Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]5[CH:29]=[N:30][N:31]([CH2:33][C@H:34]6[O:39][CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]6)[CH:32]=5)[N:22]=4)[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH:36]1[CH2:37][CH2:38][O:39][C@H:34]([CH2:33][N:31]2[CH:32]=[C:28]([NH:27][C:23]3[N:22]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([C:12]5[N:11]=[CH:10][C:9]([CH:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[CH3:8])=[CH:14][N:13]=5)[CH2:20][CH2:19]4)[N:26]=[CH:25][N:24]=3)[CH:29]=[N:30]2)[CH2:35]1
Reactant: CC(c1ccccc1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CN(C(=O)OC(C)(C)C)CCO5)c4)n3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccccc1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CNCCO5)c4)n3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-tert-butyl 2-((4-(4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (130 mg, crude) in dichloromethane (6 mL) was dropwise added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 0.5 hour and then concentrated. The residue was purified by Prep-HPLC to provide N-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amine as a white solid, which was then separated by Chiral-HPLC to afford N-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-((R)-1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amine as a white solid (15.4 mg, 17%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C@H:26]1[C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH2:29][NH:28][CH2:27]1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:28]2[CH2:29][CH2:30][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH2:27]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccccc1[C@@H]1CNCC[C@@H]1c1ccccc1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccccc2Cl)C1

Procedure:
The title compound, MS: m/e=512.2 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3-(2-chloro-phenyl)-4-phenyl-piperidine hydrochloride.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-BOC-3-hydroxyazetidine (1.0 g, 5.77 mmol), 4-dimethylaminopyridine (7 mg, 0.058 mmol) and triethylamine (0.880 mL, 6.35 mmol) in DCM (15 mL) cooled at 0° C. was added dropwise methanesulfonyl chloride (0.45 mL, 5.77 mmol). The RM was stirred 18 h at rt, diluted with DCM, washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. 3-Methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester obtained as an oil was used directly in the next step. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g 5.57 mmol) in DMF (20 mL) stirred at 0° C. was added sodium hydride (55% in oil, 0.243 g, 5.57 mmol). After addition the mixture was stirred 1 h at rt, a solution of the above obtained 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 5.57 mmol) in DMF (3 mL) was added. The RM was stirred 30 min at rt, and then 3 h at 95° C. After cooling at rt the mixture was poured in ice water and extracted with EtOAc. The combined organic phases were washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (with heptane and EtOAc as eluants) to afford the title compound as an oil (tR 4.33 min (conditions 3), MH+=350.1)
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chloroacetyl chloride (0.37 ml, 4.6 mmol) was added to a solution of indoline (0.47 ml, 4.19 mmol) and triethylamine (TEA; 0.70 ml, 5.03 mmol) in dichloromethane (DCM; 15 ml). The mixture was stirred for 3 hrs at room temperature (RT) and then quenched with water (5 ml). The phases were separated and the aqueous layer was extracted with DCM (3×5 ml). The combined organic layers were dried over MgSO4 and concentrated to a dark brown residue, 1 g (quantitative), which was used for the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:21]=2)[CH2:16][CH2:15]1>C(Cl)Cl.CN(C=O)C>[C:40]([N:37]1[CH2:38][CH2:39][N:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:22]3[N:21]=[C:20]([N:17]4[CH2:16][CH2:15][CH:14]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:19][CH2:18]4)[C:25]([F:26])=[CH:24][N:23]=3)=[CH:29][CH:30]=2)[CH2:35][CH2:36]1)(=[O:42])[CH3:41]
Reactant: N#CCC(=O)O
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(N)CC4)n3)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)CC#N)CC4)n3)cc2)CC1
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF) at room temperature, oxalyl chloride (0.082 mL, 0.94 mmol) was added. Gas evolved and suspension became clear. It was then stirred for 30 min. To the above solution cooled in an ice bath, a solution of 1-(4-(4-(4-(4-aminopiperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (70 mg, 0.17 mmol) and TEA (0.478 mL, 3.43 mmol) in DMF (2 mL) was added drop wise. The mixture was then stirred at room temperature for 3 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 481.5 (M+H); UV 204.7, 266.3 nm
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:12][CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 1,2,3,4-tetrahydro-2-naphthoic acid (2.50 g, 14.2 mmol) in 100 ml THF was treated with LiAlH4 (681 mg, 17.04 mmol) and the reaction mixture was heated at reflux for 5 hours. The suspension was cooled to 0° C.. and quenched by addition of solid Na2SO4 .box-solid.10H2O. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration. Concentration of filtrate in vacuo gave a yellowish oil (2.28 g, 98.8%); 1H NMR (CDCl3, 300 MHz) δ 1.43 (m, 1H), 2.00 (m, 2H) 2.51 (dd, J1 =16.5 Hz, J2 =10.8 Hz, 1H), 2.85 (m, 3H), 3.65 (dd, J1 =6.3 Hz, J2 =1.2 Hz, 2H), 7.09 (s, 4H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:12]1)[CH2:8]2.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[CH2:16]([CH:13]1[N:12]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[C:21]([F:20])([F:30])[F:31])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: FC(F)(F)c1ccccc1CBr
Product: CCCCC1C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1C(F)(F)F

