Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19][CH2:18]2)=[CH2:14].[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37](F)=[O:38])[C:33]=2[C:40]([F:43])([F:42])[F:41])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37]([CH:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([CH:13]=[CH2:14])[CH:16]=4)[C:21]3=[O:25])=[O:38])[C:33]=2[C:40]([F:42])([F:43])[F:41])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=Cc1ccc2c(c1)CCCC2=O
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=Cc1ccc2c(c1)CCC(C(=O)c1noc(-c3ccccc3)c1C(F)(F)F)C2=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a heat gun dried 100 mL 2-necked flask was added diisopropylamine (0.910 mL, 6.39 mmol) under a nitrogen atmosphere followed by THF (5 mL). The flask was cooled to 0° C. and n-BuLi (2.55 mL, 6.39 mmol) was added dropwise over a period of 2 min. The contents were stirred at 0° C. for 20 min., cooled to −78° C. and 6-vinyl-3,4-dihydronaphthalen-1(2H)-one (I-1B, 1 g, 5.81 mmol) dissolved in 2 mL of THF was added dropwise over a period of 3 min. The pale yellow reaction mixture was stirred at −78° C. for 20 min. Then 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (I-14, 1.505 g, 5.81 mmol) dissolved in 2 mL of THF was added dropwise over a period of 2 min. The reaction mixture was stirred at −78° C. for 20 min, bought to room temperature and stirred at room temperature for 10 min. The reaction mixture was quenched with 1N HCl (5 mL) and extracted into EtOAc (20 mL). The aqueous layer was re-extracted with EtOAc (10 mL). The combined organic layers were dried over sodium sulfate concentrated and purified by column chromatography using an ISCO setup (80 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield 2-(5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (1.55 g, 3.77 mmol, 64.9% yield) as a yellow solid. LC/MS M+1=412.12.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:14]1[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4-difluorobenzaldehyde (3.0 g, 21.1 mmol) and t-butyl piperazine-1-carboxylate (4.3 g, 23.1 mmol) in 30 mL of dry DCM is stirred for 2 h at RT, and NaHB(OAc)3 (6.7 g, 31.6 mmol) is added in portions with stirring. After the addition, the reaction mixture is stirred further overnight at RT. Water is added and the resulting mixture is extracted twice with DCM. The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain t-butyl 4-(2,4-difluorobenzyl)piperazine-1-carboxylate as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 2.40 (m, 4H), 3.42 (m, 4H), 3.54 (s, 2H), 6.78 (dt, 1H, J=10.0 Hz and 2.4 Hz), 6.85 (dt, 1H, J=8.4 Hz and 2.4 Hz), 7.33 (dd, 1H, J=15.2 Hz and 8.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:17]([NH2:19])[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CCCCO>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:19][CH:17]([C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH3:18])[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2cccnc2cc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnc2cc1-c1ccccc1
Temperature: 25 °C

Procedure:
1-(3-Phenyl-1,5-naphthyridin-2-yl)ethanamine (46 mg, 0.19 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (28.5 mg, 1.0 eq) and Hunig's base (39 μL, 1.2 eq) in n-BuOH (2 mL) was heated to 130° C. for 4 h. The mixture was cooled to rt, filtered and washed with small amount of EtOH to give a white solid as 4-amino-6-(1-(3-phenyl-1,5-naphthyridin-2-yl)ethylamino)pyrimidine-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (1H, dd, J=8.0, 4.0 Hz), 8.44 (1H, dd, J=8.0, 4.0 Hz), 8.21 (1H, s), 7.97 (1H, s), 7.84 (1H, dd, J=8.0, 4.0 Hz), 7.61-7.47 (6H, m), 7.30 (1H, br, s), 5.63 (1H, t, J=8.0 Hz)), 1.31 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 368 [M+H]+.
