 2H), 3.97-4.20 (m, 2H), 4.30-4.45 (m, 1H), 4.75 (br s, 1H), 5.09 (s, 2H), 5.48-5.58 (m, 1H), 5.62 (br s, 1H), 6.38 (br s, 1H), 6.75-6.85 (m, 2H), 6.99-7.10 (m, 2H), 7.28-7.40 (m, 5H). m/z (ESI) 500 [C27H37N3O6+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:17](=[O:18])[NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)[CH2:2]2
Reactant: Cc1ccc(N=C=O)cc1
Reactant: OC1CN2CCC1CC2
Product: Cc1ccc(NC(=O)OC2CN3CCC2CC3)cc1
Yield: 93 %

Procedure:
3-Quinuclidinol and 4-tolyl isocyanate were used. Filtration of the precipitated solid from the cooled reaction mixture afforded the title compound (93%) as a white solid: mp 186.0-187.5° C.; FAB LRMS m /z (relative intensity, %) 262 (21), 261 ([MH+ ], 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][NH:1][CH2:2][CH2:3][NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:31][CH2:30]1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: O=CC1CC1
Product: O=C(C[C@H]1CC[C@H](NCCNCC2CC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and cyclopropanecarbaldehyde following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 444 (MH)+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][C@@H:7]([CH3:29])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[CH:19][C:10]=3[O:9][CH2:8][C@@H:7]([NH:6][C:1](=[O:5])[CH2:2][OH:3])[CH3:29])[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: C[C@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)NC(=O)CO
Yield: 73 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-[(5-{[(2S)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxyacetamide in 73% yield; Mass spectrum MH+ 403.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:12]([O-])=O.[NH4+]>C(O)=O.[Pd]>[Br:1][C:2]1[C:3]2[N:9]=[CH:12][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C[O-]
Reactant: Nc1cccc(Br)c1[N+](=O)[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: O=CO
Product: Brc1cccc2[nH]cnc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 30.5 %

Procedure:
To a mixture of 3-bromo-2-nitrobenzenamine (4.7 g, 21.66 mmol) in formic acid (98%, 50 mL) was added 10% Pd/C and ammonium formate (13.6 g, 216.6 mmol) and the reaction mixture was stirred under nitrogen at 120° C. for 24 h. The catalyst was filtered, the filtrate was concentrated, the residue was dissolved in water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 1.3 g (30%) of crude 4-bromo-1H-benzo[d]imidazole (52) as dark brown solid: MS (ESI) m/z=197.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:19]3[CH:24]=[N:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[C:13]2=[O:17])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC12CCNC2=O
Product: CC(C)(C)OC(=O)N1CCCC12CCN(c1ccc([N+](=O)[O-])nc1)C2=O
Yield: 79.1 %

Procedure:
Following general N—C coupling procedure 1, 6-oxo-1,7-diaza-spiro[4,4]nonan-1-carboxylic acid tert-butyl ester (1.3 g, 5.41 mmol) was combined with 5-bromo-2-nitropyridine (1.10 g, 5.41 mmol) which gave 7-(6-nitro-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylic acid tert-butyl ester (1.55 g) in 79% yield.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[CH3:29][CH:30]([CH3:57])[C@H:31]([NH:39][C:40](=[O:56])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH3:29][CH:30]([CH3:57])[C@H:31]([NH:39][C:40](=[O:56])[C:41]1[CH:42]=[CH:43][C:44]([C:2]2[N:6]3[N:7]=[CH:8][CH:9]=[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]3=[N:4][C:3]=2[C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:45][CH:46]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: CC(C)[C@H](NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Reactant: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Product: CC(C)[C@H](NC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1)C(=O)OC(C)(C)C

Procedure:
Compound 18b was subjected to Suzuki coupling conditions with compound 43a as described in Example 38, Step A to obtain compound 43b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H38N6O4: 631.3 (M+H). Found: 631.0.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]2[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=2)=[N:2]1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]2[CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=[CH:17][N:16]=2)=[N:2]1
Reactant: C1COCCN1
Reactant: O=C(NCCNc1nsc2ccccc12)c1cc(Cl)ccn1
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)c1cc(N2CCOCC2)ccn1

