Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10](S(C)=O)[C:9]([C:15]([NH2:17])=[O:16])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C@H:20]1[CH2:25][C@@H:24]([OH:26])[C@H:23]([CH3:27])[CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:1]([NH:5][C:6]1[N:11]=[C:10]([NH:19][C@@H:20]2[CH2:21][CH2:22][C@@H:23]([CH3:27])[C@H:24]([OH:26])[CH2:25]2)[C:9]([C:15]([NH2:17])=[O:16])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Reactant: CS(=O)c1nc(NC(C)(C)C)ncc1C(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC(C)(C)C)ncc2C(N)=O)C[C@H]1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a stirring suspension of 2-(tert-butylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (0.092 g, 0.359 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (0.065 g, 0.395 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.157 mL, 0.897 mmol) and the reaction was heated to 90° C. overnight. The crude reaction mixture was concentrated under reduced pressure and then ice-cold water (20 mL) was added to the residue. The resulting mixture was vigorously stirred for 1 h and then the product was filtered, washed with water and dried under vacuum to afford 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carboxamide (0.074 g, 0.230 mmol, 64.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (br. s., 1H), 8.34 (s, 1H), 6.69 (br. s., 1H), 4.59 (d, J=5.47 Hz, 1H), 3.87 (br. s., 1H), 2.92-3.01 (m, 1H), 2.14 (d, J=10.15 Hz, 1H), 1.91 (d, J=11.71 Hz, 1H), 1.67 (dd, J=13.28, 3.12 Hz, 1H), 1.07-1.24 (m, 3H), 0.91-0.99 (m, 4H). MS (ESI) m/z 322.3 [M+1]+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][CH:5]([O:9][CH3:10])[C:6](=[O:8])[CH3:7]>CO>[Br:1][CH2:7][C:6](=[O:8])[CH:5]([O:9][CH3:10])[O:4][CH3:3]
Reactant: COC(OC)C(C)=O
Reactant: BrBr
Solvent: CO
Product: COC(OC)C(=O)CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Bromine (80 g, 0.5 mol) is added dropwise to a solution of 1,1-dimethoxy-propan-2-one 205 (59 g, 0.5 mol) in anhydrous methanol (400 mL) at 0° C. and the solution is continued stirring at room temperature for 48 h. The solvent is removed under reduced pressure and the residue is dried in vacuo and used without further purification.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CS(C)=O>[O:3]=[C:2]1[NH:4][C:5](=[O:6])[CH:7]=[CH:8][N:1]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cn1ccc(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A dimethyl sulfoxide solution (150 mL) containing 10.02 g of uracil, 3.3 mL of ethyl bromoacetate, 13.85 g of potassium carbonate and 4.52 g of sodium iodide was stirred at 90° C. for six hours. The reaction mixture was poured over water and the mixture was extracted with chloroform. The extracts were combined, dried over sodium sulfate and concentrated in vacuo. The concentrate was poured over a saturated saline solution, the mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate. After concentration, the resulting residue was recrystallized from ethyl acetate to give 2.30 g of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-acetate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23]C)=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH2:14][CH2:13][CH2:12]2)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH2:14][CH2:13][CH2:12]2)[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(=O)[nH]c1-c1ccc2c(c1)CCCN2C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(c1)CCCN2C
Temperature: 65 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a suspension of methyl 5-ethyl-6-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (200 mg, 0.61 mmol) in THF (1 mL) and H2O (1 mL) was added LiOH—H2O (85 mg, 2.03 mmol, 3.3 eq) at room temperature. The reaction mixture was heated to 65° C. and stirred for 1 h. The reaction was monitored by LC-MS. Upon complete consumption of starting material, the reaction was quenched with 1N HCl (2 mL). The precipitate was collected by filtration then washed with Et2O to afford the title compound as a yellow solid (121 mg, 0.39 mmol, 14% over three steps).
