Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19]C)=[C:14]3[C:10]=2[CH2:11][CH2:12][CH2:13]3)=[C:6]([CH2:21][CH3:22])[N:5]([CH2:23][C:24]([OH:26])=[O:25])[N:4]=1)[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[CH2:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]3[C:10]=2[CH2:11][CH2:12][CH2:13]3)=[C:6]([CH2:21][CH3:22])[N:5]([CH2:23][C:24]([OH:26])=[O:25])[N:4]=1)[CH3:2]
Reactant: CCc1nn(CC(=O)O)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1nn(CC(=O)O)c(CC)c1Cc1cc(C)c(O)c2c1CCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
To a stirred suspension of [3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic acid (6.0 gm, 0.0168 mole) in Methylene chloride (100 ml), a solution of Boron tribromide (4.2 ml, 0.0442 mole) in Methylene chloride (20 ml) was added at 0-5° C. and stirred for 2-3 hrs at 20-30° C. Water (250 ml) was charged into the reaction mixture and stirred for 1 hour. The separated solid was filtered under vacuum, washed with water. The obtained solid was dissolved in Ethyl acetate (2.0 liter) and washed with water (1 liter). Ethyl acetate was distilled under vacuum and further the obtained solid was stirred in Diethyl ether (50 ml), filtered and dried at 55-60° C. under vacuum to yield 4.5 gm of desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[C:31](=[O:32])[C:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:41])=[CH:36][N:35]=2)=[CH:29][C:28](B(O)O)=[N:27]1.C([O-])(=O)C.[Na+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:28]5[CH:29]=[C:30]([NH:33][C:34]6[CH:39]=[CH:38][C:37]([C:40]([N:42]7[CH2:43][CH2:44][O:45][CH2:46][CH2:47]7)=[O:41])=[CH:36][N:35]=6)[C:31](=[O:32])[N:26]([CH3:25])[N:27]=5)[CH:7]=[CH:6][N:5]=4)[CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cn1nc(B(O)O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1nc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}pyridine-3-carbaldehyde 109a (144 mg, 0.40 mmol), 1-methyl-5-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-ylboronic acid 258a (215 mg, 0.60 mmol), PdCl2(dppf) (16 mg, 0.020 mmol), K3PO4 trihydrate (207 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 100° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified with silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 259a as a yellow solid (80 mg, 30%). MS-ESI: [M+H]+ 640.3.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]([CH3:3])[CH3:2])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CC(C)N
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 12 %

Procedure:
Isopropylamine (372 μL, 4.37 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (162 mg, 0.437 mmol) in tetrahydrofuran (4 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Isopropylamine (37.2 μL, 0.437 mmol), sodium cyanoborohydride (82.4 mg, 1.31 mmol) and acetic acid (150 μL, 2.62 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 24 mg of the cis isomer of the title compound (15%) as a pale yellow oily substance and 20 mg of the trans isomer of the title compound (12%) as a pale yellow oily substance.
Reaction SMILES: [P:1]([O:33]C)([O:31]C)([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]([N:22]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH3:24])=[O:21])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2].C[Si](Br)(C)C>>[P:1]([OH:31])([OH:33])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]([N:22]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH3:24])=[O:21])[N:9]=1)=[C:5]([CH3:6])[CH3:7])=[O:2]
Reactant: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(OP(=O)(OC)OC)=C(C)C)c2ccc(OC)cc21
Agent: C[Si](C)(C)Br
Product: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(OP(=O)(O)O)=C(C)C)c2ccc(OC)cc21

