Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:36]1([C:39]([NH:41][NH2:42])=O)[CH2:38][CH2:37]1>CC1C=CC(C)=CC=1>[CH:36]1([C:39]2[N:26]3[C:21]4[CH:20]=[C:19]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:18]([C:15]5[CH:16]=[CH:17][C:12]([C:8]6([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]6)=[CH:13][CH:14]=5)=[N:28][C:22]=4[O:23][CH2:24][C:25]3=[N:42][N:41]=2)[CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NNC(=O)C1CC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C3CC3)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 21.8 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (150 mg, 0.308 mmol) and cyclopropanecarbohydrazide (41 mg, 0.410 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 20 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (36 mg, 32%). LCMS (Method D): RT=1.457 min, M+1=536.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[O:22][C:21]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)=[CH:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)[N:12]=2)[CH2:3][CH2:2]1.ClS([N:38]=[C:39]=[O:40])(=O)=O.[OH-].[Na+]>C(#N)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[O:22][C:21]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:28][CH2:29]4)=[CH:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:39]([NH2:38])=[O:40])=[N:17][CH:18]=3)[N:12]=2)[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3o2)CC1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(NC(N)=O)nc4)nc(N4CCOCC4)c3o2)CC1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 236 (1.0 eq) in acetonitrile (0.1M) at r.t. was added chlorosulfonyl isocyanate (10 eq) dropwise. The reaction was stirred for 40 minutes, then concentrated. To the residue was added 2N HCl and mixture was heated to 80° C. for 20 minutes. Reaction mixture was allowed to cool down to room temperature, and was neutralized with NaOH 6M. Mixture was then concentrated. The crude product was purified by reverse phase HPLC to give 6 mg of 247. MS (Q1) 517 (M+
Reaction SMILES: C(O[C:6](=[O:32])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:31])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[C:22]=1[OH:23])=[O:12])(C)(C)C.[F:33][C:34]([F:39])([F:38])C(O)=O.C(N(CC)CC)C.FC(F)(F)C(OCC)=O>C(Cl)Cl.C1COCC1>[F:33][C:34]([F:39])([F:38])[C:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:31])[N:18]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=[CH:20][C:21]=2[C:22]=1[OH:23])=[O:12])=[O:32]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCNC(=O)C(F)(F)F)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (30 mg, 0.068 mmol) was dissolved in CH2Cl2 (1.5 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added THF (3 mL), triethylamine (0.050 mL, 0.34 mmol), and ethyl trifluoroacetate (2 mL), and the mixture was refluxed for 48 h. After cooling to r.t., the mixture was concentrated to dryness. The residue was partitioned between EtOAc and water, and pH was adjusted to about 4 with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 12 mg of the title compound as a pale yellow solid. MS: (+) m/z 435.31 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22]([C:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[S:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23]
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1

Procedure:
When 2-p-methoxyphenylbenzothiophene was acylated with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 1, 3-(3',5'-dimethylbenzoyl)-2-(4'-methoxyphenyl)benzothiophene was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11](S(C3C=CC=CC=3)(=O)=O)[CH:10]=2)[N:6]=[C:5]([NH:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=2)[O:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[N:4]=1>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[N:6]=[C:5]([NH:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=2)[O:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[N:4]=1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(NCc2cccc(OCCCNC(=O)OC(C)(C)C)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2c[nH]c3ncccc23)nc(NCc2cccc(OCCCNC(=O)OC(C)(C)C)c2)n1

Procedure:
A mixture of Example 63B (600 mg, 0.93 mmol) in methanol (12 mL) and NaOH aqueous solution (1M, 4 mL) was stirred at room temperature for 16 hours. The mixture was filtered, and the solid was washed with water and dried in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.Cl.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH:33]([CH3:35])[CH3:34])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([Cl:18])=[N:6][C:5]=3[CH:4]=2)[CH2:29][C@H:28]1[CH:33]([CH3:35])[CH3:34])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (100 mg, 0.29 mmol) in DMF (3 mL) were added (R)-2-isopropyl-piperazine-1-carboxylic acid tert-butyl ester hydrochloride (87 mg, 0.33 mmol) and potassium carbonate (124 mg, 0.90 mmol). The resulting mixture was stirred at RT for 18 h, then diluted with water and DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (139 mg, 97%).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22]([C@H:24]2[CH2:30][CH2:29][CH:28]3[CH:26]([CH2:27]3)[N:25]2C(OC(C)(C)C)=O)=[O:23])[CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[CH:26]12[CH2:27][CH:28]1[CH2:29][CH2:30][C@H:24]([C:22]([NH:21][C@H:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=1)[CH3:20])=[O:23])[NH:25]2
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2)cc1
Yield: 50.6 %