Procedure:
2-(Adamantan-2-yl)-4-butyl-1,2-diazetidin-3-one and 2-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:20]2=[CH:21][CH:22]=[N:23][CH:24]=[C:19]2[C:5]2[C:6]([OH:18])=[CH:7][C:8]([CH:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:26].[N:27]1([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:26].[CH3:25][C:2]1([CH3:1])[C:20]2=[CH:21][CH:22]=[N:23][CH:24]=[C:19]2[C:5]2[C:6]([O:18][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:7][C:8]([CH:10]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC(c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2)C1CCCCC1
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2)C1CCCCC1

Procedure:
5,5-Dimethyl-8-(1-cyclohexylethyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(1-cyclohexylethyl)-5H[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][CH2:7][C:4]1[N:3]=[C:2]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[O:10][CH3:9])[S:6][N:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: ClCc1nsc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(CCl)ns2)c(OC)c1
Reaction time: 8 h

Procedure:
5-Chloro-3-chloromethyl-[1,2,4]thiadiazole (10 mmol) is added to a solution of 2,4-dimethoxybenzylamine (10 mmol) in THF at room temperature followed by addition of DIEA (10 mmol). The mixture is stirred overnight. The white precipitate is filtered and washed with THF. The filtrate is concentrated to oil and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([O:23]C)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C:15]([F:17])([F:16])[F:18])[C:11](=[O:19])[N:10]([CH2:20][C:21]([OH:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 176A, 1.27 g (3.49 mmol), were introduced in 200 ml of methanol and 100 ml of water. Then 6.98 ml (6.98 mmol) of 1M aqueous lithium hydroxide solution were added. The mixture was stirred at RT for 2 h. For purification, 15 ml of 1N hydrochloric acid were added and the mixture was freed from methanol on a rotary evaporator. The residue was diluted with 100 ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator, and dried in an HV. This gave 1.11 g (91% of theory) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)C.[NH4+:13].[OH-]>>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([NH2:13])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)Cc1csc(N)n1
Temperature: 50 °C
Yield: 47.4 %

Procedure:
A 18 ml vial was loaded with (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (500 mg, 2.68 mmole) and 5 ml of 30% NH4OH. The vial was sealed and the mixture was heated at 50° C. for 3 days. The mixture was cooled down and concentrated to half. The suspension was filtered off, solid was washed with water and dried to give 200 mg product, 47.4% yield
Reaction SMILES: [Cl:1][C:2]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.O.[CH3:16]O>>[Cl:1][C:2]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:3][C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: CC(C)(C)C(Cl)=CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)C=C(Cl)C(C)(C)C
Yield: 87 %

Procedure:
To a solution of 3-chloro-4,4-dimethylpent-2-enoic acid (0.8 g, 4.92 mmol) in methanol (20 mL) was added thionyl chloride (0.714 mL, 9.846 mmol) drop wise under stirring at ice cold temperature. The reaction mixture was refluxed for 2 h and attained to rt. The mixture was poured into ice cooled water and stirred for 15 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine, dried over sodium sulfate and filtered. Solvent was evaporated and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as eluents to give the product as a pale green color oil (750 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 6.08 (1H, s), 3.75 (3H, s), 1.24 (9H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@H:2]2[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CC=C[C@@H](c2ccccc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 18.4 %

Procedure:
To a solution of (3S,7S)-3-amino-1-methyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (1f) (120 mg) in DCM (6 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (135 mg), HOBt-hydrate (186 mg), EDAC.HCl (160 mg) and N-methyl morpholine (92 mg). The reaction mixture was stirred 1 h at 0° C. and 2.5 h at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1% MeOH/DCM) to afford the title compound as an off-white solid (45 mg, 19%). 1H NMR (300 MHz, CDCl3) δ 1.41 (d, 3H), 2.18-2.29 (m, 1H), 2.54 (s, 3H), 2.79-2.87 (m, 1H), 3.55 (s, 2H), 4.47-4.57 (m, 1H), 5.45-5.54 (m, 1H), 5.86 (m, 2H), 6.14-6.19 (m, 1H), 6.29 (bd, 1H), 6.69-6.76 (m, 1H), 6.84 (bd, 2H), 7.22-7.45 (m, 5H). MS APCI, m/z=464 (M+Na). LC/MS 2.52 min., Method A.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[N:3]=1.[O-]Cl.[Na+].[NH4+:17].[OH-]>[OH-].[Na+].O>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:17])[S:6][N:5]=1
Reactant: Fc1ccccc1-c1nsc(S)n1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccccc2F)ns1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 29.5 g of 5-mercapto-3-(2-fluorophenyl)-1,2,4-thiadiazole in 550 ml of 4.5% NaOH and a solution prepared by diluting 180 ml of 10% NaOCl to 550 ml with water were added dropwise simultaneously to 1450 ml of NH4OH solution maintained at 0° C. with an ice/methanol bath. The resulting mixture was stirred for 30 minutes and the solids were collected, washed with water and dried under high vacuum (P2O5) to give 19.0 g of solid, mp 151°-2° dec.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:22]C1C=CC(C(O)=O)=C(F)C=1>>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Product: CCOP(=O)(C=C1NCCN(C)c2cc(Cl)ccc21)OCC

