Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.[Br:32]N1C(=O)CCC1=O>CN(C=O)C>[Br:32][C:28]1[CH:29]=[CH:30][C:31]2[N:19]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:18]=4[CH:1]=3)[C:20]3[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: c1ccc2c(c1)c1ccccc1c1cc(-n3c4ccccc4c4ccccc43)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccc2c3ccccc3c3ccccc3c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of 9-(triphenylen-2-yl)-9H-carbazole (4.7 g, 11.9 mmol) in DMF (24 mL) at 0° C. under N2, NBS (N-bromosuccinimide) (2.1 g, 11.9 mmol) in DMF (24 mL) was added dropwise. After the completion of addition, the reaction mixture was warmed to room temperature overnight with vigorous stirring. The reaction mixture was precipitated with water and the solid was filtered. The pale grey solid was re-dissolved in a small amount of THF, added on a silica plug and flushed with 30% DCM/hexane. The filtrate was dried under vacuum and the white solid was used without further purification (5.5 g, 98 N.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH2:27][C:28]1[S:29][C:30]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])=[O:34])=[CH:31][N:32]=1>O1CCOCC1.CN(C)C=O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]([C:30]1[S:29][C:28]([NH:27][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:15])=[N:32][CH:31]=1)=[O:34]
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ncc(C(=O)c2ccccc2Cl)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Reaction time: 2 h
Yield: 56.4 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.29 g, 6.28 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (3 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 2 hours. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 30 mL of anhydrous 1,4-dioxane containing triethylamine (1.77 mL, 12.6 mmol). (2-Amino-thiazol-5-yl)-(2-chloro-phenyl)-methanone (1.50 g, 6.28 mmol) suspended in 10 mL of anhydrous 1,4-dioxane was slowly added to this suspension. The resulting suspension was allowed to stir for 20 minutes. The mixture was filtered and then the filtrate was evaporated to dryness. The crude product was dissolved in 50 mL of dichloromethane and washed three times with 50 mL of 1N HCl, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness to yield the product as a beige solid (1.51 g, 3.54 mmol, 56.4%). 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.24 (m, 2H), 1.54-1.57 (m, 2H), 6.01 (s, 2H), 6.88 (d, J=1.3 Hz, 2H), 6.98 (s, 1H), 7.48-7.52 (m, 1H), 7.56-7.60 (m, 3H), 7.77 (s, 1H), 11.98 (s, 1H). ESI-MS m/z calc. 426.0. found; 427.3 (M+1)+; Retention time 3.46 minutes.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:10][CH:11](Br)[CH3:12])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1>>[C:14]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(/[CH:10]=[CH:11]/[CH3:12])[C:8]#[N:9])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(Br)CC(C#N)(c1ccccc1)c1ccccc1
Solvent: C1CCNC1
Product: C/C=C/C(C#N)(c1ccccc1)c1ccccc1

Procedure:
A solution of 10.0 parts of 2,2-diphenyl-4-bromopentanenitrile in 47 parts pyrrolidine is heated to reflux for 17 hours under a nitrogen atmosphere. Then, the solution is cooled, and stripped in vacuo to leave a brown oil which is partitioned between ethyl ether and dilute hydrochloric acid. The ether phase is separated, washed with dilute sodium bicarbonate, dried over anhydrous sodium sulfate, and stripped in vacuo. The residual liquid is then distilled to afford, as a colorless liquid, 2,2-diphenyl-3-trans-pentenenitrile, boiling at about 115°-123° C. at 0.1 mm pressure. This compound is represented by the following structural formula. ##STR4##
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)([CH3:5])[CH3:4].S(Cl)(Cl)=O.[OH-].[K+]>>[CH3:5][C:3]1([CH3:4])[CH2:2][O:19][C:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=2)=[N:6]1
Reactant: CC(C)(CO)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(OC(F)(F)F)cc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a 25 ml round bottom flask was added N-(2-hydroxy-1,1-dimethylethyl)-4-(trifluoromethoxy)benzamide (4.2 g, 15.2 mmol). Thionyl chloride (3.32 ml, 45.5 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 100 g crushed ice. Solid KOH was added until the mixture became strongly basic. The mixture was extracted twice with 50 ml ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel column eluted with 1:10 ethyl acetate/hexane to give 2.6 g colorless liquid.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:24][C@H:23]([OH:25])[C@H:22]([CH2:26][OH:27])[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.Cl[S:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])(=[O:46])=[O:45]>C(C#N)(C)=O>[C:50]([O:49][C:48](=[O:54])[NH:47][S:44]([O:27][CH2:26][C@@H:22]1[CH2:21][C@@H:20]([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[CH2:24][C@@H:23]1[OH:25])(=[O:46])=[O:45])([CH3:53])([CH3:51])[CH3:52]
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(N[C@@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: CC(=O)C#N
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Product: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(N[C@@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Yield: 37 %

