Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])C.[Li+].[OH-]>>[CH2:34]([O:33][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[C:4]([OH:36])=[O:3])[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2sc(-c3cccc(C(F)(F)F)c3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2sc(-c3cccc(C(F)(F)F)c3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d, [rac]-2-ethoxy-3-(2-methyl-4-{2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(2-methyl-4-{2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid as yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12]O>CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].[O-]S([O-])=O.[Na+].[Na+].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O>[NH2:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: NC(CO)C(=O)O
Reactant: c1ccc2[nH]ccc2c1
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=S([O-])[O-]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 30 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
In 50 g of Triton X-100 was dissolved 20 g of indole, and 36 g of DL-serine, 1 g of Na2SO3, 100 mg of pyridoxal phosphate and the above-mentioned two kinds of cells collected by centrifugal separation were added to the solution so that the entire volume was 1 l. The reaction liquid was shaken at a temperature of 30° C. and pH of 8.5 for 72 hours to effect reaction. After the reaction, 28.5 g of L-tryptophan was formed and accumulated in the reaction liquid (the yield was 41% based on serine).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[O:11][CH2:12][CH3:13]>C1C=CC=CC=1>[C:1]1([CH:3]2[CH2:2][CH:1]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:6][CH2:13][C:12]2=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Solvent: c1ccccc1
Product: O=C1CCC(c2ccccc2)CC1c1ccccc1

Procedure:
The oil was dissolved in 400 mL benzene and added dropwise over 40 minutes to 83 mL (250 mmol) of a 3.0 M solution of phenylmagnesium bromide in ether, cooling so the temperature did not rise above 10° C. The reaction was then allowed to warm and heated to reflux for 14 hours. It was then cooled, quenched with aqueous ammonium chloride solution, then washed with water and brine, dried over sodium sulfate, and evaporated. The yield was 53.9 g (approximately theoretical), and the crude oil was used directly in the next step.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)#[N:3].[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([NH:18][NH2:19])=O>CO>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[N:3]=[C:2]([C:4]2[CH:9]=[N:8][CH:7]=[CH:6][N:5]=2)[NH:19][N:18]=1
Reactant: N#Cc1cnccn1
Reactant: NNC(=O)c1cnccn1
Agent: [Na]
Solvent: CO
Product: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Reaction time: 1 h

Procedure:
Sodium (50 mg.) is added to 2-cyanopyrazine (1 gram, 0.01 mole) in 20 ml. of methanol. The solution is allowed to stand 1 hour at room temperature and is added to a suspension of pyrazine carboxylic acid hydrazide (1.4 grams, 0.01 mole) in 50 ml. of methanol. The reaction mixture is heated at reflux for 2 hours and then at room temperature for 16 hours. After cooling, the intermediate acylamidrazone is removed by filtration and is then heated at temperatures between 200° to 260° C. over two and one-half hours. After cooling and recrystallization from methanol-water, 0.8 grams of 3,5-dipyrazinyl-1,2,4-triazole, m.p. 269°-270.5° C. is obtained.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[OH:11][C:12]1[C:21]2[C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:17]([CH3:25])([CH3:24])[C:16]=2[CH:15]=[C:14]([CH3:26])[CH:13]=1.[C:27](O)(=[O:29])C.Cl>C(OCC)C.O>[CH:27]([C:13]1[C:14]([CH3:26])=[CH:15][C:16]2[C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][C:20]([CH3:22])([CH3:23])[C:21]=2[C:12]=1[OH:11])=[O:29]
Reactant: CC(=O)O
Reactant: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Cc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 20 °C