Reaction SMILES: C([C@H]([C@@H](C([O-])=O)O)O)([O-])=[O:2].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([OH:34])[C@@H:19]([N:21]2[CH2:26][CH2:25][C:24]([OH:33])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[CH3:20])=[CH:14][CH:13]=1.[CH3:35][S:36](O)(=[O:38])=[O:37]>O>[OH2:2].[OH2:11].[OH2:37].[S:36]([O:34][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=1)[C@@H:19]([N:21]1[CH2:22][CH2:23][C:24]([OH:33])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][CH2:26]1)[CH3:20])(=[O:38])(=[O:37])[CH3:35]
Reactant: CS(=O)(=O)O
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Reactant: C[C@@H]([C@@H](O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Solvent: O
Product: C[C@@H]([C@@H](OS(C)(=O)=O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
The D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (5.0 g, 10.5 mmol), water (17.5 mL), and methanesulfonic acid (1.05 g, 11.0 mmol) were combined in a 50 mL, 3-neck round bottom flask under a nitrogen atmosphere. The slurry was heated to 60-65° C. to give a solution which was then filtered. The filtrate was slowly cooled over 1 hour to 15-20° C. to give a thick white suspension. The slurry was further cooled to 0-5° C. and then granulated at 0-5° C. for 1 hour. The product was filtered, the cake washed with 2.5 mL of cold water (0-5° C.) and then dried at 20-25° C. under nitrogen sweep. (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol mesylate trihydrate (4.53 g) was isolated in 90.4% overall yield as a white crystalline solid. The physical and chemical properties of the isolated trihydrate were identical to an authentic sample. 1H NMR (d6-DMSO) δ9.58 (s, 1H), 8.91 (S, 1H), 7.48 (m, 2H), 7.35 (m, 2,2H), 7.21 (m, 3H), 6.77 (d, J=8.5 Hz, 2H) 6.35 (s, 1H), 5.52 (s, 1H), 4.58 (d, J=8.1 Hz, 1H), 340 (m, 11H) 2.63 (m, 1H), 2.3 (s, 3H), 1.78 (m, 2H), 0.95 (d, J=6.6 Hz, 3H). 13C NMR (d6-DMSO) δ158.13, 148.61, 132.27, 129.27, 128.80, 127.51, 125.26, 115.89, 72.12, 68.89, 66.30, 47.40, 42.91, 35.71, 35.37. Anal. Calcd. for C20H25NO3.CH3SO3H.3H2O: C, 52.81; H, 7.39; N,2.93; S, 6.71. Found: C, 52.77; H, 7.50; N, 2.94; S, 6.96. αD=+54.5° (anhydrous basis).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1C.[C:12]([Cl:16])(Cl)([Cl:14])[Cl:13]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([C:12]([Cl:16])([Cl:14])[Cl:13])=[C:2]([Cl:1])[CH:7]=1)([O-:10])=[O:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C(Cl)(Cl)Cl)c(Cl)c1
Yield: 99.2 %

Procedure:
2-Chloro-4-nitrotoluene (2.19 g, 0.0128 mole) and dichloride monoxide (4.46 g, 0.0513 mole) in carbon tetrachloride (50 ml) were heated at 75°/18 hrs following the procedure described in Example 6. The product was dried and the solvent removed to give 1-nitro-3-chloro-4-trichloromethylbenzene (3.49 g, purity by HPLC 99.40%, yield 99.2%) as a pale yellow oil. The product was distikled in a short path still (bp 82-85/2μ) to give a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]([C:26]#[N:27])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[F:37][CH:38]([F:50])[O:39][C:40]1[CH:41]=[N:42][C:43](S(C)(=O)=O)=[N:44][CH:45]=1.CCOC(C)=O>CN1C(=O)CCC1>[F:37][CH:38]([F:50])[O:39][C:40]1[CH:41]=[N:42][C:43]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[C:14]([C:26]#[N:27])=[N:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)[C:17](=[O:18])[CH:16]=3)[CH2:21][CH2:22]2)=[N:44][CH:45]=1
Reactant: CS(=O)(=O)c1ncc(OC(F)F)cn1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCN(c4ncc(OC(F)F)cn4)CC3)cc2=O)cc1
Temperature: 100 °C
Yield: 15.4 %

Procedure:
To a stirring solution of 1-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (example 47 step A) (41 mg, 0.10 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (38.8 mg, 0.30 mmol) and 5-(difluoromethoxy)-2-(methylsulfonyl)pyrimidine (22.4 mg, 0.1.0 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. After cooling to room temperature, 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜3 ml) and loaded onto a 24 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 8 mg (15% for two steps) of 4-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a tan solid 1H NMR (400 MHz, CDCl3) δ ppm 1.75-2.27 (m, 4H) 3.08 (s, 3H) 3.66-3.97 (m, 2H) 3.97-4.24 (m, 2H) 4.54-4.95 (m, 1H) 6.34 (s, 1H) 7.84 (d, J=8.79 Hz, 2H) 8.07 (d, J=8.79 Hz, 2H) 8.24 (s, 2H). MS (ESI) 519 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=O)[CH:7]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[O:11][CH2:10]2)[CH:7]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1CN1COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (740 mg, 2 mmol), p-nitrophenyl chloroformate (407 mg, 2.02 mmol), and pyridine (330 mg, 4.17 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature for three hours. The corresponding aminoacid tert-butyl ester (2 mmol) and anhydrous triethylamine (405 mg, 4 mmol) were added and the resulting reaction mixture was stirred at room temperature overnight. After evaporation, the residue was partitioned between diethylether and dilute NaOH. The organic layer was washed with water, dilute HCl, and brine, and then dried over magnesium sulfate. The crude product was purified by either trituration or recrystallization. The tert-butyl ester was stirred in dichloromethane (5 mL) with trifluoroacetic acid (1 mL) at room temperature overnight. After evaporation of CH2Cl2 and excess TFA, the residue was recrystallized from benzene-acetone to afford pure desired product.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:12][SH:13].Cl[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH2:18]>O>[CH3:12][S:13][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH2:18]
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(N)ccc1[N+](=O)[O-]

Procedure:
A mixture of dry dimethylformamide (150 ml) and potassium carbonate (12.0 g) is stirred and methyl mercaptan is introduced as a gas for 45 minutes. After stirring for another 45 minutes, 3-chloro-4-nitroaniline (10.0 g) is added. The mixture is stirred and heated at 120°-130° C. for 18 hours. It is then cooled and poured into water (1 liter), the precipitate is collected and recrystallized from methanol to afford 8 grams of 3-methylthio-4-nitroaniline, m.p. 178°-182° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)[OH:6])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:6][C:18](=[O:20])[CH3:19])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCOC(=O)C(OC(C)=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (6 mL) of the compound (1.46 g) prepared in Example 22 in pyridine, acetic anhydride (2 mL) was added, and the mixture was stirred for 1 hour at room temperature. The title compound (135 mg) having the following physical data was obtained by concentrating the reaction mixture and azeotroping in toluene.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Yield: 86.7 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester (0.72 g) in hot methanol (10 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (4.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.6 g of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid as a colorless solid, mp 161°-162° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([CH3:30])([CH3:29])[CH2:20]O[Si](C(C)(C)C)(C)C)[CH:11]=[CH:10]2.CN([CH:34]=[O:35])C>O>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([CH3:29])([CH3:30])[CH2:20][Cl:3])[CH:11]=[C:10]2[CH:34]=[O:35]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Solvent: O
Product: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phosphorus oxychloride (2.57 mL) was added to a cooled solution of DMF (10 mL) and the reaction stirred at room temperature for 2 h before being treated with 6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)isoquinolin-1(2H)-one (Example 1c, 1.3 g) in DMF (10 mL) under nitrogen. The resulting solution was stirred at 70° C. for 10 h. The reaction mixture was diluted with water (300 mL), and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution 50% diethyl ether in isohexane) to afford the subtitle compound (0.45 g) as a solid.
