Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.S(C1C=CC(C)=CC=1)(O[CH2:20][CH2:21][F:22])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:22][CH2:21][CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FCCNc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
In a round bottom flask aniline (0.5 g, 5.4 mmol), 2,6-lutidine (0.58 g, 5.4 mmol) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (1.17 g, 5.4 mmol) were combined in DMF (2.5 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (50 mL). This was washed with water (3×20 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (100 g, 0-100% B, 18 CV, 85 mL/min) to give 435 mg (60%) of (2-fluoro-ethyl)-phenyl-amine (24) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.41 (1H, t, J=3 Hz, NCH2CH2F), 3.50 (1H, t, J=3 Hz, NCH2CH2F), 3.93 (1H, s, br), 4.54 (1H, t, J=3 Hz, NCH2CH2F), 4.71 (1H, t, J=3 Hz, NCH2CH2F), 6.65-6.82 (3H, m, 2×NCCH, NCCHCHCH), 7.14-7.28 (2H, m, 2×NCCHCHCH).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][Ti:20](Cl)([Cl:31])[C:21]1([CH3:30])[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([CH3:28])=[C:22]1[CH3:29]>C1(C)C=CC=CC=1>[Cl:19][Ti:20]([Cl:31])([C:21]1([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]([CH3:27])=[C:25]1[CH3:26])[O:16][C:5]1[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Reactant: CC(C)c1cccc(-c2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(-c3ccccc3)cccc2C(C)C)C(C)=C1C
Temperature: 25 °C
Yield: 67 %

Procedure:
700 mg (3.28 mmol) of 2-isopropyl-6-phenylphenol and 236 mg (9.84 mmol) of sodium hydride were dissolved in 10 ml of toluene, and then refluxed for 4 hours. The refluxed solution was cooled to room temperature, and then a solution of 930 mg (3.21 mmol) of trichloro(pentamethylcyclopentadienyl)titanium (IV) was slowly added dropwise thereto, and the mixture was refluxed for 24 hours. After completion of the reflux reaction, volatile components were removed from the reaction solution, and the residue was washed with purified hexane, recrytallized from a mixed solvent of toluene/hexane −35° C., filtered, and then dried in a vacuum, thus obtaining 1.0 g of a red solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]([NH2:18])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16](/[N:18]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Solvent: C1COCCO1
Product: CN(C)/C=N/C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 12-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (100 mg, 0.380 mmol) in 1,4-dioxane (3 mL) was added DMF-DMA (147 mg, 1.14 mmol). The resulting mixture was stirred at 100° C. for 1 h under nitrogen atmosphere. After removal of the solvent, the residue was washed with ether to afford 12-bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (80 mg, 68% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 363.3 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][Br:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cccc(CBr)c1
Temperature: 60 °C
Yield: 34.6 %