Procedure:
Formylation. Hexamethylenetetramine (21 g, 0.15 mol) and 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene were added in one portion with stirring to acetic acid (250 mL) and the mixture was heated at 95°-100° C. for 2 h. After cooling to 80°-85° C., water (250 mL) and concentrated hydrochloric acid (60 mL) were added and the mixture was heated at 95°-100° C. for a further 2 h. The reaction product was then cooled to 20° C., diethyl ether (150 mL) was added and the mixture was stirred vigorously. The organic layer was separated, washed with brine (2×50 mL), neutralized with 5% sodium bicarbonate solution (100 mL), and dried (Na2SO4). The solvent was removed by distillation and the residue was distilled to yield 2-formyl-1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (4a) (18 g), mp 91°-92° C., GLC purity 99%+. 1H-NMR (CDCl3) δ12.92 (1H, s), 10.21 (1H, s), 6.73 (1H, s), 1.68 (3H, s), 1.67 (4H, s), 1.48 (6H, s), 1.32 (6H, s). 13C-NMR (CDCl3) δ194.4 (1C, d), 163.5 (1C, s), 156.5 (1C, s), 138.0 (1C, s), 130.8 (1C, s), 120.1 (1C, d), 116.2 (1C, s), 37.7 (1C, t), 35.3 (1C, s), 34.6 (1C, t), 33.9 (1C, s), 31.0 (2C, q), 27.7 (2C, q), 17.8 (1C, q). IR (KBr) 1615, 1628 cm-1, MS (m/e) 246.2 (M+, 23.9) 231.2 (100.0), 189.1 (19.9), 161.2 (19.2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([CH3:21])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([N:13]1[C:14]2[CH:15]=[C:16]([CH3:21])[N:17]=[CH:18][C:19]=2[NH:20][C:28]1=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1cc(C)ncc1N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of (R)-3-(5-amino-2-methyl-pyridin-4-ylamino)-3-phenyl-propionic acid ethyl ester (594 mg, 1.98 mmol) in THF (20 mL) was added CDI (483 mg, 2.98 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 484 mg (75%) of the title compound as light brown solid. LCMS, M++1, m/z: 326.85.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:14][C:15](N)=[C:10]2[C:9]([CH3:23])=[N:8]1)[CH3:2].N([O-])=[O:27].[Na+].[OH-].[NH4+].C(O)(=O)C>S(=O)(=O)(O)O.O>[CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:14][C:15](=[O:27])[C:10]2=[C:9]([CH3:23])[NH:8]1)[CH3:2]
Reactant: CCN(CC)CCCn1nc(C)c2c(N)nc(-c3ccncc3)nc21
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)CCCn1[nH]c(C)c2c(=O)nc(-c3ccncc3)nc1-2
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 1-(3-diethylaminopropyl)-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-amine in 50% sulfuric acid (25 ml) was cooled to 0° C. and stirred for 1 hour. A solution of sodium nitrite (0.78 g, 11.4 mmol) in water (5-7 ml) was added and the reaction mixture was stirred at 0° C. for 4 hours, then at room temperature for 24 hours. The reaction mixture was poured onto ice-water, treated with ammonium hydroxide and the pH adjusted to 7 with acetic acid. The aqueous layer was extracted with chloroform (4×250 ml) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized in tert-butylmethyl ether/chloroform to afford 0.51 g (66%) of 1-(3-diethylaminopropyl)-3-methyl-6-(4-pyridyl)pyrazolo-[3,4-d]pyrimidin-4-one- 1/2 hydrate as an off-white powder, m.p. 164°-166° C. when dried at 80° C. for 16 hours in high vacuum.
Reaction SMILES: [CH2:1]([C:3]([CH3:16])([O:6][C:7]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[O:8])[CH2:4][CH3:5])[CH3:2].[OH-].[Li+]>CO.O>[CH2:1]([C:3]([CH3:16])([O:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:4][CH3:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(CC)CC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(CC)OC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (1.30 mmol) of ethyl {[(1-ethyl-1-methylpropoxy)carbonyl]-amino}acetate was dissolved in 2.5 ml of a solvent mixture of methanol:water (2.3:1). 1.56 ml of 1 N aqueous lithium hydroxide solution was added to the obtained solution. After stirring at room temperature for 2 hours, “DOWEX” (50W-X2 100 to 200 mesh H form) (an exchange resin of The Dow Chemical Company) was added to the reaction mixture under gentle stirring until pH of the mixture had become 5. The resin was obtained by the filtration under suction and then the filtrate was concentrated under reduced pressure and then dried to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=O)[NH:11][N:10]=1.O=P(Cl)(Cl)[Cl:25]>C(#N)C>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]([CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:22])=[N:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Solvent: CC#N
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reaction time: 3 h
Yield: 110.6 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-2H-phthalazin-1-one (10 g, 25.5 mmoles), prepared as described in example 38, in acetonitrile (300 ml), was added with POCl3 (22.2 ml, 230 mmoles) and the mixture was refluxed. After 3 hours, the solution was concentrated, taken up in CH2Cl2, in water, and the pH was brought to 7-8 by Na2CO3. The organic phases were discoloured with charcoal, anhydrified and concentrated to give 10 g of the title compound (stoichiometric yield). m.p.: 156-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cncc(F)c4)c3)c2cc1OC
Yield: 50.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (159 mg, 0.45 mmol), described in the previous step, to afford 1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (84 mg, 50%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 9H), 3.97-3.99 (m, 6H), 6.42 (s, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.34-7.40 (m, 2H), 7.54 (d, J=5.1 Hz, 2H), 7.98 (d, J=10 Hz, 1H), 8.55 (s, 1H), 8.61-8.71 (m, 3H), 9.24 (s, 1H); LC-MS (ESI) m/z 558 (M+H)+.
Reaction SMILES: ClC1C(C(OO)=[O:9])=CC=CC=1.[CH2:12]([O:14][C:15](=[O:37])[C:16]([Cl:36])([Cl:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH3:13]>ClCCl>[CH2:12]([O:14][C:15](=[O:37])[C:16]([Cl:36])([Cl:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)=[O:9])[CH3:13]
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCSc1ccc(Cl)cc1
Reactant: O=C(OO)c1ccccc1Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCS(=O)c1ccc(Cl)cc1
Yield: 79.8 %