Procedure:
The title compound (D102) (17.5 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (3R)-tert-butyl 3-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (diastereoisomers mixture) (D71) (46 mg).
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7](Cl)(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1C=CC=CC=1>[C:7]([O:4][CH2:3][CH:2]([SH:1])[CH2:5][SH:6])(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCC(S)CS
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCC(S)CS
Yield: 38.8 %

Procedure:
2,3-Dimercaptopropanol (12.0 g) is dissolved in benzene (75 ml) and thereto is added dropwise lauroyl chloride (21.5 g) with stirring. The mixture is refluxed with stirring for about 3.5 hours until the generation of hydrogen chloride is ceased to evolve. The mixture is then distilled to remove benzene and the resulting residue is distilled to give 2,3-dimercaptopropyl laurate (11.5 g) as a yellow oily substance, b.p. 167° - 175° C/1 mmHg.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]2[CH2:11][CH2:10][C@@H:9]([N:12]([CH2:20][C:21](O)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:57][C@@H:58]1[CH2:62][NH:61][C@H:60]([C:63]([NH2:65])=[O:64])[CH2:59]1.C(N(CC)CC)C>ClCCl.O>[N:1]1([CH2:6][C@H:7]2[CH2:11][CH2:10][C@@H:9]([N:12]([CH2:20][C:21]([N:61]3[CH2:62][C@@H:58]([F:57])[CH2:59][C@H:60]3[C:63]([NH2:65])=[O:64])=[O:22])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@@H]1CC[C@H](Cn2cncn2)C1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC(=O)N1C[C@@H](F)C[C@H]1C(N)=O)[C@@H]1CC[C@H](Cn2cncn2)C1
Yield: 74.8 %

Procedure:
To a stirred and cooled (0° C.) mixture of [(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)-cyclopentyl-N—BOC-amino]-acetic acid (10 g, 30.5 mmol) and 1-hydroxybenzotriazole (5 g, 36.9 mmol) in dichloromethane (200 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.1 g, 36.9 mmol) in portions and the mixture was stirred for 0.5 h at the same temperature to result a clear solution. A solution of (2S,4S)-4-fluoropyrrolidine-2-carboxamide p-toluenesulfonate (5.71 g, 33.9 mmol) and triethylamine (6.4 ml, 4.62 mmol) in dichloromethane (60 ml) was added and the mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with DCM (100 ml) and water (200 ml) and the layers were separated. The organic layer was washed with 0.5N HCl (100 ml) and then with brine (50 ml). The solvent was evaporated under reduced pressure to give 10 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.25-1.33 (m, 2H), 1.42 (s, 9H), 1.70-1.99 (m, 5H), 2.04-2.47 (m, 2H), 2.80-2.82 (m, 1H), 3.63-3.91 (m, 4H), 4.14-4.17 (m, 2H), 4.35-4.37 (m, 2H), 4.74 (d, J=9.6 Hz, 1H), 5.25-5.42 (m, 1H), 7.93 (s, 1H), 8.06 (s, 0.6H, rotomer), 8.08 (s, 0.4H, rotomer).
Reaction SMILES: [OH:1][C:2]1([C:9]([F:12])([F:11])[F:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:13]1([NH:16][CH:5]2[CH2:6][CH2:7][C:2]([C:9]([F:12])([F:11])[F:10])([OH:1])[CH2:3][CH2:4]2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: O=C1CCC(O)(C(F)(F)F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1(C(F)(F)F)CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 93 %

