Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.0241 mL, 0.297 mmol) at room temperature followed by methanesulfonyl chloride (0.0120 mL, 0.149 mmol) and the reaction mixture stirred for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 22 as described in general methods) to obtain N-(5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)methanesulfonamide (50.0 mg, 69.8%) as a white solid. LCMS (Condition 4): retention time 2.45 min, [M+1]=482.2. HPLC (Condition 28): retention time=6.83 min, purity 97.53%. 1H NMR (400 MHz, DMSO-d6) δ 2.97 (s, 3 H), 4.51 (d, J=4.8 Hz, 2 H), 5.06 (t, J=4.8 Hz, 1 H), 7.02-7.03 (m, 2 H), 7.22-7.28 (m, 3 H), 7.43-7.52 (m, 5 H), 7.68 (dd, J=2.4 Hz, J=5.6 Hz, 1 H), 7.72 (br s, 1 H), 7.87-7.90 (m, 2 H), 8.35 (br s, 1 H), 8.40 (d, J=1.6 Hz, 1 H), 10.25 (br s, 1 H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CN(C=O)C.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:4][CH2:3][CH2:2][N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][CH2:6][O:7][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCNCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCCN(CCOCc2ccccc2)Cc2ccccc2)cc1
Reaction time: 8 h

Procedure:
Diethanolamine (42.0 g., 0.4 mole) is stirred under nitrogen in 800 ml. of dry DMF at 0° C. and 50% NaH in mineral oil (57.6 g., 1.2 mole) is added in small portions. After the sodium hydride has reacted, benzyl bromide (205.3 g., 1.2 mole) is added dropwise. The mixture is allowed to come to room temperature while stirring overnight. The reaction mixture is poured into water and is extracted with ether. The ether solution is extracted with dilute HCl. The acid extract is basified with NaOH and extracted with ether. Crude product is recovered by drying, filtering and evaporating the ether. The residual liquid (138.4 g.) is subjected to distillation at 290° C. and 0.01 mm. to remove volatile impurities. This gives 114.4 g. of amber oil.
Reaction SMILES: C(O[C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])C.[OH-].[Na+].[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH2:34])[CH2:29][O:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(O)C>[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH:34][C:4]([C:6]2[S:14][C:9]3=[CH:10][N:11]=[CH:12][CH:13]=[C:8]3[C:7]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[O:5])[CH2:29][O:28]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: CCOC(=O)c1sc2cnccc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)OC[C@H](CONC(=O)c2sc3cnccc3c2Nc2ccc(I)cc2F)O1
Temperature: 65 °C
Reaction time: 19 h
Yield: 66.9 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (50 mg, 0.11 mmol), 1N aqueous NaOH solution (0.12 ml, 0.12 mmol) and ethanol (2 ml) was heated at 65° C. for 45 minutes. The reaction mixture was concentrated then azeotroped with toluene (2×2 ml) to give a solid residue. The solid residue was dissolved in anhydrous THF (4 ml) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (27 mg, 0.23 mmol), EDCI (27 mg, 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59 μl, 0.34 mmol) were added. After stirring for 19 hours the solvent was evaporated and the residue partitioned between ethyl acetate (20 ml) and water (15 ml). The organic layer was isolated, dried over sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 80:20 to 0:100) to afford the title compound as an orange oil (40 mg, 66%). LCMS (method B): RT=3.30 min, M+H+=544.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]2[CH2:8][C:9]3[C:14]([CH2:15][CH:3]12)=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][CH:10]=3.[I:18]I.N.CO.CCOC(C)=O>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]2[CH2:8][C:9]3[C:14]([CH2:15][CH:3]12)=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:10]=3[I:18]
Reactant: COc1cccc2c1CC1C(C2)OCCN1C
Reactant: II
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(I)c2c1CC1C(C2)OCCN1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
A solution of 4-methyl-6-methoxy-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazine (0.37 g, 1.6 mmol) was dissolved in 7 ml of AcOH and heated to 50° C. To the solution of the amine was added a solution of Hg(OAc)2 (0.62 g, 19 mmol) and I2 (1.0 g, 3.8 mmol) in 30 ml of AcOH. The resulting solution was stirred for 1 h at 50° C. and 1.5 h at 25° C. The reaction mixture was filtered to remove mercury salts and concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (5% NH3 sat'd MeOH-EtOAc) to yield 0.25 g (44%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 2.04 (m, 1H), 2.32 (dd, 1H, J=11.0, 18.0 Hz), 2.41 (s, 3H), 2.49 (m, 1H), 2.62 (dd, 1H, J=11.0, 17.0 Hz), 2.76 (m, 1H), 3.12 (dd, 1H, J=6.0, 17.0 Hz), 3.33 (dd, 1H, J=5.6, 17.0 Hz), 3.56 (m, 1H), 3,81 (s, 3H), 3.88 (m, 2H), 6.47 (d, 1H, J=7.8 Hz), 7.66 (d, 1H, J=7.8 Hz).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[S:28][C:29]([CH:32]2[CH2:34][CH2:33]2)=[N:30][N:31]=1>C(#N)C>[CH:32]1([C:29]2[S:28][C:27]([CH2:26][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])=[N:31][N:30]=2)[CH2:34][CH2:33]1
Reactant: BrCc1nnc(C2CC2)s1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(C2CC2)s1
Yield: 61 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.200 g, 0.793 mmol) in anhydrous acetonitrile (30 mL) was added Cs2CO3 (0.298 g, 0.915 mmol) and 2-(bromomethyl)-5-cyclopropyl-1,3,4-thiadiazole (0.300 g, 1.37 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.189 g, 61% yield): MS (ES) m/z 390 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH:32]1[CH2:37][CH2:36][N:35](C(OCC)=O)[CH2:34][CH2:33]1)=[O:17].C(OCC)(=O)C>Br.O.[OH-].[NH4+]>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)N1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)CC1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCNCC3)c2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
ethyl 4-{[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}piperidine-1-carboxylate (198 mg, 0.313 mmol) were dissolved in 62% aqueous HBr (4 mL) in a screw cap pirex tube and stirred at 70° C. for 1 hour. The mixture was then diluted with water and 30% ammonium hydroxide and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated to dryness. After purification by chromatography on silica gel (DCM/MeOH/NH3 7% in MeOH, 80:10:10) 127 mg of pure product were obtained (72% yield). The product was slurried with ethyl acetate, filtered, washed with n-hexane and dried at 45° C. under high vacuum for 3 hours to give 88 mg of title compound as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]([S:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:40])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Sc2nc3cc([N+](=O)[O-])ccc3[nH]2)c(-c2ccccn2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(S(=O)c2nc3cc([N+](=O)[O-])ccc3[nH]2)c(-c2ccccn2)c1
Reaction time: 0.5 h