Procedure:
(1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (27.6 mg, 0.117 mmol) and 2,6-di-tert-butyl-4-methylpyridine (48.5 mg, 0.236 mmol) were suspended in AcCN (1.57 mL) and cooled to 0° C. tert-Butyl (chlorosulfonyl)carbamate was added and the mixture was allowed to warm to rt overnight. The reaction was quenched via addition of MeOH (1.00 mL) and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM afforded the title compound (15.2 mg, 37%). LC/MS: Rt=1.29 min, ES+ 544 (FA standard).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH2:17]O)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:28][CH2:17][C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:4]=3)=[CH:9][N:10]=[C:11]2[N:16]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(CO)ccn23)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(CBr)ccn23)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2′-fluoro-5′-(7-hydroxymethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (100 mg, 0.291 mmol) in dichloromethane (5 ml) was added carbon tetrabromide (289 mg, 0.872 mmol) and polymer-supported triphenylphosphine (291 mg, 0.872 mmol). This mixture was stirred at ambient temperature for 1 h followed by removal of the polymer by filtration. N,N-Dimethylformamide (5 ml) was added to the reaction mixture and dichloromethane removed by evaporation under vacuum without heating to give 5′-(7-bromomethylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile as a solution in N,N-dimethylformamide.
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[N:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH2:51])=[CH:45][CH:44]=1>CC(N(C)C)=O>[N:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH:51][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:10])=[CH:45][CH:44]=1
Reactant: NCCc1ccncc1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCc1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 2-pyridin-4-yl-ethylamine (39 mg, 2 eq.). The mixture was stirred at rt for 18 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with ethanol to give the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](Cc3ccc(F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70724.7 %

Procedure:
(2S,4S)-Methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (81 mg, 0.24 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 2 mL, 11.42 mmol) and the mixture stirred at room temperature for 24 h, then more hydrogen bromide (33% in acetic acid, 0.5 mL) was added and stirring continued overnight, then more hydrogen bromide (33% in acetic acid, 1 mL) was added and stirring continued overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: Agilent, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-(4-fluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (46.9 g, 70%). 1H NMR (400 MHz, cd3od) δ 1.73-1.83 (m, 1H), 1.98-2.17 (m, 3H), 2.81-3.10 (m, 3H), 3.20-3.28 (m, 2H), 3.32-3.41 (m, 1H), 5.48 (d, 1H), 7.01-7.09 (m, 2H), 7.20-7.27 (m, 2H). HRMS Calculated for [C15H17FN2O2+H]+: 277.1352. Found: 277.1346
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[N:6][C:7]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].C(=O)(O)[O-].[Na+]>Cl>[CH:3]([C:4]1[CH:5]=[N:6][C:7]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:20])[CH3:21])([CH3:18])[N:17]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])=[O:2]
Reactant: COC(OC)c1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C1(C)N=C(c2ncc(C=O)cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A fourth hapten is prepared by reacting a solution of 5-dimethoxymethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (3.65 g, 10.9 mmol) with 2N hydrochloric acid (20 mL) with stirring at room temperature for 20 hours. The reaction mixture is basified to pH 3.1 with sodium bicarbonate and concentrated in vacuo to give a gum. The gum is triturated with an acetone/ethanol (1:1) solution, filtered and the filtrate concentrated in vacuo to obtain 5-formyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid, fourth hapten, as a yellow solid (3.07 g, mp 187°-198° C., 97%). This hapten is identified by IR and NMR spectral analyses. The above reactions are illustrated below. ##STR13##
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COCCN
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NCCOC)cccc23)n1
Yield: 93 %