Reaction SMILES: Cl[CH2:2][O:3][C:4]([N:6]1[C@H:11]([CH3:12])[CH2:10][O:9][C@:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[C@@H:7]1[CH3:22])=[O:5].[CH:23]1[CH:24]=[C:25]([CH2:28][NH:29][C:30]2[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:32]([Cl:43])[CH:31]=2)[O:26][CH:27]=1.[Cs].[I-].[Na+].CCCCCCC>O1CCCC1.C(OCC)(=O)C>[NH2:42][S:39]([C:33]1[C:32]([Cl:43])=[CH:31][C:30]([NH:29][CH2:28][C:25]2[O:26][CH:27]=[CH:23][CH:24]=2)=[C:35]([CH:34]=1)[C:36]([O:38][CH2:2][O:3][C:4]([N:6]1[C@H:11]([CH3:12])[CH2:10][O:9][C@:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[C@@H:7]1[CH3:22])=[O:5])=[O:37])(=[O:41])=[O:40]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1C(=O)OCCl
Agent: [Cs]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1C(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 60 °C
Yield: 13.3 %

Procedure:
To a stirring solution of (2S,3S,5R)-2-(3,5-difluorophenyl)-2-hydroxy-3,5-dimethylmorpholine-4-carboxylic acid chloromethyl ester (1410) (2.24 g, 6.67 mmol) in 150 mL of anhydrous tetrahydrofuran was added the furosemide cesium salt (10c) (3.09 gm, 6.67 mmol) and sodium iodide (1.10 gm, 7.34 mmol). The mixture was heated to ˜60° C. and monitored by TLC (1:1 heptane:ethyl acetate). After heating for 6 hours, TLC analysis indicated a slowing down of product formation with starting materials remaining. The reaction was halted so as not to allow by-product formation. The solvent was removed from the crude yellow mixture, and it was dried onto silica gel. This crude material was purified on an Optix Companion Automated Chromatography system using an 80 gm silica cartridge and eluting with ethyl acetate/heptane (0 to 70% over 50 minutes). This material was dried on a vacuum pump for 24 hours and afforded 0.560 g of (2S,3S,5R)-4-[5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (1420) as a light yellow foamy solid. Melting point range was 105° C. to 110° C. Elemental analysis calculated for [C26H26N3 0.3 EtOAc]: C, 49.76; H, 4.36; N, 6.4. found C, 50.08; H, 4.65; N, 6.23. 1H NMR (400 MHz, CDCl3) δ 0.86-0.89 (t, 3H), 1.34 (m, 3H), 3.60-3.67 (m, 1H), 4.23 (m, 1H), 4.33 (m, 1H), 4.45-4.46 (d, 2H), 4.47 (s, 1H), 5.07-5.11 (d, 2H), 6.00-6.05 (dd, 2H), 6.28 (s, 1H), 6.35 (s, 1H), 6.75-6.79 (t, 1H), 6.89 (m, 1H), 7.12-7.14 (br. d, 2H), 7.37-7.39 (d, 1H), 8.53 (br. d., 1H), 8.63 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][C:19]([NH2:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][C:19]([NH:22][C:29]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:30])([CH3:20])[CH3:21])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl-4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and cyclopentane carboxylic acid as a yellow solid (33%). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=4.0 Hz, 3H), 1.37 (s, 6H), 1.42-1.53 (m, 6H), 1.64-1.69 (m, 2H), 2.58 (m, 1H), 2.62 (s, 3H), 4.32 (s, 2H), 4.35 (m, 2H), 6.96 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.58 (m, 1H), 7.66 (s, 1H), 8.41 (d, 2H). MS 414 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([O-:11])=O)[CH2:4][CH:3]1[CH2:12][O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].[Na+].[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][NH2:33])=[N:30][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][NH:33][C:9](=[O:11])[CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH2:12][O:13][Si:14]([CH:21]([CH3:22])[CH3:23])([CH:18]([CH3:19])[CH3:20])[CH:15]([CH3:16])[CH3:17])[CH2:4]2)=[N:30][CH:31]=1
Reactant: CC(C)[Si](OCC1CN(CC(=O)[O-])CCN1C)(C(C)C)C(C)C
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)[Si](OCC1CN(CC(=O)NNc2ccc(F)cn2)CCN1C)(C(C)C)C(C)C
Reaction time: 18 h

Procedure:
To a mixture of Intermediate 56b (390 mg, 1.06 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (135 mg, 1.06 mmol) and HOBt.H2O (14.4 mg, 106 mop in DCM (15 mL) was added EDC (245 mg, 1.27 mmol) and stirred for 18 h. The mixture was washed with water, sat. aq. NaHCO3 and brine, and concentrated in vacuo to leave the title compound as a brown residue (412 mg, 86%). LCMS (Method 3): Rt 3.00 min, m/z 454 [MH+].