Procedure:
A solution of the sulphide of step (a) above (1.15 mmoles) in methanol (70 ml)/dichloromethane (50 ml) was stirred at 10°. Solid m-chloroperbenzoic acid (80%; 1.38 mmoles) was added portionwise over 5 minutes. The solution was stirred at 10° for a further 30 minutes and then concentrated to approximately 25 ml. Silica gel (approximately 10 g) was added and the remaining solvent removed. Flash chromatography using dichloromethane containing 20 % ethyl acetate as eluant gave a pale orange solid (0.20 g) which was slurried in dichloromethane (50 ml) and filtered to give the title compound as an off-white solid, mp 208°-9° (dec).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C.CCOCC>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 65 °C
Reaction time: 120 h
Yield: 76.6 %

Procedure:
4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77%).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32]>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:1]([C:2]2[CH:3]=[CH:4][N+:5]([O-:8])=[CH:6][CH:7]=2)=[O:10])=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
A suspension of isonicotinic acid 1-oxide (4.16 g, 29.9 mmol) and 1,1'-Carbonyldiimidazole (5.33 g, 32.9 mmol) in dry dimethylformamide (50 ml) was stirred for 40 minutes under an air-lock and treated with 4-chloro-3-trifluoromethylbenzenamine (6.43 g, 32.9 mmol). The reaction mixture was heated at 100° for 5.3 hours and cooled to room temperature. The solution was evaporated in vacuo and the residue triturated with ethanol (2×20 ml) to give the title compound (5.379 g), m.p. 263°-265°.
Reaction SMILES: C(NC(=O)C(C)=CC1C=C(OC)C(OC)=CC=1N)CC1C=CC=CC=1.C([O:28][C:29](=[O:44])[C:30]([CH3:43])=[CH:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[NH2:42])C.[OH-].[Na+].Cl>O1CCCC1>[NH2:42][C:33]1[CH:34]=[C:35]([O:40][CH3:41])[C:36]([O:38][CH3:39])=[CH:37][C:32]=1[CH:31]=[C:30]([CH3:43])[C:29]([OH:44])=[O:28]
Reactant: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1N
Agent: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N)c(C=C(C)C(=O)O)cc1OC

Procedure:
Into 10 ml of tetrahydrofuran (THF), 1.0 g of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid ethyl ester was dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted at 40° C. for 4 hours. After the completion of the reaction, the mixture was cooled with 10 ml of 1-N hydrochloric acid being added thereto, and the precipitated crystal was filtered out, whereby 0.85 g of the aimed compound was obtained (95%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=S.C(N)CCC.[CH2:11]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C(OCC)(=O)C>[ClH:3].[CH2:20]([N:15]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22][CH3:23]
Reactant: S=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCCCN
Product: Cl