Procedure:
0.59 g (3.41 mmol) chloroperbenzoic acid dissolved in 15 ml dichloromethane was added dropwise to a solution of 1.5 g (3.41 mmol) 104 in 30 ml dichloromethane analogously to example 25 (preparation of 77). 1.24 g (80%) 105 was obtained after flash chromatography on silica gel. 1.24 g (2.72 mmol) 105 was admixed with 5.5 ml ethanol and 5.5 ml 1 N KOH and cooled for 5 hours at room temperature. It was cooled to 0° C. and acidified with 2 N HCl. The precipitated precipitate was suction filtered, washed with water and isohexane and dried in a vacuum, yield: 0.65 g (56%) 55. The sodium salt prepared from 55 and pulverized NaOH in ethanol melted at 91-94° C.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1C=NC=CC=1)[CH2:4][CH2:3]2.Cl.Br[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1COCC1>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1)[CH2:4][CH2:3]2
Reactant: Brc1ccncc1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccncc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 4-bromopyridine hydrochloride (0.018 g, 0.091 mmol) was used in place of 3-bromopyridine, and an additional 1.2 equivalents of sodium tert-butoxide, 2.0M solution in THF (for a total of 5.6 equivalents, 0.212 mL, 0.424 mmol) was employed. The product was isolated after reverse phase preparative HPLC purification using Prep HPLC Method 7 as a beige solid (74 mg, 54% yield) bis TFA salt. LCMS: m/e 650.4 (M+H)+, 3.85 min (method 16). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.19-7.97 (m, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.06 (br. s., 2H), 5.28 (d, J=4.6 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 3.96-3.81 (m, 2H), 3.31-3.19 (m, 2H), 2.88-2.76 (m, 1H), 2.18-2.03 (m, 3H), 1.97 (dd, J=10.4, 6.4 Hz, 3H), 1.83 (d, J=12.5 Hz, 1H), 1.72 (s, 3H), 1.68 (br. s., 1H), 1.66-1.45 (m, 7H), 1.44-1.28 (m, 5H), 1.24 (d, J=8.2 Hz, 1H), 1.18-1.11 (m, 1H), 1.09 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:32])=[CH:4][CH:5]1[N:9](C(OCC)=O)[C:8](=[O:15])[N:7]([CH2:16][C:17]2[N:24]3[C:20]([S:21][C:22]([CH2:25][O:26]C)=[N:23]3)=[N:19][C:18]=2[C:28]([F:31])([F:30])[F:29])[CH2:6]1>>[Cl:1][C:3]([F:32])([F:2])[CH2:4][CH:5]1[CH2:6][N:7]([CH2:16][C:17]2[N:24]3[C:20]([S:21][C:22]([CH2:25][OH:26])=[N:23]3)=[N:19][C:18]=2[C:28]([F:31])([F:30])[F:29])[C:8](=[O:15])[NH:9]1
Reactant: Cl
Reactant: CCOC(=O)N1C(=O)N(Cc2c(C(F)(F)F)nc3sc(COC)nn23)CC1C=C(F)F
Product: O=C1NC(CC(F)(F)Cl)CN1Cc1c(C(F)(F)F)nc2sc(CO)nn12
Temperature: 100 °C
Reaction time: 60 h
Yield: 12 %