Procedure:
A mixture of N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chloropicolinamide (50 mg) in morpholine (1 mL) was microwaved at 160° C. for 30 min. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 1% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure to give N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-morpholinopicolinamide as a white solid. 1H NMR (300 MHz, DMSO-d6): 8.80 (broad s, 1H), 8.20 (m, 1H), 8.10 (m, 1H), 7.91 (m, 1H), 7.30-7.60 (m, 3H), 7.00 (m, 1H), 3.60-3.80 (m, 4H), 3.30 ppm (m, 8H). MW=383 confirmed by LC-MS, tr=8.06 min (Method Y) MH+=384.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13](=O)[CH2:14]Br.C([O-])(O)=O.[Na+]>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:14]=[C:13]([C:12]3[CH:17]=[CH:18][C:19]([CH3:20])=[C:10]([CH3:9])[CH:11]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)cc1C
Reactant: Nc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2cn3ccc(Cl)cc3n2)cc1C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred solution of 2-amino-4-chloro-pyridine (0.39 g, 3.03 mmol) in ethanol (25 ml) was added 3,4-dimethyl-phenacylbromide (0.69 g, 3.03 mmol). The reaction mixture was stirred under reflux conditions for 16 h, poured into sat. NaHCO3 solution (70 ml) and extracted with dichloromethane (70 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated to give the crude product as a brown solid (0.84 g). Further purification by column chromatography on silica gel (ethyl acetate/toluene 1:9) and crystallization from ethyl acetate/hexane yielded the title compound (0.54 g, 69%) as a pale yellow solid, m.p. 144° C. and MS: m/e=256.2 (M+).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.C(OC([NH:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1)=O)(C)(C)C.CO>O>[NH2:35][C:36]1([C:39]([N:2]2[CH2:3][CH:4]([C:6]3[CH:27]=[CH:26][C:9]4[C:10]5[N:14]([CH:13]=[C:12]([C:18]6[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=6)[N:11]=5)[CH2:15][CH2:16][O:17][C:8]=4[CH:7]=3)[CH2:5]2)=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)C4(N)CC4)C3)cc1OCC2

Procedure:
Following the procedure for 127, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid. The crude product was subjected to reverse phase HPLC (Gemini C18 column, gradient 20 to 95% MeOH in H2O+0.1% HCO2H) to give 193 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.36 (1 H, d, J=8.28 Hz), 8.09 (1 H, s), 7.88-7.86 (2 H, m), 7.14 (1 H, dd, J=8.35, 1.82 Hz), 7.01 (1 H, d, J=1.78 Hz), 5.88-5.80 (1 H, m), 4.50-4.44 (4 H, m), 3.83-3.71 (2 H, m), 1.44 (6H, d, J=6.60 Hz), 1.05 (2 H, d, J=4.13 Hz), 0.67 (2 H, d, J=4.01 Hz). 2 Exchangeable protons not seen. 4 protons obscured by water peak. LCMS: RT=6.73 min, M+H+=434
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14](O)[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.[C:24]1(C)[C:25]([S:30](Cl)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14]([S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=2)=[O:31])[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: Cc1ccccc1S(=O)Cl
Reactant: CCOP(=O)(CO[C@@H]1C=C[C@@H](O)C1)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CO[C@@H]1C=C[C@@H](S(=O)c2ccccc2)C1)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trans-1-diethylphosphonomethoxycyclopent-2-en-4-ol (0.4 g; 1.6 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. in an icebath under a nitrogen atmosphere. Triethylamine (0.3 g; 2.9 mmol) was then added followed by a solution of toluenesulfinyl chloride (0.4 g, 2.9 mmol)in CH2Cl2 (2 mL). The reaction mixture was stirred at 0° C. for 1 hr. The ice bath was removed and the reaction mixture concentrated in vacuo. The residual oil was purified by flash column chromotography with 2% methanol/98% dichloromethane as eluent. The product(0.54 g; 87%) was isolated as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH2:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:25])=[CH:27][CH:28]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: CCCCc1ccc(C(=O)O)cc1
Product: CCCCc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-butylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) as a yellow foam (20 mg, 15%). HPLC, Rt: 4.45 min. (purity 82.6%). LC/MS, M+(ESI): 361.1, M−(ESI): 359.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 59.6 %

Procedure:
Prepared from (3-amino-3′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G38) (151 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (175 mg, 0.76 mmol) according to the general procedure K. Obtained as an orange solid (141 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][N:27]([CH3:36])[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[CH2:29][CH2:28][N:27]([CH3:26])[CH3:36])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)CCC1CCCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CCN(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(2-dimethylaminoethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.01 minutes; C26H31Cl2N5O2 (516.47); mass spectrum: (M−H)−=515/517 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[N:13]1([C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCNC1
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: CCO
Product: CCOC(=O)c1cccnc1N1CCCNCC1
Yield: 82.6 %

Procedure:
10.0 g of ethyl 2-chloronicotinate were heated to reflux for 2 h with 21.6 g of homopiperazine in 150 ml of ethanol. After removing the solvent, the residue was partitioned between NaCl solution and ethyl acetate and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated, 11.1 g (83%) of the product being obtained.