Procedure:
To this end, thiophosphoryl chloride and a primary alkylamine, for example n-butylamine, are reacted in molar ratios of preferably 0.9 to 1.1 mol of amine per mole of thiophosphoryl chloride in an inert solvent, for example ethyl acetate. The auxiliary base used is a trialkylamine, for example tri-n-butylamine, which is reacted to give the tri-n-butylamine hydrochloride. In a second reaction step, the N-alkylthiophosphoryl dichloride which has been formed in the first reaction is reacted with ammonia at temperatures of between preferably −20° C. and 50° C. to give the desired product N-alkylthiophosphoric triamide. In parallel with, and independently of, the second reaction step, ammonia acts as base 2 and accepts the hydrogen chloride from the trialkylamine hydrochloride with formation of ammonium chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: N#Cc1ccccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: N#Cc1ccccc1OCCCN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 7.41 g (0.025 mole) of [4-[bis(4-fluorophenyl)methyl]piperidine, 4.90 g (0.025 mole) of 2-(3-chloropropoxy)benzonitrile, and potassium carbonate, 5.54 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was concentrated to dryness and the resulting residue was partitioned several times between water and chloroform. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give a brown oil. The oil was triturated with ethyl ether and placed in a freezer overnight. White crystals were obtained and dried in vacuo overnight at room temperature. A yield of 5.15 g (46.1%) of analytically pure material, m.p. 88.5°-90° C., was obtained.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9]2)C=CC=CC=1.Cl>[OH-].[Pd+2].[OH-].C(O)C>[NH:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:9]1
Reactant: N#CC1(c2ccc(OCC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)CCOCC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: N#CC1(c2ccc(OCC3CNC3)cc2)CCOCC1
Yield: 38.6 %

Procedure:
4-(4-{[1-(diphenylmethyl)azetidin-3-yl]methoxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile (0.605 g, 1.38 mmol), palladium hydroxide (0.08 g), concentrated hydrochloric acid (0.115 mL, 1.38 mmol), and ethanol (8 mL) were combined and hydrogenated for 18 hours at 40° C. at 40 psi. The mixture was filtered through Arbocel® and rinsed with ethanol. The filtrate was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with 10% aqueous sodium carbonate (20 mL). The organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a green oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1) to provide the title compound (0.145 g, 39%) as a yellow oil. LRMS APCI+ m/z 273 [MH]+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:24].Cl.[CH2:27](O)[CH2:28][CH2:29]C>>[CH2:2]([O:3][C:4]([C:5]1[N:6]=[C:14]([OH:15])[C:13]2[C:8]([C:7]=1[OH:24])=[CH:9][CH:10]=[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:12]=2)=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCO
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)cc3)cc2C1=O
Agent: Cl
Agent: [Na]
Product: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc(F)cc3)ccc2c1O
Temperature: 70 °C

Procedure:
Sodium (7.2 g, 310 mmol) was dissolved in n-butanol (300 ml) with stirring at 70° C. Afterwards, the temperature was raised to 95-100° C. and a solution of [5-(4-Fluoro-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester (49.4 g, 150 mmol) in hot n-butanol (300 ml) was added with vigorous stirring. The mixture was stirred for another 90 min at 95-100° C. and was then allowed to cool to 60° C. with stirring before 2 N HCl (160 ml) was added. The mixture was stirred vigorously for 30 min and was then allowed to cool to ambient temperature. Subsequently, the mixture was submitted to vacuum filtration. The filter cake was washed thoroughly with water and dried in vacuo at 70° C. to give a pale yellow solid. Purification by flash column chromatography on silica gel using CH2Cl2 EtOAc=98 2 as the eluent gave the title compound (14.4 g, first fraction); 1H NMR (CDCl3) δ=8.40 (br s, 1H), 8.14 (d, 1H), 7.80 (d, 1H), 7.42 to 7.48 (m, 1H), 7.04 to 7.14 (m, 4H), 4.39 (t, 2H), 1.70 to 1.85 (m, 2H), 1.37 to 1.55 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:5]([C:7]1[S:20][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6].CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([NH:1][CH2:2][CH2:3][N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:5]([C:7]1[S:20][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6])(=[O:39])[CH3:38]
Reactant: NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Yield: 17.4 %

Procedure:
To a solution of N-(2-aminoethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 131 (0.300 g, 0.6 mmol) in methylene chloride (1.5 ml) was added DIEA (0.262 ml, 1.5 mmol). The reaction mixture was cooled with an ice water bath and acetyl chloride (0.0944 g, 1.2 mmol) was added drop-wise via syringe. The reaction mixture was stirred at cool temperature for 30 minutes and equilibrated to room temperature. The reaction mixture was washed with water, then saline and concentrated to a solid. The crude solid was taken into DMF and purified by RP-HPLC to give 46 mg of 258 (yield 18% of theoretical). MS: (ESI+) 441.1
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH3:17][NH:18][CH3:19]>CC(C)=O>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:18]([CH3:19])[CH3:17])[N:3]=[CH:4][N:5]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C)c1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 45 °C
Yield: 92.9 %

Procedure:
To a mixture of 7.76 g of 4, 6-dichloro-5-nitropyrimidine, 3.70 g of sodium hydrogencarbonate and 80 ml of acetone was gradually dropwise added 50% aqueous dimethylamine (3.79 g) with ice cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. Every 30 minutes, 50% aqueous dimethylamine (0.7 g) was added three times to the mixture, and the solvent was evaporated in vacuo. The residue was mixed with 70 ml of ethyl acetate, heated at 45° C. and the insoluble material was filtered off. The filtrate was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was mixed with n-hexane and triturated. The precipitated crystals were filtered off to give 7.53 g of 4-chloro-6-dimethylamino-5-nitropyrimidine.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12e and 4-bromoanisole