Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]1([CH2:32][CH:33]2[CH:38]([NH2:39])[CH:37]3[CH2:40][CH2:41][N:34]2[CH2:35][CH2:36]3)[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:39][CH:38]1[CH:37]2[CH2:36][CH2:35][N:34]([CH2:41][CH2:40]2)[CH:33]1[CH2:32][N:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:9]
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Reactant: NC1C2CCN(CC2)C1CN1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NC2C3CCN(CC3)C2CN2CCCC2)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 62.9 %

Procedure:
a suspension of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (3.13 g, 14.5 mmoles) in anhydrous tetrahydrofuran (20 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (2.44 g, 15 mmoles), stirred for 90 minutes, cooled (0° C.), and treated with 2-(1-pyrrolidinylmethyl)-1-azabicyclo[2.2.2]octane-3-amine (3.14 g, 15.0 mmoles) in anhydrous tetrahydrofuran (10 ml). After 24 hours at room temperature and one hour at 60° C., the solution was concentrated in vacuo and partitioned between methylene chloride (100 ml) and 1.0N aqueous sodium carbonate (50 ml). The organic layer was separated and the aqueous solution was extracted with methylene chloride (40 ml). The combined organic solution was washed with brine (50 ml), dried (Na2SO4), concentrated in vacuo, dissolved in tetrahydrofuran, and filtered. The filtrate was passed through alumina (eluted with 15% methanol/ethyl acetate), and concentrated in vacuo to provide 3.71 g (63%) of a colorless foam.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(Cl)Cl>O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 10.5 g. (0.054 mol.) of 2-phenylbenzofuran and 11.5 g. (0.058 mol.) of 3,5-dimethyl-4-methoxybenzoyl chloride in 100 ml. of methylene chloride is added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture is allowed to warm to ambient temperature, then stirred for 2 hours. Water is slowly added to the mixture and it is stirred an additional 30 minutes. The layers are separated and the organic phase is washed with water until the washings are neutral, dried (MgSO4) and concentrated to give 3-(3,5-dimethyl-4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:45])[NH:12][C:13]2[CH:14]=[C:15]([CH:42]=[CH:43][CH:44]=2)[O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][C@H:30]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:46]>O1CCOCC1.ClCCl>[ClH:46].[ClH:46].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:12][C:13]2[CH:44]=[CH:43][CH:42]=[C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][C@H:30]5[CH2:34][CH2:33][NH:32][CH2:31]5)=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:14]=2)=[O:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Yield: 67 %

Procedure:
A solution of (S)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate from the previous step (35 mg, 0.0566 mmol) and hydrochloric acid (0.1 mL of a 4N solution in 1,4-dioxane, 0.40 mmol) in dry dichloromethane (0.01 mL) was stirred at room temperature for 2 h. Concentrated under reduced pressure to afford (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea dihydrochloride as a colorless solid (22 mg, 67%), which did not require further purification. 1H NMR (300 MHz, MeOH-d4) δ 9.02 (brs, 1H), 7.82 (s, 1H), 7.73 (brs, 1H), 7.54 (s, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 7.06 (m, 1H), 6.32 (s, 1H) 5.56 (brs, 1H), 4.04 (s, 3H), 3.50-3.85 (m, 5H), 2.50-2.60 (m, 2H), 1.35 (s, 9H); LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: Br[CH2:2]Br.[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][C:10]([CH3:17])([CH3:16])[CH2:9][C:8]2=[O:18].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH2:2]1[O:15][C:14]2[CH:13]=[C:12]3[C:7]([C:8](=[O:18])[CH2:9][C:10]([CH3:16])([CH3:17])[O:11]3)=[CH:6][C:5]=2[O:4]1
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Reactant: BrCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)c2cc3c(cc2O1)OCO3
Yield: 81.7 %