Reaction SMILES: BrCCBr.Br[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[F:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:19][O:20][C:16]=2[CH:15]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:27]2([OH:30])[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][CH2:21][C:18]3[C:17]4[CH:31]=[CH:32][C:14]([F:13])=[CH:15][C:16]=4[O:20][N:19]=3)[CH2:29][CH2:28]2)=[CH:7][CH:8]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OC1(c2ccc(Br)cc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To 25 ml of ethyl ether was added 1.0 g of magnenesium turnings, 0.5 ml of 1,2-dibromoethane and a few drops of a solution of 9.4 g of 1,4-dibromobenzene in 50 ml of ethyl ether. The reaction was initiated with heat and maintained by the addition of the solution of 1,4-dibromobenzene. The resultant solution was stirred at ambient temperature for fifteen mins and then a solution of 7.0 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml of tetrahydrofuran was added with vigorous stirring. After the addition was complete, the mixture was stirred at ambient temperature for thirty mins and then poured into an ice cold solution of ammonium chloride. After dilution with 200 ml of ethyl ether, the organic layer was collected, washed with water (2×), saturated sodium chloride solution and then dried over anyhydrous magnesium sulfate. After filtering, the solvents were evaporated to an oil, which was triturated with petroleum ether. The resultant precipitate was collected and dried to give 4.4 g (41%) of product, mp 138°-145° C. Recrystallization four times from ethyl ether gave the analytical sample, mp 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:18]([O:20][CH3:21])=[O:19]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:18]([O:20][CH3:21])=[O:19])[N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COC(=O)Cl
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Solvent: Cc1ccccc1C
Product: COC(=O)n1nc(-c2cc(Cl)c(C)c(Cl)c2)ccc1=O
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 2.55 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone, 4.7 g of methyl chloroformate and 25 ml of xylene was heated under reflux for 1.5 hours. The reaction mixture was then left to cool at room temperature and the precipitate thus produced was collected by filtration and washed with hexane, giving 2.94 g (94%) of the desired Compound No. 23 in the form of colourless prisms having, after recrystallization from benzene, a melting point of 203°-206° C.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([CH3:29])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([CH3:29])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(-c2ccc3oc(=O)n(C)c3c2)nc2c(OCc3ccccc3)cccn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2ccc3oc(=O)n(C)c3c2)nc2c(O)cccn12
Yield: 63.6 %

Procedure:
A solution of 5-(8-benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (1.6 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (wet, 0.5 g) under an atmospheric pressure of hydrogen at ambient temperature for an hour. The catalyst and an insoluble material were filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of tetrahydrofuran and ethanol to give 5-(8-hydroxy-3-methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (0.78 g). mp. >280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>CO.[Zn]>[NH2:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15]
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Yield: 75.3 %

Procedure:
4′-Chloro-4-ethyl-3-nitrobiphenyl (22.6 g, 0.086 mol) is suspended in methanol (250 ml) and the reaction mixture is stirred at room temperature. Distilled water (100 ml) is added, followed by zinc dust (39.0 g, 0.60 mol) and ammonium chloride (13.8 g, 0.26 mol) and the mixture is heated to reflux for 1 hour. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth and the filtrate is evaporated in vacuo to remove most of the methanol. The residue is partitioned between ethyl acetate (200 ml) and water and the aqueous phase is re-extracted with ethyl acetate (200 ml). The organic extracts are combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give 3-amino-4′-chloro-4-ethylbiphenyl (15.0 g) as a colourless solid. The product is used directly without further purification in Step 5.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:19][CH:18]=1)#[N:17]
Reactant: CCOC(=O)C(F)Br
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 200 mg, 0.49 mmol) in tetrahydrofuran (4 mL) is cooled in an ice bath. Lithium diisopropylamide (2 M in tetrahydrofuran, 270 μL, 0.54 mmol) is added, and the mixture is stirred for 15 min. Ethyl 2-bromo-2-fluoroacetate (135 mg, 0.73 mmol) is added, and the mixture is warmed at room temperature and stirred over night. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 70 mg; ESI mass spectrum [M+H]+=516; Retention time HPLC: 0.67 min (X012_S01).
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][NH:3]1.Cl[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19].C[Si](C)(C)[O:26][C:27]1[CH:28]=[C:29]([N:38]2[CH2:42][CH2:41][N:40]([Si](C)(C)C)[C:39]2=[O:47])[CH:30]=[CH:31][C:32]=1[O:33][Si](C)(C)C>C(OCC)(=O)C>[OH:26][C:27]1[CH:28]=[C:29]([N:38]2[CH2:42][CH2:41][N:40]([S:18]([NH:21][C:22]([N:3]3[CH2:4][C@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:2]3=[O:1])=[O:23])(=[O:20])=[O:19])[C:39]2=[O:47])[CH:30]=[CH:31][C:32]=1[OH:33]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C[Si](C)(C)Oc1ccc(N2CCN([Si](C)(C)C)C2=O)cc1O[Si](C)(C)C
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3.9 g (17.8 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 30 ml of ethyl acetate was added 2.5 g (17.8 mmol) of chlorosulfonyl isocyanate. The reaction mixture was stirred for one hour at room temperature and a solution of 7.14 g (17.8 mmol) of 1-[3,4-bis[(trimethylsilyl)oxy]phenyl]-3-(trimethylsilyl)-2-imidazolidinone in 30 ml of ethyl acetate was added dropwise. After stirring overnight at room temperature, the mixture was washed with brine, dried over sodium sulfate and evaporated in vacuo; yield: 8.46 g.