Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=1)(=[O:5])=[O:4].[ClH:24]>CN(C=O)C.[Pd]=O>[ClH:24].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide (8.6 kg) and 10% palladium oxide on charcoal (2.58 kg, 50% wet pastel in DMF (86 L) and 2 N hydrochloric acid (12.3 kg) was hydrogenated at atmospheric pressure over 21 h. The catalyst was removed by filtration. The filter cake was washed with DMF/water (1:1; 30 L). The combined washings and filtrate were then treated with decolourising charcoal (0.86 kg) at 75°-80° for 2 h. The suspension was filtered and the residue washed with DMF/water (2×30 L). The filtrates from two hydrogenations could be combined for work-up. Thus the combined solutions were treated with 2M hydrochloric acid (1.72 L) then concentrated in vacuo to approximately 52 L. Ethyl acetate (120 L) was added, the resulting suspension cooled to 3° and aged for 1 h. The product was collected by filtration, washed with ethyl acetate (2×26 L) and dried in vacuo at 40°-50° overnight (15.96 kg, 83% of theory). Recrystallisation from hot IMS/water (7:1; 206 L) gave fine, off-white crystals (13.02 kg, 84% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:19][CH:18]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:34])[C:7]=2[CH:35]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:22]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:34])[C:7]=2[CH:35]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl](methyl)amino}propanoate (350 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (308 mg, 94%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:10]=[C:9]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=1.[OH-].[Na+]>CN(C=O)C.O>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:9]2[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH:7]=3)[N:12]=[C:11]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: COC(=O)CCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 3-[4-(3-chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionic acid methyl ester (1.04 g, 2.39 mmol, 1.0 eq.) in DMF (20 mL) was added a solution of NaOH (0.57 g, 14.3 mmol, 6.0 eq.) in H2O (8 mL). The mixture was stirred at room temperature for 2 h. 50 mL of water was added to the mixture. After filtration, the resulting filter cake was washed with water and dried in vacuo to give 933 mg of xxx-a as a yellow solid (yield 93%). LCMS m/z=423.1, 425.1 (M+1) (Method A) (retention time=1.51 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16]C#N)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.SC[C@H]([C@@H](CS)O)O.OP([O-])(O)=O.[K+]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([SH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2
Reactant: COC(=O)COc1ccc(SC#N)c2c1CCCO2
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CO
Product: COC(=O)COc1ccc(S)c2c1CCCO2
Yield: 60.7 %