Procedure:
A mixture of 20 ml of water, 5.2 g (30 millimole) of dibromo-methane and 0.5 g (1 millimole) of Adogen 464 (Aldrich) is heated to boiling under vigorous stirring. A solution of 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone and 50 ml of a 5% sodium hydroxide solution is added dropwise within 2 hours and heated to boiling for a further hour. The mixture is diluted with 100 ml of water and extracted twice with 50 ml of chloroform each. The organic layer is washed twice with 50 ml of water, dried over sodium sulfate, the solvent is removed and the residue crystallized from hexane. Thus 3.6 g of the desired compound are obtained, yield 85%. Mp.: 61°-62° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1cc(N)n[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Temperature: 100 °C
Yield: 35.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 5-methyl-1H-pyrazol-3-amine (1 g, 10 mmol) (1), 3,5-dibromo-1-methylpyridin-2(1H)-one (4 g, 15 mmol) (2), and cesium carbonate (6.4 g, 20 mmol). Xantphos (400 mg, 0.8 mmol) and Pd2(dba)3 (700 mg, 0.8 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on flash column eluting with DCM:MeOH (20:1) to afford 115a (1.0 g, 35%). MS: [M+H]+ 283.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>C(N(CC)CC)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc(NC(CO)CO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 49.7 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.4 g of 2-amino-1,3-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 1.45 g of 2-(4-nitro-3-methylphenylamino)propane-1,3-diol (11) were obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]([NH:14][C:15]([CH3:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[I-].[Na+].[C:20]([NH:23][CH2:24][C:25]#[C:26][CH2:27]Cl)(=[O:22])[CH3:21]>O1CCOCC1.C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C:8]([NH:14][C:15](=[O:16])[CH3:17])([CH2:27][C:26]#[C:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:13]
Reactant: CC(=O)NCC#CCCl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(CC#CCNC(C)=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of sodium hydride (60% dispersion in mineral oil, 3.48 g) in dioxane (70 ml) was added dropwise absolute ethanol (70 ml). The mixture was allowed to warm to room temperature and a solution of diethyl acetamido malonate (20.5 g) in dioxane (70 ml) was added dropwise. Sodium iodide (9.07 g) was added and a solution of 1-acetylamino-4-chloro-2-butyne (11 g) in dioxane (140 ml) was added dropwise at room temperature. After addition of another 100 ml of ethanol the mixture was refluxed for 2.5 h. The reaction mixture was cooled and the precipitate formed was filtered off. Purification using chromatography on silica (eluent: ethyl acetate/methanol 9/1 v/v) yielded acetamido(4-acetamido-2-butynyl)-malonic acid diethyl ester. (15.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].Cl[CH2:11][CH:12]=O>>[Br:1][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: O=CCCl
Product: Clc1cc(Br)c2nccn2n1
Temperature: 50 °C
Yield: 61.2 %

Procedure:
To a solution of 4-bromo-6-chloropyridazin-3-amine (6.0 g, 28.8 mmol) was added 2-chloroacetaldehyde (22.60 g, 144 mmol) (50% water solution). The reaction mixture was heated to 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with CH2Cl2. Then, saturated NaHCO3 was added slowly until bubbling ceased. The layers were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was washed with water and brine, dried over Na2SO4. The crude product was purified by BIOTAGE® (10-40% EtOAc/CH2Cl2, 2.1 L) to give 4.1 g (61%) product as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (1H, s), 7.84 (1H, s), 7.39 (1H, s); 13C NMR (101 MHz, CDCl3) δ ppm 145.92 (1 C, s), 136.93 (1 C, s), 134.77 (1 C, s), 124.20 (1 C, s), 121.22 (1 C, s), 118.81 (1 C, s).
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:16]>C(Cl)Cl>[CH:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][Br:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccccc1C1CCCCC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1ccccc1C1CCCCC1
Yield: 79 %