Procedure:
A mixture of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (56 mg, 0.14 mmol) and 2-methoxyethylamine (5 mL) was heated to reflux for 24 hours, then cooled and concentrated. Flash column chromatography eluting with 3:1 hexanes:ethyl acetate afforded 3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-7-amine (57.1 mg, 93%) as a yellow foam. 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.76 (d, 1H), 7.65 (m, 2H), 7.32 (t, 1H), 7.15 (t, 2H), 6.29 (m, 2H), 6.05 (d, 1H), 5.10 (broad, 1H), 3.72 (t, 2H), 3.57 (q, 2H), 3.47 (q, 2H), 3.43 (s, 3H), 1.69–1.44 (m, 4H), 0.98 (t, 3H); MS m/z 435 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2([C:16]#[N:17])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: N#CC1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(c2cc(Cl)nc(Cl)c2)CCOCC1
Reaction time: 0.08 h

Procedure:
To a stirring solution of 2,4,6-trichloropyridine (4.65 g, 24.7 mmol) and tetrahydropyran-4-carbonitrile (2.29 g, 20.6 mmol) in THF (100 mL, 0.2 M) and under nitrogen at −78° C. was added lithium bis(trimethylsilyl)amide (29 mL, 29 mmol, 1.0 M in THF) and after 5 min, the cooling bath was removed. After stirring a further 40 min, the reaction was quenched by the addition of sat. aq. NH4Cl and then concentrated. The mixture was extracted with CH2Cl2 and organics dried over MgSO4. Following concentration, the residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) but care needed to be taken to prevent compound precipitation on the column. After purification, 4-(2,6-dichloro-4-pyridyl)tetrahydropyran-4-carbonitrile was obtained a white solid (3.75 g, 71%); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=0.6 Hz, 2H), 4.17-4.05 (m, 2H), 3.93-3.84 (m, 2H), 2.15-1.99 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:8][C:9](=[N:11][OH:12])[CH3:10]>>[CH3:8][C:9](=[N:11][O:12][CH2:2][C:3]([OH:5])=[O:4])[CH3:10]
Reactant: CC(C)=NO
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=NOCC(=O)O
Temperature: 25 °C