Procedure:
A solution of (8-thiocyanato-chroman-5-yloxy)-acetic acid methyl ester (1.3 g, 4.6 mmol), dithiothreitol (910 mg, 6 mmol), and KH2PO4 (4.6 mL of a 0.02M solution) in 30 mL MeOH was heated at reflux for 1 hour after which time the reaction was cooled and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 10% EtOAc/hexanes to 35% EtOAc/hexanes) gave the title compound (710 mg, 61%) as a pale yellow solid. 400 MHz 1H NMR (DMSO-d6) δ 6.97 (d, 1H, J=8.5 Hz), 6.31 (d, 1H, J=8.5 Hz), 4.70 (s, 2H), 4.40 (s, 1H), 4.11 (t, 2H, J=5.4 Hz), 3.63 (s, 3H), 2.56 (t, 2H, J=6.3 Hz), 1.84 (m, 2H).; MS m/z 255 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(CSC)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CSC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(methylthiomethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[NH:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[H-].[Na+].Cl[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[CH3:29][O:28][C:26](=[O:27])[NH:22][C:14](=[N:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][C:4]=1[Cl:12])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19]
Reactant: COC(=O)Cl
Reactant: N=C(Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)NC(=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
First, 0.18 g (0.50 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionamidine as present compound 4 was dissolved in 10 ml of N,N-dimethylformamide, to which 0.04 g (1.0 mmol) of sodium hydride (about 60% in oil) was added under ice cooling, and the mixture was stirred for 10 minutes. Then, 0.05 g (0.50 mmol) of methyl chloroformate was added to the reaction mixture, which was stirred at room temperature for 6 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.08 g of [1-(2,6-dichloro-4-trifluoromethylphenylimino)-2,2,3,3,3-pentafluoropropyl]carbamic acid methyl ester (hereinafter referred to as present compound 60).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[CH2:14]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1,4-dioxa-spiro[4.5]decan-8-ol (11.0 g, 70 mmol) in dry tetrahydrofuran (50 ml) is added dropwise to a stirred suspension of 60% sodium hydride disperse in mineral oil (2.80 g, 70 mmol) in dry tetrahydrofuran (50 ml). Once the addition is complete the reaction mixture is stirred for 2 hours at room temperature. A solution of benzyl bromide (13.2 g, 77 mmol) in dry tetrahydrofuran (50 ml) is added dropwise over a period of 20 minutes and stirred at room temp overnight. The reaction mixture is poured into water (200 ml), neutralised with 0.5 N aqueous hydrochloric acid and extracted with methylene chloride (2×100 ml). The combined organic layer was dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is absorbed onto silica gel and purified on flash chromatography to give 8-benzyloxy-1,4-dioxa-spiro[4.5]decane (16 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][C:8]1([OH:25])[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH:12]([N:10]1[CH2:9][C:8]([CH2:7][NH:6][C:3](=[O:4])[CH2:2][Cl:1])([OH:25])[CH2:11]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.846 mL) was added dropwise over 30 minutes to a vigorously stirred mixture of 3-(aminomethyl)-1-benzhydrylazetidin-3-ol (example 33, step c) (2.1 g) in ethyl acetate (100 mL) and potassium carbonate (3.03 g) in water (100 mL) at 0° C. The mixture was stirred for a further 30 minutes at 0° C. and then extracted with ethyl acetate, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.6 g.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15]>COCCOCCOC.C1COCC1>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOCCOC
Product: OCCCCCCCCCCCBr
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
Sodium Borohydride (28.8 g, 0.76 mole) was dissolved in diglyme (700 ml) and THF (300 ml) and the solution cooled to 20° (dissolution of the NaBH4 is slightly exothermic). BF3OEt2 (145 g, 1.02 mole) was then added dropwise, with external cooling, at such a rate to keep the temperature of the mixture below 15°. After the addition was complete the mixture was stirred for 0.5 hour at 10°. This reducing agent was then added slowly to a solution of 11-bromoundecanoic acid (200 g, 0.76 mole) in THF (400 ml) keeping the temperature below 20°. After the addition was complete, the reaction was stirred at room temperature for 1.5 hours then quenched by pouring onto water (3 L) and concentrated HCl (100 ml). The quenched mixture was stirred for 0.5 hour at room temperature then cooled to 5°. The crystalline product was filtered off, washed with water (3×1 L) and dried under vacuum to give 11-bromoundecanol (189.2 g, 99.2%).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(2-tert-butoxy-2-oxoethylamino)-4-oxobutanoate (40 mg, 0.088 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) is allowed to stir for 2 hours at room temperature. The reaction is concentrated under reduced pressure, and the obtained residue is suspended in DCM (0.5 mL) and heptane (2 mL), and collected on a funnel, giving (R)-3-biphenyl-4-ylmethyl-N-carboxymethyl-succinamic acid (9.6 mg). HPLC retention time=1.26 minutes (condition A); MS (m+1)=342.0; 1H NMR (400 MHz, CD3OD) δ ppm 2.39 (dd, J=16.67, 5.31 Hz, 1 H) 2.63-2.82 (m, 2 H) 2.98-3.14 (m, 2 H) 3.84 and 3.95 (AB, 2 H, J=17.8 Hz) 7.26-7.33 (m, 3 H) 7.40 (t, J=7.71 Hz, 2 H) 7.56 (dd, J=19.96, 8.08 Hz, 4 H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:12][N:11]=1)(=[O:25])=[O:24]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1ccc(COCC2CC2)cn1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1ccc(COCC2CC2)cn1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.06 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.096 g) as an off-white solid (0.069 g). MS (ESI−): 399.1 ([M−H]−)
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:24]4[CH:25]=[CH:26][C:21]([C:19](=[O:20])[CH3:18])=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cc1
Temperature: 120 °C
Yield: 22.2 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.15 g), 4-fluoroacetophenone (0.133 g) and potassium carbonate (0.177 g) were dissolved in DMSO (2 ml) and heated at 120° C. for 7 min in the microwave reactor. The crude reaction mixture was passed through an SCX column (10 g, eluting with methanol [80 ml] then 2 N NH3 in methanol [80 ml]). Chromatography of the crude ketone (silica gel, eluting with methanol/dichloromethane, 0-25%) afforded the title compound (E25) (0.05 g). MS electrospray (+ion) 355 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[Cl:14].[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][O:13][C:9]1[CH:10]=[C:11]([Cl:12])[C:6]([O:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])=[C:7]([Cl:14])[CH:8]=1)[CH3:20]
Reactant: Oc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1)OCC
Temperature: 90 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A mixture of 0.85 g of 4-(2-chlorobenzyloxy)-3,5-dichlorophenol, 0.47 ml of bromoacetaldehyde diethyl acetal, 0.46 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 90° C. for 6 hours. After cooling to room temperature, the reaction mixture was poured into ice water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, and dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 0.85 g of 4-(2-chlorobenzyloxy)-3,5-dichlorophenoxyacetaldehyde diethyl acetal (72% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH2:13]([NH2:16])[C:14]#[CH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[CH:15]=[CH:14][CH:13]=[N:16][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C#CCN
Reactant: O=C1CCc2cc(Br)ccc2C1
Product: Brc1ccc2c(c1)CCc1ncccc1-2
Yield: 69 %