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][B:21]1OB(C)OB(C)O1>C1(C)C=CC=CC=1>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:8][B:21]([CH3:20])[N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Reactant: CB1OB(C)OB(C)O1
Solvent: Cc1ccccc1
Product: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Under argon stream, to a solution of (S)-α,α-diphenyl-2-pyrrolidine methanol (3 g, 11.8 mmol) in dry toluene (90 ml) was added trimethyl boroxine (1.13 ml, 8.0 mmol), followed by stirring for 1.5 hours. After the argon stream was stopped and the toluene (22.5 ml) was recovered under normal pressures on an oil bath at 140° C., dry toluene (22.5 ml) was added. Furthermore, after this recovery operation was repeated twice, the resultant product was concentrated under normal pressures, and subsequently under a reduced pressure, to thereby obtain the titled compound as a colorless crystalline.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH2:15])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH:15][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[N+:30]([O-:32])=[O:31])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCCOC(=O)c1cc2c(o1)c(N)nn2C(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)c1cc2c(o1)c(NC(=O)c1ccccc1[N+](=O)[O-])nn2C(=O)OCC
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
To a solution of 3-amino-furo[3,2-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester 5-propyl ester (500 mg, 1.606 mmol) and diisopropylethylamine (DIEA, 0.824 mL, 4.818 mmol) in tetrahydrofuran (THF, 20 mL) at 0° C., 2-nitro-benzoyl chloride (0.318 mL, 2.409 mmol) was added. The reaction mixture was kept at the same temperature for 10 minutes then allowed to reach room temperature and let react overnight. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (DCM) and washed with a 10% solution of acetic acid (AcOH), water, saturated NaHCO3 and brine. The crude was purified on silica gel (eluant dichloromethane/methanol 96/4) yielding 512 mg (69%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:26][C:24]1([CH3:27])[CH2:23][C:22]([CH3:28])([CH3:29])[CH2:21][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[CH2:25]1
Reactant: CC1(C)CC(c2ccccc2C2=CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(c2ccccc2C2=CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a solution of 4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (570 mg, 1.43 mmol) produced in Example (102d) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL), followed by stirring for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 430 mg of the title compound as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][N:16]=2)[CH:3]=1.C([N:28]([CH2:32][CH3:33])[CH:29](C)C)(C)C.N1CCC1>C(O)CCC>[N:28]1([C:2]2[N:7]=[C:6]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[N:5]=[C:4]([NH:14][C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[NH:17][N:16]=3)[CH:3]=2)[CH2:29][CH2:33][CH2:32]1
Reactant: Fc1cnc2[nH]nc(Nc3cc(Cl)nc(C4CCCCC4)n3)c2c1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Solvent: CCCCO
Product: Fc1cnc2[nH]nc(Nc3cc(N4CCC4)nc(C4CCCCC4)n3)c2c1
Temperature: 125 °C
Yield: 59.4 %

Procedure:
A mixture containing N-(6-chloro-2-cyclohexylpyrimidin-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (78 mg, 0.22 mmol), N, N-diisopropylethylamine (158 μL, 0.91 mmol), azetidine (45 μL, 0.67 mmol) and n-butanol (6 mL) was heated at 125° C. for 20 min in the microwave. The reaction mixture was cooled to room temperature and the resulting solid was filtered and the solid washed with Et2O, sNH4Cl and Et2O. The resulting solid was air dried to give the title compound as a white solid (48 mg, 58%). MS (ES+) m/e=368. 1H NMR: (DMSO) 1.08-1.92 (10H, m), 2.26-2.58 (3H, m), 3.89-4.06 (4H, m), 6.50 (1H, brs), 8.32-8.62 (2H, m), 9.79 (1H, s), 13.03 (1H, s)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:13])[CH2:9][CH2:10][C:11]#[CH:12].Cl[CH2:15][C:16]([N:18]1[CH2:37][CH2:36][C:21]2[N:22]=[C:23]([NH:26][CH:27]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28]3)[N:24]=[CH:25][C:20]=2[CH2:19]1)=[O:17]>O1CCCC1>[CH2:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH:27]1[NH:26][C:23]1[N:24]=[CH:25][C:20]2[CH2:19][N:18]([C:16](=[O:17])[CH2:15][NH:13][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])[CH2:37][CH2:36][C:21]=2[N:22]=1
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C#CCCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCCNCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 55 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
Add triethylamine (0.434 mL; 2.0 equiv; 3.12 mmoles) followed by 4-pentyn-1-amine (0.194 mL; 1.50 equiv; 2.34 mmoles) to a solution of 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (0.534 g; 1.0 equiv; 1.56 mmoles) in tetrahydrofuran (5.19 mL). Stir for 48 hours at 55° C. The solution was directly concentrated to afford 1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-2-(pent-4-ynylamino)ethanone (0.606 g; 100%): MS (m/z): 390(M+1).
Reaction SMILES: [CH3:1][O-:2].[K+].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[N:9][C:10]=1F>[Cl-].[NH4+]>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[N:9][C:10]=1[O:2][CH3:1]
Reactant: C[O-]
Reactant: CN(C)c1ccc(Br)c(F)n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Product: COc1nc(N(C)C)ccc1Br
Temperature: 25 °C

Procedure:
To a solution of potassium methoxide (25% in methanol, 74.2 mL, 251 mmol) was added Intermediate (5-bromo-6-fluoro-pyridin-2-yl)-dimethyl-amine (18.36 g, 83.8 mmol). The reaction was stirred at reflux for 3 h before cooling to room temperature. The contents were poured into a solution of saturated ammonium chloride (500 mL) and this was extracted with ethyl acetate (3×300 mL). The combined organics were washed with brine (250 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford desired product as an oil that solidified upon standing to give an off white/yellow solid (18.3 g, 95% yield). 1H NMR (CDCl3, 400 MHz) 5=7.49 (d, J=8.59 Hz, 1 H) 5.95 (d, J=8.59 Hz, 1 H) 3.96 (s, 3 H) 3.05 (s, 6 H); MS (FID)=230.1 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S-:25].[Na+].[Na+].N1CCC[C@H]1C([O-])=O>CS(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:25][CH3:24])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Reactant: C[S-]
Agent: [Cu]I
Agent: O=C([O-])[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Temperature: 90 °C
Yield: 86.8 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.4 g, 5.51 mmol) in DMSO (40 mL) is added Sodium thiomethoxide (0.463 g, 6.621 mmol), CuI (0.105 g, 0.552 mmol) and L-proline sodium salt (0.151 g, 1.103 mmol) and heated the mixture at 90° C. for 24 h. Reaction mixture is quenched with water and extracted with ethyl acetate. Organic layer is washed with brine and dried over sodium sulphate, concentrated and purified by CombiFlash using 120 g column with 9.26% ethyl acetate in hexane as an eluent to afford title compound (1.7 g) as faint yellow solid. 1H-NMR (400 MHz, DMSO): δ 1.42 (s, 9H), 1.47 (s, 3H), 1.59 (s, 3H), 2.47 (s, 3H), 3.73-3.79 (m, 1H), 4.37-4.92 (m, 1H), 4.71-4.94 (m, 1H), 5.01 (d, J=7.44 Hz, 1H), 7.27 (d, J=8.28 Hz, 2H), 7.39 (d, J=8.36 Hz, 2H). LC-MS (m/z): M+H=356.2.