Procedure:
4-hydroxy-4-(trifluoromethyl)cyclohexanone (570 mg, 3.13 mmol) was dissolved in 1,2-dichloroethane (20 ml), followed by sequential addition of cyclopropylamine (0.24 ml, 3.44 mmol), NaBH(OAc)3 (1.06 g, 5.01 mmol), and acetic acid (0.18 ml, 3.13 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 13 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (20 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 650 mg of yellow solid (93%).
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][CH:32]([CH2:34]Br)[CH2:31][C:30]=2[CH:36]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:10][CH2:11][N:12]([CH2:34][CH:32]3[CH2:31][C:30]4[CH:36]=[C:26]([O:25][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:27]=[CH:28][C:29]=4[O:33]3)[CH2:13][CH2:14]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC2(O)CCNCC2)cc1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: CC(C)c1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1

Procedure:
The title compound MS: m/e=472.6 (M+H+) was prepared from 4-(4-isopropyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:30]=[CH:31][CH:32]=[N:33][C:11]2=3)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>CO>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][C:18]2[C:13]3[C:12]4[CH:30]=[CH:31][CH:32]=[N:33][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:28]#[N:29])[CH2:21][CH2:22]1)[CH3:27]
Reactant: CCN1CCC(Cc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1CCC(Cc2c(C#N)ncc3[nH]c4ncccc4c23)CC1
Yield: 50.9 %