Procedure:
The title compound is prepared from 6-bromo-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 69% of theory; Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CCCP(=O)O)=CC=3OC)N=2)=CC=1.[Br:38][C:39]1[N:44]=[C:43]([C:45](=[O:48])[NH:46][CH3:47])[C:42]([NH:49][C:50]2[C:55]([C:56]([F:59])([F:58])[F:57])=[CH:54][N:53]=[C:52]([NH:60][C:61]3[CH:75]=[CH:74][C:64]([CH2:65][CH2:66][CH2:67][CH2:68][PH:69](=[O:73])[O:70]CC)=[CH:63][C:62]=3[O:76][CH3:77])[N:51]=2)=[CH:41][CH:40]=1>>[Br:38][C:39]1[N:44]=[C:43]([C:45](=[O:48])[NH:46][CH3:47])[C:42]([NH:49][C:50]2[C:55]([C:56]([F:59])([F:57])[F:58])=[CH:54][N:53]=[C:52]([NH:60][C:61]3[CH:75]=[CH:74][C:64]([CH2:65][CH2:66][CH2:67][CH2:68][PH:69](=[O:70])[OH:73])=[CH:63][C:62]=3[O:76][CH3:77])[N:51]=2)=[CH:41][CH:40]=1
Reactant: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)O)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 67B replacing Compound 67C with ethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinate (Compound 74C). MS (ESI): m/z 617.55/619.52 [M+H]+. UPLC: tR=1.31 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][N:20]([CH2:23][O:24]CC[Si](C)(C)C)[C:18]=3[N:19]=2)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][N:20]([CH2:23][OH:24])[C:18]=3[N:19]=2)[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(N2CCN(c3ccccc3F)CC2)nc2c1ccn2CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
A solution of 2-(4-(2-fluorophenyl)piperazin-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (30 mg, 67.6 μmol) in methylene chloride (3.38 mL) was treated dropwise with trifluoroacetic acid (1.13 mL). The reaction was stirred at room temperature for 2 h, and was then concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 40-80% ethyl acetate/hexanes) afforded 2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-7-hydroxymethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light grey solid (11.2 mg, 48.2%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.97-3.15 (m, 4H) 3.71 (d, J=5.08 Hz, 4H) 5.32 (d, J=7.42 Hz, 2H) 6.28 (d, J=3.52 Hz, 1H) 6.31-6.39 (m, 1H) 6.85 (d, J=3.52 Hz, 1H) 6.93-7.21 (m, 4H) 10.89 (s, 1H). LC-MS calcd. for C17H19FN5O2 [(M+H)+] 344, obsd. 344.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([C:15](OC)=[O:16])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([CH2:15][OH:16])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1CN1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1CN1CCOCC1
Temperature: 0 °C

Procedure:
Methyl 6-chloro-2-(morpholin-4-ylmethyl)pyridine-3-carboxylate (0.5 g, 1.847 mmol) was take up in THF (9 mL) and cooled to 0° C. LiAlH4, 2 M in THF (1.847 mL, 3.69 mmol) was added dropwise and the resulting mixture maintained at 0° C. for 5 hours. Saturated aqueous NH4Cl was added and the products extracted into EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (12-100% EtOAc-hexanes followed by 0-10% MeOH-EtOAc) gave the title compound as a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2.[CH:16]([NH2:19])([CH3:18])[CH3:17]>O1CCOCC1>[CH:16]([NH:19][CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)([CH3:18])[CH3:17]
Reactant: c1cc2c(c(OCC3CO3)c1)SCCC2
Reactant: CC(C)N
Solvent: C1COCCO1
Product: CC(C)NCC(O)COc1cccc2c1SCCC2

Procedure:
A mixture of 6.9 g of crude 8-(2,3-epoxy propyloxy) thiochroman prepared as described above, 26 ml of isopropylamine and 53 ml of dry dioxan were refluxed for 20 hours. The reaction mixture was then evaporated to dryness, under vacuum. The residue was taken up with chloroform and diluted hydrochloric acid. The acid aqueous phase was made alkaline with an aqueous sodium hydroxide solution. There were obtained 4.6 g of dl 8-(3-isopropylamino-2-hydroxy propyloxy) thiochroman, melting (K) at 90° to 92° C., which recrystallized in cyclohexane, melted at 91° to 92° C. 3.9 g of this base were dissolved in 20 ml of ethanol and a solution of dry hydrochloric gas in ether was added.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1.[ClH:18]>>[ClH:18].[OH:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1
Reactant: COCOc1cncc(N2CCCNCC2)c1
Agent: Cl
Product: Oc1cncc(N2CCCNCC2)c1

Procedure:
1-(5-Methoxymethoxy-3-pyridyl)-homopiperazine (8.5 g, 35.9 mmol) was stirred in hydrochloric acid (4 M, 100 ml) at room temperature for 1 h. The excess of hydrochloric acid was evaporated. A crystaline compound was obtained by triturating with a mixture of 5% methanol and ether. Yield 9.56 g, 100%. Mp 290-300° C.