Procedure:
A dry 100 mL 3-necked flask equipped with a nitrogen inlet, a condenser, a thermometer, and a magnetic stirrer was charged with 2.0 g of 3-tert-butyltoluene (Wiley Organics, Coshocton, Ohio 43812), 2.40 g of N-bromosuccinimide (Aldrich), and 30 mL of CCl4. The mixture was treated with 0.16 g of benzoyl peroxide (Aldrich) and heated at 60° C. under N2. Careful temperature control is important to minimize by-product formation. After 1 h at 60° C. the reaction mixture was cooled to 0° C., filtered to remove succinimide, and the filtrate was concentrated in vacuo to afford a light yellow liquid. Analysis of this material by tlc (SiO2, hexane) indicated a major new component at Rf=0.50, a minor component at Rf=0.55, and a trace of 3-tert-butyltoluene at Rf=0.75. The crude product was purified by flash chromatography on 100 g of silica gel (hexane) to afford 1.06 g (35%) of 3-tert-butylbenzyl bromide as a clear liquid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[C:4]([CH3:11])=[N:3]1.[C:12]([O:16][C@@H:17]([C:23]1[C:38]([CH3:39])=[CH:37][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=3)[S:29][C:25]=2[C:24]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])([CH3:14])[CH3:13]>CN1C(=O)CCC1>[C:12]([O:16][C@@H:17]([C:23]1[C:38]([CH3:39])=[CH:37][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([N:7]4[CH2:8][CH2:9][C:10]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:11])[C:5]=5[CH2:6]4)[CH:31]=3)[S:29][C:25]=2[C:24]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nn(C)c2c1CNCC2
Solvent: CN1CCCC1=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCc5c(c(C)nn5C)C4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (47.6 mg, 0.315 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (32 mg, 0.060 mmol) in anhydrous NMP (1.0 mL) was heated at 90-110° C. for 40 h. Reaction mixture was cooled to room temperature, filtered through a syringe filter and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). Product-containing fractions were diluted with ethyl acetate, washed with saturated sodium bicarbonate solution. Aqueous layer was back-extracted with ethyl acetate and the combined organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give product. LCMS-ESI+: calc'd for C35H39ClN5O3S: 644.2 (M+H+); Found: 644.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.O>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:21]=1
Reactant: ClCc1cccnc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(3,3,3-Trifluoropropyl)malononitrile (407 mg) was dissolved in N,N-dimethylformamide (5 ml), and potassium carbonate (347 mg) was added thereto, and then, a solution of 3-(chloromethyl)pyridine (320 mg) in N,N-dimethylformamide (1 ml) was added dropwise to the mixture, followed by stirring overnight at room temperature. To the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 400 mg of 2-((3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (6)).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[F:16][C:17]([F:35])([F:34])[C:18]([C:24]1[CH:29]=[CH:28][C:27](F)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].N1(C(OC(C)(C)C)=O)CCNCC1>>[C:12]([O:11][C:9]([N:3]1[CH2:4][C@@H:5]([CH3:8])[N:6]([C:27]2[CH:28]=[CH:29][C:24]([C:18]([OH:23])([C:17]([F:35])([F:34])[F:16])[C:19]([F:20])([F:21])[F:22])=[CH:25][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:7][C@@H:2]1[CH3:1])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: O=[N+]([O-])c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Similar reaction and treatment as Example 43-b) was conducted except that (2S,5R)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate obtained in Example 14-1-a-2-2) was used in place of 1,1,1,3,3,3-hexafluoro-2-(4-fluoro-3-nitrophenyl)propan-2-ol obtained in Example 43-a) and tert-butyl piperazine-1-carboxylate, and the title compound was obtained as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[C:15]([F:19])=[CH:16][CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[OH-].[K+].C([O:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])(=O)C>ClCCl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[C:44]([OH:43])([CH3:49])[CH3:48])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-5-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 61) (100 mg, 0.208 mmol) in dichloromethane (0.5 mL),pyridine (0.5 mL) and potassium hydroxide (11.67 mg, 0.208 mmol) was treated with 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.054 mL, 0.37 mmol) and the mixture was stirred for 2.5 h. The reaction mixture was concentrated in vacuo and the orange residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (58 mg, 49%). LCMS (System A) RT=1.04 min, ES+ve m/z 567/569 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH:37]([CH2:40][OH:41])[CH2:38][OH:39]>>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH:37]([CH2:40][OH:41])[CH2:38][OH:39])=[O:18])=[O:7])=[CH:31][CH:32]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC(CO)CO
Product: CON=C1C[C@@H](C(=O)NC(CO)CO)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 2-amino-1,3-propanediol, the title compound was obtained in 70% purity by HPLC. MS(ESI+): m/z=440.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)[CH:13]=1)=[O:6]
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)O)cc1
Yield: 73.3 %

Procedure:
Methyl 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate (1.63 g, 4.28 mmol) and lithium hydroxide monohydrate (376 mg, 9.0 mmol) were mixed in water (5 ml) and THF (10 ml) and stirred at room temperature for 90 h. The pH was adjusted to pH3 by addition of hydrochloric acid (2N) and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (75 ml), brine (75 ml), dried (magnesium sulphate) and concentrated under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/ethanol/ammonia (30:8:1 then 20:8:1). The solvents were evaporated under vacuum to give 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylic acid (1.15 g, 73%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[C:17]([CH2:18][N:19]([CH2:33][C:34]2[CH:51]=[CH:50][C:37]3[N:38]([CH2:48][CH3:49])[C:39](=[O:47])[C:40]([CH3:46])([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:36]=3[CH:35]=2)[CH2:20][CH2:21][N:22]2[CH:27]=[CH:26][C:25]3[O:28][C:29]([CH3:31])=[CH:30][C:24]=3[C:23]2=[O:32])=[CH:16][CH:15]=[CH:14][N:13]=1)(=O)C>CO>[CH2:48]([N:38]1[C:39](=[O:47])[C:40]([CH3:46])([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:36]2[CH:35]=[C:34]([CH2:33][N:19]([CH2:18][C:17]3[C:12]([CH2:11][OH:10])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:20][CH2:21][N:22]3[CH:27]=[CH:26][C:25]4[O:28][C:29]([CH3:31])=[CH:30][C:24]=4[C:23]3=[O:32])[CH:51]=[CH:50][C:37]1=2)[CH3:49]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3COC(C)=O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3CO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Potassium carbonate (2.0 g) was added to a methanol solution (30 mL) of (3-((((1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl)(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)pyridin-2-yl)methyl acetate (3.0 g) and the mixture was stirred overnight at room temperature. The resulting mixture was filtered and evaporated. The residue was purified by column-chromatography (methanol: ethyl acetate=0:100→1:9) to give the titled compound as ivory powder (1.95 g).
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][O:4][CH2:3]2.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:15]=2[N:16]=1.C(N(CC)CC)C.C(Cl)Cl>C(O)C>[Cl:10][C:11]1[N:12]=[C:13]([N:9]2[CH:6]3[CH2:7][CH2:8][CH:2]2[CH2:3][O:4][CH2:5]3)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:15]=2[N:16]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: Clc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A slurry of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.1064 g, 0.7112 mmol) in ethanol (2 mL) was added to 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (0.1 g, 0.3556 mmol). triethylamine (0.250 mL, 1.778 mmol) was added and the mixture was stirred overnight at room temperature. DCM (2 mL) was added to form a complete solution and the mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was dissolved in DCM (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with DCM (2×2 mL). The combined organic layers were evaporated to give a brown oil. Mass: 162 mg. This was purified by silica chromatography (10 g cartridge; eluent petrol/ethyl acetate 0 to 15%; all output collected) and the second eluting peak isolated to give 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a white solid (111 mg). LCMS: RT=4.95 min. M+1=358.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][CH2:13][NH:14][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: NCCc1c[nH]c2cc(Cl)c(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2cc(Cl)c(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 14.6 %