Procedure:
A solution of 9-benzenesulfonyl-5-(1-ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (200 mg, 0.4 mmol) and triethylamine (4 mL) in methanol (40 mL) was stirred at ambient temperature for 6 days. The mixture was concentrated in vacuo and the residue purified by flash chromatography (silica, 2 g column, Si-SPE, 0-20% MeOH in DCM). The resultant material was triturated with acetonitrile and methanol to afford the title compound as a white solid (65 mg, 51%). 1H NMR (DMSO-D6, 400 MHz): 12.85 (s, 1H), 8.90 (s, 1H), 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.65 (dd, J=8.0, 1.6 Hz, 1H), 7.46 (dd, J=8.0, 4.8 Hz, 1H), 2.86-2.77 (m, 2H), 2.24 (q, J=7.2 Hz, 2H), 1.84-1.58 (m, 5H), 1.54-1.40 (m, 2H), 0.95 (t, J=7.1 Hz, 3H). LCMS (Method H): RT=4.56 min, M+H+=320.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:38]1[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]1)(=O)=O.Cl.O1CCOCC1>CN(C=O)C.O>[NH:40]1[CH2:41][CH:38]([N:22]2[CH:21]=[CH:20][C:19]([C:7]3[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=4)[C:10]4[CH:11]=[CH:12][C:13]5[N:14]([C:15]([CH3:18])=[N:16][N:17]=5)[C:9]=4[CH:8]=3)=[N:23]2)[CH2:39]1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cccc(Cl)c3)n12
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in DMF (1.5 mL) was treated with Cs2CO3 (34 mg, 0.10 mmol, Aldrich) and tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (26 mg, 0.10 mmol, prepared as in WO 2012004703). The mixture was heated at 70° C. for 14 hours. After cooling to room temperature, the mixture was diluted with water and extracted with three portions of EtOAc. The combined extracts were washed twice with brine, then were dried over sodium sulfate, filtered, and concentrated. The residue, dissolved in acetonitrile (1.0 mL) was treated with 4.0 M HCl in dioxane (0.40 mL, 1.6 mmol). After 20 minutes, the solvent and excess HCl were removed in vacuo. The residue was re-dissolved in methanol and pH was made basic by the addition of a few drops of NH4OH solution. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (13.2 mg, 46%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)=[CH:6][CH:5]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:29]=[N:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:32][CH:33]=1.C(OCC)(=O)C>O1CCCC1>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[N:30]=[N:29][C:28]([O:18][CH2:17][C:15]3[N:16]=[C:12]([CH:11]=[CH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=4)[O:13][CH:14]=3)=[CH:33][CH:32]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: OCc1coc(C=Cc2ccc(OC(F)(F)F)cc2)n1
Reactant: Clc1ccc(CCCCn2ccnn2)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)nn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.050 g, 0.17 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (2 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.019 g, 0.19 mmol). After stirring for 15 min at r.t. 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine (0.035 g, 0.15 mmol) is added slowly and stirred for further 4 h at 60° C. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over Na2SO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 97:3) 3-(4-[1,2,3]triazol-1-yl-butyl)-6-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine is isolated as a colorless solid. Yield 0.049 g (69%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([O:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[O:35][CH:34]=[N:33][C:32]=2[C:36](O)=[O:37])[CH:28]=[CH:29][CH:30]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:36]([C:32]3[N:33]=[CH:34][O:35][C:31]=3[C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH2:23][O:22][CH:19]([CH3:21])[CH3:20])[CH:26]=3)=[O:37])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)OCCc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(CCOC(C)C)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=463.35.
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].C(Cl)(=O)OCC(C)C.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[NH2:36][CH:37]1[CH2:46][C:45]2[C:40](=[C:41]([N:47]3[CH2:51][CH2:50][CH2:49][C:48]3=[O:52])[CH:42]=[CH:43][CH:44]=2)[N:39]([CH2:53][C:54]2[CH:58]=[CH:57][S:56][CH:55]=2)[C:38]1=[O:59].[OH-].[Na+].[Cl-].[Na+]>O1CCCC1.O.C(N(CC)CC)C>[CH3:14][CH:12]([CH3:13])[CH2:11][C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[C:15](=[O:17])[NH:36][CH:37]1[CH2:46][C:45]2[C:40](=[C:41]([N:47]3[CH2:51][CH2:50][CH2:49][C:48]3=[O:52])[CH:42]=[CH:43][CH:44]=2)[N:39]([CH2:53][C:54]2[CH:58]=[CH:57][S:56][CH:55]=2)[C:38]1=[O:59]
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
N-tert-Butoxycarbonyl-D-leucine monohydrate (25.00 g) was dissolved in tetrahydrofuran (224 mL), and triethylamine (20.30 g) and isobutyl chlorocarbonate (13.06 g) were sequentially added thereto at 5° C. or lower under cooling on ice. To the mixture was added 3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one D-(−)-tartrate (44.80 g) in an aqueous sodium hydroxide solution (a mixture of 25% aqueous sodium hydroxide solution (14.58 g) and water (89.6 g)) at 5° C. or lower. The mixture was stirred for 10 minutes under cooling on ice, and then the temperature was raised to room temperature. Saturated aqueous sodium chloride solution (44.8 g) was added to the reaction mixture to partition the mixture, and the aqueous layer was further extracted with tetrahydrofuran (224 mL). The organic layers were combined, and the combined organic layer was concentrated to half volume, whereby a solution of the title compound in tetrahydrofuran was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16]C(C)(C)C)=[O:15])[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from step E (5.54 g, 12 mmol) in 30 mL of dichloromethane was added 13 mL of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 16 h then was concentrated in vacuo and excess trifluoroacetic acid removed by azeotropic distillation with dichloromethane to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ; 8.00 (d, J=8.2 Hz, 2H); 7.83 (d, J=1.8 Hz, 2H); 7.41 (d, J=1.9 Hz, 1H); 7.36 (d, J=8.3 Hz, 2H); 7.32 (s, 1H); 5.94 (s, 2H); 4.87 (s, 3H).
Reaction SMILES: C(O)(=O)C.C([N:12]1[CH2:24][CH2:23][C:15]2([CH2:20][C:19](=[O:21])[NH:18][C:17](=[O:22])[CH2:16]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:20]1[C:15]2([CH2:14][CH2:13][NH:12][CH2:24][CH2:23]2)[CH2:16][C:17](=[O:22])[NH:18][C:19]1=[O:21]
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)CC(=O)N1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CC2(CCNCC2)CC(=O)N1
Reaction time: 18 h
Yield: 86.2 %

Procedure:
Palladium hydroxide (20% on carbon; 100 mg) and acetic acid (250 μL) were added to a solution of 9-benzyl-3,9-diazaspiro[5.5]undecane-2,4-dione (0.38 g, 1.40 mmol) in ethanol (5 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated to give the acetate salt of the title compound (220 mg). MS 183.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: COc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol) and 2-methoxy-5-nitroaniline (39 mg, 0.230 mmol), similar to Example 180 and was isolated as a yellow solid (30 mg, 51%). 1H NMR (CDCl3): 9.760 (d, J=1.5 Hz, 1H), 8.86 (dd, J=1.8, 2.7 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H), 8.10 (dd, J=2.7, 9.0 Hz, 1H), 7.34 (s, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.08 (s, 3H).