Procedure:
Reaction of 1-(1-{2-[(3,3-dimethylbutyl)(ethyl)amino]-2-oxoethyl}-6-methoxy-1H-indazol-3-yl)-2-methylprop-1-en-1-yl dimethyl phosphate with trimethylsilyl bromide as described in Example 2 provided the title compound. It was isolated by RP-HPLC using 10-100% MeCN gradient without TFA as a colorless solid following lyophilization. 1H NMR (CD3CN, 500 MHz) showed two amide rotomers in about 6:7 ratio: δ 7.55 (d, 8.7 Hz, 1H), 6.88 & 6.87 (d, 1.9 Hz, 1H), 6.84 (dd, 2.1 & 8.9 Hz, 1H), 5.23 & 5.21 (s, 2H), 3.88 & 3.87 (s, 3H), 3.31˜3.48 (m, 4H, overlapping with residual water peak), 1.94 (d, 1.8 Hz, 3H), 1.81-1.82 (m, 3H), 1.61-1.64 & 1.42˜1.46 (m, 2H), 1.26 & 1.10 (t, 7.1 Hz, 3H), 0.99 & 0.91 (s, 9H). LC-MS: 3.18 min. (m/Z=370.2, 468.1).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(C)C)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(C)C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2cccc(O)c2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 40.0 mg (0.076 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.00 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 7.90 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.4 Hz), 7.35 (2H, s), 7.15-7.07 (2H, m), 6.77-6.69 (3H, m), 5.92 (1H, t, J=4.7 Hz), 2.25 (2H, d, J=4.7 Hz), 1.23 (6H, s).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cccnc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3cccnc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}benzoic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (181 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (329 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg), and the mixture was stirred at room temperature for 1 day. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane) to give the title object compound (330 mg, 87%) as a pale-brown solid.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4)cc3OCC)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (460 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (397 mg).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][NH2:17])=[CH:10][CH:9]=1>C(O)=O>[C:8]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:9]=[CH:10][C:11]([C:14]([C:21]2[CH:22]=[CH:23][C:18]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:20]=2)=[CH:15][CH2:16][NH:17][CH:5]=[O:7])=[CH:12][CH:13]=1
Reactant: NCC=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Acetic anhydride (1ml) was added to a solution of 1, 1 - di(4 - biphenylyl 3 - amino - prop - 1 -ene (1g) in 99% formic acid (5ml) and the mixture was refluxed for 1 hour then poured onto ice. The solid was collected, washed with water, dried and then recrystallised from benzene/ n - propanol to furnish 1, 1-di(4 biphenylyl) -3 - formamido - prop - 1 ene (m.p. 171°- 173°C). This compound, reduced with lithium aluminium hydride in ether/tetrahydrofuran at -30°C, afforded 1, 1-di (4 -biphenylyl -3 - methylamino - prop- 1 - ene identical with that described in Example 4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][OH:8])=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][O:8][C:12]2[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:20]=3)[N:17]=2)=[N:3]1
Reactant: Cn1cnc(CO)n1
Reactant: Clc1nn2c(-c3cnccn3)nnc2cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(COc2nn3c(-c4cnccn4)nnc3cc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210; 0.044 g, 0.39 mmol) in dimethyl formamide (10 ml) was added sodium hydride (0.016 g of a 60% dispersion in oil, 0.390 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 0.5 h. After this time, the product from Example 1 step e) (0.1 g, 0.325 mmol) was added and the reaction mixture stirred for 2.5 h. The solvent was removed under high vacuum. Water (5 ml) was added to the residue and the solid produced was collected by filtration. The solid was recrystallised from ethyl acetate/ethanol to give the required product (0.049 g, m.p. 256.9-257.8° C.). 1H NMR (360 MHz, CDCl3) δ 3.94 (3H, s), 5.62 (2H, s), 7.47 (3H, m), 7.67 (2H, m), 8.04 (1H, s), 8.10 (1H, s), 870 (1H, s), 8.84 (1H, s), 9.80 (1H, s) MS (ES+) m/e 386 [MH+].
Reaction SMILES: C(O)(=O)C.C(O[C:8]1(O[Si](C)(C)C)[CH2:10][CH2:9]1)C.[NH2:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])([CH3:32])[C:23]2=[O:40])=[C:19]([O:43][CH3:44])[CH:18]=1.C([BH3-])#N.[Na+]>CO>[Cl:31][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([CH2:21][C:20]1[CH:41]=[CH:42][C:17]([NH:16][CH:8]3[CH2:10][CH2:9]3)=[CH:18][C:19]=1[O:43][CH3:44])[C:23](=[O:40])[C:24]2([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[CH3:32]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: COc1cc(N)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(NC2CC2)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.54 ml of acetic acid, 0.4 g of 3 Å molecular sieve and 0.207 ml of (1-ethoxycyclopropyl)oxytrimethylsilane are added to 0.4 g of the compound of Example 48 in solution in 10 ml of methanol. After stirring for 30 minutes at room temperature, 0.265 g of sodium cyanoborohydride is added and then the mixture is heated at reflux for 10 hours. After cooling, hydrolysis is carried out with 20 ml of 2N sodium hydroxide solution, filtration is carried out through celite and the celite is rinsed with ethyl acetate. The organic phase is washed with a 10% aqueous sodium chloride solution and dried over sodium sulphate and the solvents are evaporated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6](O)[CH2:7][O:8][C:4]=2[CH:3]=1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH:6]1[C:5]2[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=2[O:8][CH2:7]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1COc2cc(Br)ccc21
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC1COc2cc(Br)ccc21

Procedure:
In analogy to the procedures described for the preparation of intermediates A-2 [B] and A-2 [C], (rac)-6-bromo-2,3-dihydro-benzofuran-3-ol was treated with diphenylphosphoryl azide, DBU in toluene to give (rac)-3-azido-6-bromo-2,3-dihydro-benzofuran, which was subsequently reduced with triphenylphosphine in THF/water to yield the title compound as light yellow oil. MS: 213 (M+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]([C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])([CH2:12][CH3:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:22][N:23]([CH:25](N(C)C)N(C)C)[CH3:24]>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]([C:14](=[O:20])[N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])([CH2:12][CH3:13])[C:10]=1/[CH:11]=[CH:22]/[N:23]([CH3:25])[CH3:24])=[O:5])[CH3:2]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCOC(=O)C1=C(C)C(CC)(C(=O)N(CC)CC)OC1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(/C=C/N(C)C)C(CC)(C(=O)N(CC)CC)OC1=O
Reaction time: 17 h
Yield: 90.2 %

