Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:13])=[C:9]([CH:12]=1)[CH2:10][NH2:11])([O-:4])=[O:3].[C:14](Cl)(=O)[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[N+:2]([C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[C:14]([C:15]1[CH:23]=[CH:22][C:21]3[O:20][CH2:19][O:18][C:17]=3[CH:16]=1)[N:11]=[CH:10]2)([O-:4])=[O:3]
Reactant: NCc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a suspension of 5-nitro-2-amino-benzylamine hydrochloride (31 g, 0.152 mol) in DCM (450 ml) was added at 0° C. TEA (52.6 ml, 0.38 mol) and a solution of piperonyloyl chloride (27.3 g, 0.16 mol) in DCM (80 ml). The mixture was stirred for 2 hours at r.t. The solvent was removed i.v. and the residue triturated with ethanol/water 1/9, then with diisopropyl ether. The obtained solid was dried and suspended in toluene (900 ml) and POCl3 (670 ml). The mixture was heated at reflux for 2 hours, then the solvent was removed i.v. and the residue was triturated with water/ammonia, washed with water, dried over P2O5. A mixture of the obtained product and chloranil (32.7 g, 0.129 mol) in toluene (500 ml) was heated at reflux for 2 hours. The mixture was concentrated i.v. and the residue was triturated with NaOH 1M, washed with water and with methanol. The obtained solid was dried i.v. (37 g, 82.5% yield). C15H9N3O4, MW: 295.26, mp 220-222° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44](OS(C)(=O)=O)[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44]([N:18]2[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:30])[F:31])[CH:23]=3)[N:21]=[C:17]2[CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)[CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.9 %

Procedure:
To a solution of 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1000.00 mg; 2.24 mmol; 1.00 eq.) in DMF 8 ml added NaH (107.27 mg; 2.68 mmol; 1.20 eq.), stirred at RT for 20 mins, added 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1186.02 mg; 4.47 mmol; 2.00 eq.), the reaction mixture was stirred 85° C. for 5 hr, lc-ms showed around 40% desired, continued stirring for over night, no big changed, purified the product by HPLC (basic) with 30-100% acetonitrile/water, collected title compound 220 mg, yield 16%.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[CH:35][N:34]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[CH:37]=[CH:38][N:33]=[N:34][CH:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)ccc3C)c(F)c12
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.050 g, 0.114 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.015 g, 0.113 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.060 g, 0.594 mmol, 5.0 eq) and BOP reagent (0.076 g, 0.172 mmol, 1.5 eq). The reaction mixture was stirred at RT. overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield: 0.030 g (50.0%). 1H NMR (400 MHz, CDCl3): δ 9.03 (d, J=5.6 Hz, 1H), 8.98 (m, 1H), 8.01-7.98 (m., 2H), 7.81-7.78 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=2 Hz, 1H), 7.44 (d, J=8.4, 2 H), 7.28-7.26 (dd, 1H), 7.23-7.18 (m, 3H), 7.08 (s, 1H), 6.20 (bs, 1H), 3.04 (d, J=5.2 Hz, 3H), 2.29 (s, 3H), 1.61-1.54 (m, 4H). 19F NMR (376.57 MHz, CDCl3): δ −109.53, −119.52. LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[N:15][C:16]([I:17])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:30])=[N:15][C:16]([I:17])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCn2cnc(I)c2C1CCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)nc(I)c2C1CCc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of 1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.000 g; 1.918 mmol) in chloroform (30 ml) was added N-chlorosuccinimide (307 mg; 2.298 mmol; 1.2 eq.), and the resulting mixture was heated to reflux (70° C.) for 2 h30. Additional N-chlorosuccinimide (120 mg; 0.898 mmol; 0.46 eq.) was then added and the resulting mixture was additionally refluxed for 2 h30. The reaction mixture was allowed to cool to rt, diluted with DCM (50 ml), and washed with brine (80 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=1/1) afforded the expected product 3-chloro-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (475 mg; 45%). LC-MS: tR=1.13 min.; [M+H]+=556.24 g/mol.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH:46]1[CH2:48][CH2:47]1)[C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][N:9]1[S:33]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)(=[O:35])=[O:34])=[O:7])#[N:2].[NH4+].[Cl-].[N-:51]=[N+:52]=[N-:53].[Na+].CCOC(C)=O>CN(C=O)C.O>[CH:46]1([N:5]([CH2:4][CH2:3][C:1]2[NH:53][N:52]=[N:51][N:2]=2)[C:6]([C@@H:8]2[CH2:12][C@@H:11]([S:13][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][N:9]2[S:33]([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=2)(=[O:35])=[O:34])=[O:7])[CH2:47][CH2:48]1
Reactant: N#CCCN(C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1)C1CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C([C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1)N(CCc1nnn[nH]1)C1CC1
Yield: 40 %