Procedure:
To bromoacetic acid (500 g, 3.60 mol) and ice (400 g) was added dropwise 40% sodium hydroxide (375 g, 3.75 mol) at below 20° C. Acetone oxime (239 g, 3.27 mol) was added. At below 20° C., 40% sodium hydroxide (375 g, 3.27 mol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight and extracted with 500 ml of ether. The aqueous phase was acidified to pH 2 and extracted with ether (3×500 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. Hexane (250 ml) was added to the residue and the precipitate was collected to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:9][CH2:8][N:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>C1C=CC=CC=1>[C:24]([N:3]1[C:4]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:5]=2[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][CH2:8][CH2:9][C:2]1=[NH:1])(=[O:25])[CH2:23][C:22]([CH3:21])=[O:26]
Reactant: C=C1CC(=O)O1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NCC1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)N1C(=N)CCN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
To a suspension of 5.0 parts of 2-amino-8-chloro-3,4-dihydro-6-phenyl-1,5-benzodiazocine in 100 parts by volume of benzene is added 3.0 parts by volume of diketene at 25°C with stirring. The reaction mixture is further stirred for 1.5 hour. Resulting colorless crystals are collected by filtration, washed with ether, whereby 1-acetoacetyl-8-chloro-2-imino-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine is obtained. Melting point 149°-150°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON[C:18](=[O:24])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:15])[C:9]([CH3:14])([CH3:13])[C:10]([O:12][N:23]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CCC(=O)NO
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl(methyl)amino)-2-methylpropanoic acid (5 g), N-hydroxysuccinamide (2.65 g) in DCM (100 mL) was added triethylamine (6.42 mL) and EDC (4.41 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with sodium bicarbonate (100 mL), dried with magnesium sulfate, filtered and then concentrated to afford 2,5-dioxopyrrolidin-1-yl 2-(tert-butoxycarbonyl(methyl)amino)-2-methylpropanoate as a colourless oil (5.1 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:45][CH3:46])=[C:35]([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:36]=2)[N:31]=[CH:30][N:29]=1>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:45][CH3:46])=[C:35]([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCS(C)(=O)=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (92 mg, 0.32 mmol) was treated with cesium carbonate (113 mg, 0.35 mmol) in anhydrous tetrahydrofuran (2 mL) and the suspension stirred at 40° C. for 20 minutes. 4-Chloro-7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazoline from the previous step (100 mg, 0.32 mmol) was carefully added in portions and the resulting mixture heated at 40° C. for 2 h. Cesium carbonate was filtered off, the filtrate concentrated under reduced pressure and the residue purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazolin-4-ylthio)phenyl)urea (36.88 mg, 20%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 7.85 (s, 1H), 7.53-7.40 (m, 4H), 7.30-7.28 (d, 1H), 6.49 (s, 1H), 4.59-4.56 (m, 2H), 4.00 (s, 3H), 3.78-3.74 (m, 2H), 3.20 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 572 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:32]=2[CH3:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:32]=2[CH3:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(C)c(-c3cccc(Cl)c3)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 75 °C
Yield: 55.8 %

Procedure:
A solution of (2S)-ethyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.025 g, 0.043 mmol) in MeOH (2 mL) was treated with 1.0 M NaOH (0.215 mL, 0.215 mmol) and the reaction was stirred with heating (75° C. oil bath) for 16 hrs. The reaction was concentrated under reduced pressure to give a white paste. This was partitioned between 0.1N HCl (5 mL) and CH2Cl2 (5 mL). The layers were separated and the organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure, affording an off-white solid. The product was purified by preparative-HPLC. Product fractions were pooled and concentrated to 1/2 volume and the resulting solid was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure, affording the product, (2S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (0.014 g, 0.024 mmol, 55.9% yield), as an off-white solid. 1H NMR (500 MHz, CDCl3) d: 7.69-7.64 (m, 1H), 7.57 (dt, J=7.0, 1.7 Hz, 1H), 7.36-7.28 (m, 2H), 6.89 (d, J=10.7 Hz, 1H), 5.06 (s, 1H), 4.30 (t, J=5.2 Hz, 2H), 2.77-2.69 (m, 5H), 2.53-2.48 (m, 3H), 2.14 (m, 2H), 1.91 (s, 3H), 1.21-1.17 (m, 9H). LCMS (M+H)=552.4. The following examples 159-164 were prepared according to the procedure for Example 158 using appropriate esters.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]1=2)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1)[CH2:16][N:15]([CH:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:10]1=2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (7.9 g, 14.0 mmol) in dichloromethane (100 mL) add a solution of trifluoroacetic acid (50 mL) in dichloromethane (50 mL). After stirring at room temperature for 1 h, neutralize the reaction with concentrated sodium bicarbonate. Separate the organic phase and wash with water (100 mL) and brine (100 μL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. Crystallize the compound from dichloromethane/hexane. This provides the title compound (5.3 g, 81%) as a colorless solid: MS (ES+): 465 (M+H).