Procedure:
N-(2-(5,6-Dichloro-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5,6-dichloro-1H-indol-3-yl)ethanamine (0.149 g; 0.651 mmol), 4-(3-fluorobenzyl)benzoic acid intermediate (0.150 g, 0.651 mmol), HATU (0.248 g; 0.651 mmol) and N,N-diisopropylethylamine (0.281 mL; 1.63 mmol) in DMF (5 mL). Flash chromatography (twice) on silica gel (eluent 2 to 60% ethyl acetate in heptane and 1 to 10% ethyl acetate in dichloromethane) furnished 0.042 g (14%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[C:6](Cl)=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1.[F:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[C@@H:25]([CH3:26])[CH2:24][N:23]([C:27](=[O:30])[CH2:28][OH:29])[C@H:22]([CH3:31])[CH2:21]2)=[CH:17][CH:16]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[C:6]([O:29][CH2:28][C:27]([N:23]2[CH2:24][C@H:25]([CH3:26])[N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:33][CH:32]=3)[CH2:21][C@H:22]2[CH3:31])=[O:30])=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1.[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:13])[C:6]([O:29][CH2:28][C:27]([N:23]2[CH2:24][C@H:25]([CH3:26])[N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:33][CH:32]=3)[CH2:21][C@H:22]2[CH3:31])=[O:30])=[N:7][CH:8]=1
Reactant: COC(=O)Cc1cc(Cl)cnc1Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CC(=O)O
Temperature: 25 °C

Procedure:
To a 0° C. solution of (2,5-dichloro-pyridin-3-yl)-acetic acid methyl ester (0.45 g, 2.05 mmol) and 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0.52 g, 1.86 mmol) in toluene (5.5 mL) was added sodium hydride (0.082 g, 2.05 mmol, 60% dispersion in mineral oil) in toluene (9.3 mL). The reaction mixture was slowly warmed to ambient temperature and then heated to reflux overnight. The resulting reaction mixture was cooled to ambient temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.14 g) and (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acetic acid (0.20 g).
Reaction SMILES: [Br:1]Br.[C:3]1([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: BrBr
Reactant: c1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.94 ml (134.8 mmol) of bromine in 25 ml of acetic acid is slowly added dropwise over a period of 40 min to a solution of 20 g (122.5 mmol) of N-phenylmorpholine in 170 ml of acetic acid at room temperature. After stirring at room temperature for 30 min, the reaction mixture is stirred into 750 ml of water and adjusted to pH 11 with 45% strength sodium hydroxide solution. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. Recrystallization from ethanol results in 18.6 g (62.9% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].CN(C)C(=O)C.Cl.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([NH:31][CH3:32])[C:28]([NH2:33])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:33][C:6](=[O:7])[C:2]([CH3:9])([CH3:1])[C:3](=[O:4])[N:31]([CH3:32])[C:29]=2[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: CNc1cc(OCc2ccccc2)ccc1N
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1C(=O)C(C)(C)C(=O)Nc2ccc(OCc3ccccc3)cc21
Reaction time: 2.5 h
Yield: 83 %

Procedure:
Under ice cooling, dimethylmalonic acid dichloride (9.9 mL, 74.9 mmol) was added dropwise to a N,N-dimethyl acetamide (90 mL) solution of 5-benzyloxy-N1-methylbenzene-1,2-diamine hydrochloride (18.0 g, 68.0 mmol). The mixture was stirred at the same temperature for 2.5 hours, and water (90 mL) was added thereto. The reaction solution was stirred at 10° C. or less for 30 minutes, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, then added to methanol (180 mL), and heated under reflux. The mixture was cooled and stirred at 10° C. or less for 30 minutes, and precipitated crystals were collected by filtration. The resulting crystals were washed with methanol (36 mL), and dried at 60° C., thereby obtaining 18.3 g of a white, powdery target compound (yield: 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)(O)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)=[CH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: C=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
A mixture of 17.0 g (44.5 mmol) of 18, 220 mL of 40% HBr, and 440 mL of glacial acetic acid was refluxed for 10 hr, and then additionally stirred for 12 hr at room temperature. To the resulting mixture 2000 mL of water and 500 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was extracted with 2×200 mL of dichloromethane. The combined organic extract was washed with saturated aqueous NaHCO3, dried over K2CO3, and then evaporated to dryness. This procedure gave 15.7 g (97%) of 19 which was further used without an additional purification.