Reaction SMILES: C[O:2][C:3]1(O)[CH:18]=[CH:17][C:6]2[S:7][C:8]3[S:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:9]=3[C:5]=2[CH2:4]1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH:4]1[C:5]2[C:9]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:8]=3[S:7][C:6]=2[CH:17]=[CH:18][C:3]=1[OH:2]
Reactant: COC1(O)C=Cc2sc3sc4ccccc4c3c2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2sc3sc4ccccc4c3c2c1
Temperature: -78 °C
Yield: 94.1 %

Procedure:
2-Methoxy benzo[b]benzo[4,5]thieno[3,2-d]thiophen-2-ol (2.8 g, 10.36 mmol) was dissolved in 100 mL dry DCM and cooled down to −78° C., to which was added 1M BBr3 DCM solution (15.53 mL), and the reaction was allowed to stir as the reaction was allowed to rise to room temperature. The reaction was monitored by TLC. After workup, 2.5 g (94%) of product was obtained, which was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]CC)=[O:17])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:21]([F:24])([F:22])[F:23])[CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)Cn2nc(C(F)(F)F)cc2C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of ethyl 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinylcarboxylate (3.6 g, 10.36 mmol) (i.e. the product of Example 17, Step C) in methanol (10 mL) was treated with 1 M sodium hydroxide aqueous solution (15.54 mL, 15.54 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then 1 M hydrochloric acid (15.54 mL, 15.54 mmol) was added, and most of methanol was evaporated in vacuo leaving white crystals. The crystals were filtered and dried to give 2.25 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([SH:13])[C:10](O)=[O:11]>C1(C)C=CC=CC=1>[SH:13][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)=[O:11]
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)CS
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)CS)c1

Procedure:
Freshly distilled meta-toluidine (10.168 g) was dissolved in toluene (50 ml) and treated with thioglycollic acid (7 ml). The mixture was heated under reflux, and water collected in a Dean and Stark apparatus overnight. The reaction mixture was then cooled and poured into hexane (50 ml). The product separated as an oil and the solvents were removed under reduced pressure to give a white solid (17.975 g). Attempts at recrystallisation resulted in failure and the residue was chromatographed on silica gel. The product (14.84 g), still contaminated with meta toluidine, was taken up in ethyl acetate and washed with 2M hydrochloric acid. The title compound was then isolated in the usual manner as a white solid, yield 13.13 g, mp 58°-60° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)[CH3:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:8][CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]2)=[CH:19][CH:18]=3)=[O:21])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 40b), from 5-[[1-(1-methylethyl)-4-piperidinyl]oxy]-1H-Indole-2-carboxylic acid and 1-(tert-butoxycarbonyl)piperazine. Light-yellow solid. MS (m/z): 471.1 (M+H)+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.[CH2:37](O)[CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+].BrCCCCBr>O>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([N:29]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: CCCCO
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: BrCCCCBr
Product: CC(C)N1CC2N(C(=O)C(N3CCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
32 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 2 ml of 1-butanol were added. 1 mmol of potassium carbonate and 200 μl of 1,4-dibromobutane were added to this mixture. The reaction mixture was stirred at 90° C. for 16 hours and evaporated. The residue was suspended in 5% Et3N/ethyl acetate, filtered and evaporated. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=612.11 (calculated, monoisotopic); measured value (M+H)+: 613.4.