Procedure:
(8-chloro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, as described in Example 1 by replacing 2-fluorobenzoic acid with 4-chloro-2-fluorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([Cl:19])[N:11]=1>C(O)C>[Cl:19][C:12]1[N:11]=[C:10]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1Cl
Temperature: 180 °C
Yield: 58.8 %

Procedure:
2-Chloroaniline (1.32 mL, 10.4 mmol) was added to 2,6-dichloro-3-nitropyridine (1.00 g, 5.18 mmol) in ethanol (4 mL) and the solution was heated to 180° C. for 12 minutes under microwave irradiation in a heavy walled sealed tube. After cooling to room temperature, the resulting precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound (0.8650 g). LCMS m/z=284.1 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 6.97 (d, J=8.6 Hz, 1H), 7.23 (td, J1=7.8 Hz, J2=1.6 Hz, 1H), 7.41 (td, J1=8.0 Hz, J2=1.5 Hz, 1H), 7.55 (dd, J1=8.0 Hz, J2=1.5 Hz, 1H), 8.20 (dd, J1=8.2 Hz, J2=1.50 Hz, 1H), 8.54 (d, J=8.6 Hz, 1H), 10.36 (broad s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[CH3:19][NH:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)c1ccc(C(C)N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC(C)c1ccc(C(C)C)cc1
Yield: 69.4 %

Procedure:
A suspension of 1-(4-isopropylphenyl) ethylamine (81 g) was stirred vigorously in a solution of sodium hydroxide (50 g) in water (250 ml) at room temperature. Dimethyl sulphate (64 g) was added dropwise to the stirred suspension over a period of 1 hour. The suspension was stored in a refrigerator overnight and three layers were formed. The top layer of organic material was extracted with ether and the ether solution was separated and dried over anhydrous magnesium sulphate. The ether was evaporated under reduced pressure to give a yellow oil which was distilled at a water pump to give N-methyl-1-(4-isopropylphenyl) ethylamine (61 g, 69%) colourless oil, boiling point 112° to 114° C./20 mm.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:5][C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[C:3]1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO>[O:1]=[C:2]1[NH:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:5][C:4]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[C:3]1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23]
Reactant: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)[nH]c1=O

Procedure:
This compound is prepared according to general method D from methyl 2-(6-oxo-2-(piperidin-1-yl)-4-p-tolyl-1,6-dihydropyrimidin-5-yl)pentanoate (1 eq), sodium hydroxide 10N (10 eq) in methanol (6 mL/mmol) at 60° C. for 18 h. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in water and extracted with diethyl ether. The pH of the aqueous layer is adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The suspension is extracted twice with ethyl acetate and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([O:28][C:29](=[O:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)C>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][C:29]([OH:45])=[O:28])[CH:35]=5)[CH:25]=[CH:24][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: O=C(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid ethyl ester to give 152. MS (ESI+) 477.0. 1HNMR (400 MHz, DMSO) δ 13.61-12.69 (br, 1H), 8.31-8.26 (m, 2H), 8.25 (s, 1H), 7.99 (s, 1H), 7.44 (dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.95 (s, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H)
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH:23]=O)[CH:22]=1)=[O:17].C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH2:23][NH:7][C:4]2[CH:3]=[CH:2][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)[CH:22]=1)=[O:17]
Reactant: COC(=O)c1cc(C=O)c(C)o1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A solution of biphenyl-4-ylamine (150 mg, 0.883 mmoles) and 4-formyl-5-methyl-furan-2-carboxylic acid methyl ester (157) (135 mg, 0.803 mmoles) in methanol (2.0 ml) was stirred over molecular sieves (type 3 Å) for 1 hour. Sodium cyanoborohydride (55 mg, 0.883 mmoles) was added and the mixture stirred for 18 hour at room temperature. The mixture was concentrated and partitioned between ethyl acetate (25 ml) and saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was re-extracted with ethyl acetate (2×25 ml) and the combined extracts were washed with brine (50 ml) and dried (MgSO4). After removal of the solvent, the residue was purified by by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158(75 mg).