Procedure:
A solution of 336 mg (0.5 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid (2-cyano-ethyl)-cyclopropyl-amide, 267 mg (5 mmol) NH4Cl and 325 mg (5 mmol) NaN3 in 10 ml DMF were heated at 70° C. for 22 h. 267 mg (5 mmol) NH4Cl and 325 mg (5 mmol) NaN3 together with 40 ml DMF were added and heated at 100° C. (24h) and at 120° C. (24h). The reaction was poured in H2O (0° C.)/EtOAc (3×). The organic phases were washed with aqueous 10% KHSO4, 10% NaCl solution and dried over Na2SO4. Purification by flash-chromatography on silicagel (CH2Cl2/MeOH: 99:1) gave 143 mg (40%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid cyclopropyl-[2-(1H -tetrazol-5-yl)-ethyl]-amide, MS: 715 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:21][OH:22].C([O-])(=O)C.[NH4+].C(O)C>C(OCC)(=O)C.C1CCCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:21][OH:22])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2cc(F)ccc2O)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(=O)N1CCC(C(=NO)c2cc(F)ccc2O)CC1
Yield: 65.6 %

Procedure:
A mixture of 12.7 g of 1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)-piperidine, 6.6 g of hydroxylamine hydrochloride, 11.0 g of ammonium acetate and 200 ml of ethanol-ether was heated under reflux for 10 hrs. After cooling, most of the ethanol was removed under reduced pressure. The resultant suspension was diluted with water and extracted with dichloromethane. The dichloromethane was evaporated in vacuo to give an oil. The oil was dissolved in ethyl acetate and cyclohexane was added to precipitate a solid. The solid was recrystallized from ethyl acetate to give 8.8 g (65.4%) of product, mp, 181°-183°. The chromatogram showed 2 spots.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O-:8])(=O)[CH3:6].[C:9]([O-:12])(=O)[CH3:10].C([O-])(=O)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:25]([Pb+3])=[CH:24][CH:23]=2)=[CH:20][CH:19]=1.Cl.[C:34]1(C)[CH:39]=CC=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:25]([CH:6]3[C:5](=[O:8])[CH:35]4[CH2:36][CH:10]([CH2:39][CH2:34]4)[C:9]3=[O:12])=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1C1C(=O)C2CCC(C2)C1=O
Temperature: 80 °C

Procedure:
Bicyclo[3.2.1]-2,4-dione (0.20 g, 1.44 mmol) and 4-dimethylaminopyridine (0.88 g, 7.21_mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml), and the reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4′-Chloro-3-ethylbiphen-4-yllead triacetate (0.95 g, 1.58 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 3-(4′-chloro-3-ethylbiphen-4-yl) bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C(CCC)CCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(C(CCC)CCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:8](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:7][CH2:6]2.[N-:30]=[N+:31]=[N-:32].[Na+].C1OCCOCCOCCOCCOC1>CN(C)C=O>[N:30]([C@H:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N+:31]=[N-:32]
Reactant: COc1ccc2c(c1)CC[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@@H]2c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC[C@H](N=[N+]=[N-])[C@@H]2c1ccccc1
Temperature: 0 °C
Yield: 58.1 %

Procedure:
A N,N-dimethylformamide solution (50 mL) of crude trans-6-methoxy-1-phenyl-2-(4-methylbenzenesulfonyl)oxy-1,2,3,4-tetrahydronaphthalene 30 (3.4 g), sodium azide (3.78 g, 58.3 mmol) and 15-crown-5 (6.61 mL, 33.2 mmol) was heated at 75° C. for 7 h. The reaction mixture was poured into ice water (200 mL), and the product was extracted into diethyl ether (3×50 mL). The organic extracts were combined and washed successively with water (4×100 mL) and a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. The solvent was evaporated in vacuo, and the remaining residue was purified by medium pressure chromatography using 3% ethyl acetate in hexanes as the eluent to give crude cis-2-azido-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalene 31 (1.35 g, ~62%) as an oil which was used without further purification in the subsequent step.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:46]1N=N[C:48]2C=CC=[CH:52][C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:46][CH:47]([CH3:52])[CH3:48])=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)NC(C)C)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and isopropylamine (7.03 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.1 mg, 53%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:5])[O-:4].[CH3:6][N+:7]([CH3:10])([CH3:9])[CH3:8].O>CO>[C:3](=[O:2])([O-:5])[OH:4].[CH3:6][N+:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: O
Solvent: CO
Product: O=C([O-])O
Reaction time: 3 h