Procedure:
According to example 17, 3.36 g of 2-cyclohexylbenzyl alcohol was treated with 0.59 mL of PBr3 in 25 mL of anhydrous CH2Cl2 to afford 3.90 g of crude product (90% pure by 1H-NMR). This material was vacuum distilled via short path (1.0 mmHg, 117-120° C.) to afford 3.54 g (79%) of 2-cyclohexylbenzyl bromide as a clear liquid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:2]1.Cl.[NH2:15][OH:16]>>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]2)[CH2:2]1.[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]2)[CH2:2]1
Reactant: NO
Reactant: O=C1CCN(CC2CCOC2)CC1
Agent: Cl
Product: ON=C1CCN(CC2CCOC2)CC1

Procedure:
1-(3-Tetrahydrofuranylmethyl)-4-piperidone Oxime 1-(3-Tetrahydrofuranylmethyl)-4-piperidone oxime is prepared from 1-(3-tetrahydrofuranylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)([CH3:5])[CH3:4].[CH3:33][C:34](OC(C)=O)=[O:35]>C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:6]([C:3]([CH3:4])([CH3:5])[CH2:2][NH:1][C:34](=[O:35])[CH3:33])[CH:7]=[C:8]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:17]=2)[CH:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)CN)c2)n1CC1CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCC(C)(C)c1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of compound 48 (100 mg, 0.22 mmol) in dry DCM (5 mL) was added Ac2O (25 mg, 0.24 mmol) at 0° C. and then the solution was stirred overnight at rt, concentrated and purified by prep-TLC to afford compound 49 (60 mg, 54%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.64-0.67 (2H, m), 0.93-0.95 (3H, m), 1.26-1.30 (20H, m), 1.46 (3H, d, J=6.8 Hz), 1.77 (3H, s), 2.43 (3H, s), 3.28 (2H, d, J=5.6 Hz), 3.76 (3H, d, J=7.2 Hz), 6.28 (1H, s), 6.91 (2H, s), 7.09 (1H, s), 7.16 (1H, s), 7.35 (1H, s), 7.67 (1H, m). MS Calcd.: 501; MS Found: 502 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:7]=1)=[O:5])[CH3:2].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[N:8]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: COCCOCCBr
Reactant: CCOC(=O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(COCCOCCOC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 0.17 h

Procedure:
To a solution of 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 2 ml DMF 11 mg NaH (60% in mineral oil) were added at RT and stirred for 10 min. Then 100 mg 1-Bromo-2-(2-methoxy-ethoxy)-ethane were added and the mixture was stirred for 16 h. After addition of 5 ml of water the mixture was filtered through a Chem Elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The crude residue was directly subjected to the next reaction step. Yield: 130 mg.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:27][NH:26][C:24](=[O:25])[CH2:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: Cc1ccc(S(=O)(=O)CC(=O)NN)cc1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)CC(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[(4-methylphenyl)sulfonyl]acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 199 mg of the title compound (82%) as a yellow solid in 91.1% purity by HPLC (Rt: 5.38, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:31]([C:30]3[CH:29]=[CH:28][C:27]([N:17]([CH3:16])[C:18](=[O:26])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:35][CH:34]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A mixture of 0.291 g of 6,11-dihydro-5H-dibenz[b,e]azepine, 0.518 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride and 0.182 g of triethylamine in 10 ml of tetrahydrofuran is stirred at room temperature for 2 hours. The solvent is removed, the residue diluted with water and extracted with dichloromethane. The extract is washed with 1N HCl water, 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and chilled to give 0.52 g of crystals, m.p. 160°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)=[CH:11][C:10]([C:24](O)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([F:23])[CH:14]=3)=[CH:11][C:10]([C:24]([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Solvent: O=CO
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(C(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 97A in analogy to the synthesis of the compound of Example 23 with the addition of 0.1% formic acid in the preparative HPLC. 60 mg (51% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[CH:14](N)=[O:15]>C(O)=O>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH:14]=[O:15])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: NC=O
Solvent: O=CO
Product: O=CNC1CCN(Cc2ccccc2)C1