Procedure:
HCl (37%, 4 ml) is added to ethyl 5-(2,2-difluoroethenyl)-3-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-2-oxoimidazolidine-1-carboxylate a22 (226 mg, 0.48 mmol) at room temperature then stirred at 100° C. for 60 h. After cooling and neutralization by sodium carbonate, the reaction mixture is extracted with CH2Cl2 (2×30 ml), dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by chromatography (basic conditions; gradient; eluent: H2O/CH3CN/NH4CO3/NH4OH 95/5/0.1/0.005 to 40/60/0.1/0.005; 7 min) to afford 25 mg of pure 4-(2-chloro-2,2-difluoroethyl)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}imidazolidin-2-one 18.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][N:7]([CH3:15])[CH2:6]1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:15][N:7]1[CH2:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1
Reactant: O=C=Nc1ccccc1
Reactant: CN1Cc2ccccc2C(CCCN)(c2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2C(CCCNC(=O)Nc2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
To a solution of 4-(3-aminopropyl)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (0.4 g) in chloroform (10 ml) was added phenyl isocyanate (0.25 g) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness and the residue was crystallized from methanol-isopropyl ether to provide the title compound (0.39 g) as colorless powder.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:67][N:68]([CH3:73])[CH2:69][CH2:70][CH2:71][NH2:72]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:72][CH2:71][CH2:70][CH2:69][N:68]([CH3:73])[CH3:67])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NCCCN(C)C)cc3OC)ncc21
Reaction time: 18 h
Yield: 42.3 %

Procedure:
To a mixture of 0.06 g (0.13 mmole) of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-156), 0.06 g (0.17 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.33 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 mL (0.33 mmole) of 3-(dimethylamino)-propylamine was added. The mixture was stirred for 18 hours, and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.030 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-160).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[BrH:13]>S(=O)(=O)(O)O>[Br:13][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12]
Reactant: Br
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 43 %

Procedure:
To a stirred solution of 5-amino-1H-isoindole-1,3(2H)-dione (1.0 g, 6.2 mmol) dissolved in sulfuric acid solution (2 mL of Con. H2SO4 in 7.5 mL of H2O) at 0° C., was added ice cold sodium nitrite solution (0.8 g in 2 mL of H2O) dropwise. After 45 min of stirring at 0° C., CuBr (3.4 g, 23.7 mmol) and HBr[48%] (13.6 mL, 4 vol. w.r.t. CuBr) were added at the same temperature. The resulting mixture was stirred at 80° C. for 8 h then poured into crushed ice. Filtered the solid, washed with ice cold water and dried thoroughly to give 0.6 g (43.0%) of 5-bromo-1H-isoindole-1,3(2H)-dione as a brown colour solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)[C:33](O)=[O:34])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=2)[C:33]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]3[C:16]4[N:12]([N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[CH:11]=[CH:10]3)[CH:4]=2)=[O:34])[CH2:28][CH2:29]1
Reactant: CN1CCN(c2cc(C(=O)O)cc(C(F)(F)F)c2)CC1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(C(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
40 mg (0.14 mmol) of the compound of Example 6A and 44 mg (0.14 mmol) of 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/029038-A1, Example 14.2] were reacted and worked up analogously to the procedure of Example 33. This gave 43 mg (53% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=O)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:31])=[O:29])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(S(=O)(=O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(S(=O)(=O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
A suspension of methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)sulfonyl)phenyl)acetate (0.109 g, 0.25 mmol) in 7N NH3 in MeOH was heated at 100° C. in a sealed tube. After 24 h, the mixture was concentrated and purified by silica gel chromatography eluting with 100% methylene chloride to 1:1 methylene chloride/89:9:1 (methylene chloride/methanol/concentrated ammonium hydroxide) to afford the title compound (0.055 g, 53%) as a white solid. MW=426.92. 1H NMR (DMSO-d6, 300 MHz) δ 8.20-8.18 (m, 2H), 8.10-8.08 (m, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.56-7.51 (m, 5H), 6.98 (s, 1H), 3.50 (s, 2H), 3.12 (t, J=7.6 Hz, 2H), 3.03 (t, J=7.8 Hz, 2H), 2.13-2.08 (m, 2H); APCI MS m/z 427 [M+H]+.