Procedure:
108.0 g of tetramethylammonium monomethylcarbonate, 72.0 g of water and 32.0 g of methanol were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 100° C., the reaction was continued for 3 hours at 100° C. Tetramethylammonium hydrogencarbonate was obtained in a yield of 98.5 mol %.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(OC([NH:33][C@@H:34]([CH3:41])[CH2:35]OS(C)(=O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:33][C@@H:34]([CH3:41])[CH2:35][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with methanesulfonic acid (S)-2-tert-butoxycarbonylamino-propyl ester (described in WO 2005100321) gave, after treatment with TFA and subsequent neutralization, the title compound.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:14][CH:13]([CH2:15]Br)[CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:11]1=[O:24])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1>[CH3:1][C:2]([N:10]1[CH2:14][CH:13]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)([CH2:15]2)[C:11]1=[O:24])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)(c1ccccc1)N1CC(CBr)C(c2cccc(F)c2)C1=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(c1ccccc1)N1CC2CC2(c2cccc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To 15 ml of toluene were added 0.8 g of 1-(1-methyl-1-phenylethyl)-4-bromomethyl-3-(3-fluorophenyl)pyrrolidine-2-one and 0.4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the solution was then stirred at room temperature for 2 hours. After water was added to the solution, extraction was made with toluene, and the resultant extract was then dried over anhydrous sodium sulfate. After the solvent was distilled off, silica gel column chromatography was done to obtain 0.45 g of the desired 3-(1-methyl-1-phenylethyl)-1-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-one.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23]C[CH2:25][CH2:26][OH:27]>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:25][CH2:26][OH:27])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: OCCCBr
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCO)(CC1)C2
Product: [Br-]
Yield: 31.2 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and 3-bromo-1-propanol (0.020 mL, 0.282 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0196 g, 31.1%). EI-MS m/z 333 (M+) Rt (1.43 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[S:17][C:16]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[N:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[S:17][C:16]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:25])([CH3:26])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[N:15][N:14]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(c1nnc(-c2ccc(F)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a stirred suspension of (2-chloro-4-fluorophenyl)boronic acid (251 mg, 1.44 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (400 mg, 1.2 mmol) in dioxane (10 mL) under nitrogen was added Pd(PPh3)4 (69 mg, 0.06 mmol) followed by a solution of Na2CO3 (382 mg, 3.6 mmol) in water (2.5 mL). The reaction mixture was sealed and heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM (100 mL) and washed with saturated NaHCO3(aq) (40 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was diluted with MeOH (10 mL) and SiliaMetS-DMT (0.61 mmol/g, 0.984 mg, 0.6 mmol) was added. The resulting suspension was stirred at room temperature for ˜18 hours then filtered. The filtrate was concentrated in vacuo to afford the crude product as a yellow/orange oil. The crude material was purified by flash chromatography using a 24 g silica cartridge running a gradient from 2-10% [2M NH3 in MeOH]/DCM to afford the title compound as a pale yellow solid (312 mg, 68% yield). LC-MS: Rt 0.97 min; MS m/z 383.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (dd, J=8.84, 6.32 Hz, 1H), 7.65 (dd, J=9.09, 2.53 Hz, 1H), 7.36-7.43 (m, 1H), 4.34 (tt, J=12.38, 3.28 Hz, 1H), 3.00 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H), 1.43 (t, J=12.38 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.08 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.Br[CH2:19][C:20]([C:22]1[CH:23]=[C+:24][CH:25]=[CH:26][CH:27]=1)=O>C(O)CCC.[Cl-].[Na+].O>[C:7]1([C:5]2[N:6]3[CH:19]=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:1]=[C:2]3[S:3][C:4]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)C1=CC=C[C+]=C1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)c1sc2nc(-c3ccccc3)cn2c1-c1ccccc1
Temperature: 25 °C
Yield: 18.3 %

Procedure:
A solution of ethyl 2-amino-4-phenylthiazole-5-carboxylate 93 (0.7 g, 2.82 mmol) and 3-(2-bromoacetyl)benzene-1-ylium 68 (0.34 mL, 2.82 mmol) was stirred at 120° C. in butanol (9 mL) for 3 d. The solution was cooled to room temperature, diluted with brine and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 3,6-diphenylimidazo[2,1-b]thiazole-2-carboxylate 94 (0.18 g, 18% yield) as a tan solid after purification by flash chromatography (0 to 30% MeOH in ethyl acetate) followed by trituration in hexane. LRMS (ESI): (calc) 348.42 (found) 349.2 (MH)+