Procedure:
3-Amino-1-benzylpyrrolidine [J. Med. Chem., 11, 1034 (1968)] was allowed to react with formic acid and formamide to give 1-benzyl-3-formylaminopyrrolidine. This compound was reduced with sodium bis(2-methoxyethoxy)-aluminium hydride to give 1-benzyl-3-methylaminopyrrolidine, b.p. 134°-136° C./5-6 mmHg. This compound was treated with acetic anhydride to give 3-(N-acetyl-N-methylamino)-1-benzylpyrrolidine, b.p. 144°-147° C./0.5 mmHg. This compound was hydrogenated catalytically in the presence of 5% palladium-carbon to give 3-(N-acetyl-N-methylamino)-pyrrolidine as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH2:11]([NH2:13])[CH3:12].C(N(CC)C(C)C)(C)C>>[CH2:11]([NH:13][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1)[CH3:12]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Yield: 67.2 %

Procedure:
2,4,6-Trichloro-s-triazine (1, 1 g, 5.4 mmol), and ethylamine hydrochloride (0.44 g, 5.4 mmol) were combined in a round bottom flask and cooled to −5° C. using an ice-salt bath. To the cooled, stirred solution was added N,N-diisopropylethylamine (1.88 mL, 10.8 mmol). The resultant yellow colored solution was stirred at −5° C. for 1 h, the solvents removed under reduced pressure, and the resultant residue was dissolved in 1:1 v/v of ethyl acetate and water. The organic layer was separated, washed with saturated solution of NaHCO3, and dried over Na2SO4. The organic solvent was removed under reduced pressure to yield an orange colored solid. The solid was triturated with hexane to yield the product 2 as a yellow-orange powder (0.7 g) with a yield of 68%.
Reaction SMILES: [F-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](=[O:12])=[O:11]>>[CH:5]1[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[C:3]([OH:9])[CH:4]=1
Reactant: O=C=O
Reactant: Oc1ccccc1
Agent: [F-]
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Temperature: 120 °C
Yield: 10 %

Procedure:
Using apparatus 4, 10.3 g of KF and 4.3 g phenol were added to apparatus 4. The reactor was pressurized to 114 bar with CO2, the stirrer was set to 800 rpm, and heated at 120° C. for 86 h. Analysis by method 2 showed a yield of 10% PHBA and 5% SA.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:47]=[CH:46][C:34]([C:35]([NH:37][C@@H:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([OH:41])=O)=[O:36])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:32]=[CH:33][C:34]([C:35]([NH:37][C@H:38]([C:39]([N:4]([CH3:5])[CH3:1])=[O:41])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])=[CH:46][CH:47]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.080 mmol) was added to a mixture of (2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoic acid (14 mg, 0.026 mmol), dimethylamine (0.034 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 0.032 mmol) in DMF (0.4 mL). The mixture was stirred at RT overnight. The residue was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=555.1.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:19])=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[N:25][C:24](Br)=[CH:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Si:1]([O:8][C:9]1[C:10]([F:19])=[C:11]([C:24]2[N:25]=[CH:26][C:21]([NH2:20])=[N:22][CH:23]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1ccc(B(O)O)c(F)c1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cnc(N)cn2)c(F)c1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C

Procedure:
(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic acid (292 mg, 1.03 mmol), 2-amino-5-bromopyrazine (179 mg, 1.03 mmol), 1,4-dioxane (6.1 mL), and Na2CO3(2.1 mL, 2 M) were added to a microwave vial and the resultant mixture sparged with argon for 10 minutes. Pd(dppf)Cl2.DCM was then added the mixture, the vial sealed, and then heated at 80° Celsius for 16 hours. The reaction mixture was then cooled to rt, diluted with water (5 mL), and extracted with EtOAc (4×5 mL). The combined organic extracts were then dried over Na2SO4, filtered, and concentrated to dryness to provide the title compound. This compound was used directly in the next synthetic step without purification.