Procedure:
To a solution of 500.0 mg of compound (12) as obtained from example 5 (22.73 mmol) in 3.0 mL dimethyl formamide were added at room temperature 3.0 mL tris(dimethylamino)methane (17.3 mmol, 10.3 eq). The color of the reaction mixture changed from orange to brown and further to green. After 17 h, the mixture was diluted with 50 mL dichloromethane, washed with 25mL aqueous hydrochloric acid (1.0 M) and washed again three times with 50 mL brine. The organic phase was dried over 2 g sodium sulfate and was filtered. The filter cake was washed with 4 mL dichloromethane. After evaporation of the solvent in a rotary evaporator (50° C., 5 mbar), the crude product was obtained as an orange oil (627.0 mg, 106% by weight), which was liberated from residual dimethyl formamide in a high vacuum rotary evaporator (50° C., 0.5 mbar) yielding the title product (536.0 mg, 1.517 mmol, 90% by weight) as orange crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C:19]#[N:20].C(N(CC)CC)C>CN(C)C=O.O>[C:19]([CH2:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:10]=2)[NH:14][CH:13]=1)#[N:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 3 h

Procedure:
Dimethyl sulphamoyl chloride (1.2 ml) was added dropwise to a stirred solution 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry dimethyl-formamide (50 ml) containing triethylamine (2.8 ml). After 3 h, the resulting suspension was diluted with water (20 ml) and stirred for 30min. The resulting solution was poured into water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (100 ml) and brine (2×100 ml), dried (Na2SO4) and evaporated in vacuo, to give a dark brown oil which was purified by column chromatography (Kieselgel 60, 100 g) eluted with ether/ethyl acetate, (9:1) to give the title compound as white solid (0.75 g) m.p. 147°-150°.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:36]4[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=4)(=[O:44])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(OC)c(OC)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3,4-dimethoxy-benzenesulfonyl chloride. Purity (ELSD, based on MW=621.7)=94%.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11](=[O:14])[CH2:12][CH3:13])[CH2:8]C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>N1C=CC=CC=1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11](=[O:14])[CH2:12][CH3:13])[CH:8]=[CH:21][CH2:22][C:23]([OH:25])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: CCC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)C(C=CCC(=O)O)(c1ccccc1)c1ccccc1
Yield: 72.9 %

Procedure:
A mixture of 3,3-diphenyl-4-oxo-hexanal (45 mg)[from Example 2], malonic acid (40 mg) and pyridine (1.5 ml) was heated at 80°-90° C. for 18 hours, with stirring. The volatiles were removed in vacuo and the residue was partitioned between water and chloroform (3×). The combined extracts were washed with water and dried (Na2SO4). Rotary evaporation of the solution gave a crude material which was purified by PTLC. Development with hexane/ethyl acetate (2:1) produced two bands. The lower band which was near the origin was scraped off the plate and eluted with methanol. Rotary evaporation of the solution yielded 38 mg of 5,5-diphenyl-6-oxo-3-octenoic acid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[CH:17]=[C:16]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[NH:21][N:20]=3)[CH:15]=[CH:14][C:13]=2[F:30])[C:6]1=[O:31].CO>N>[F:30][C:13]1[CH:14]=[CH:15][C:16]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21][N:20]=2)=[CH:17][C:12]=1[N:7]1[C:8](=[O:11])[CH:9]([CH3:10])[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]1=[O:31]
Reactant: COC(=O)CN1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1C
Agent: N
Solvent: CO
Product: CC1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)O
Temperature: 60 °C

Procedure:
{3-[2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5-methyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid methyl ester (39)(0.03 g, 0.068 mmol) was dissolved in solution of 7N ammonia in methanol (2 ml, 14 mmol) and placed in a sealed tube. The reaction was then heated to 60° C. for 18 hours. The resultant solution was concentrated in vacuo absorbed onto a 1 ml silica cartridge. The material was eluted with neat ethyl acetate. RF of 0.65 yielding pure amide product. Single peak in LC-MS, (8 mg, 100% purity) and required no further purification; m/z (LC-MS, ESP), RT=2.84 mins (M+H) 424;
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[O:15]1[CH2:20][CH2:19][NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]1=2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:18]1[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH2:20][CH2:19]1)=[O:14]
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: O=C(CSc1nc2ccccc2s1)N1CCOc2ccccc21
Yield: 78 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 3,4-dihydro-2H-benzo[b][1,4]oxazine to yield 44 as a white solid (78%): MS m/z: 343 (M+H)+. Anal. Calcd. For, C17H14N2O2S2: C, 59.63; H, 4.12; N, 8.18; S, 18.73. Found: C, 59.73; H, 4.17; N, 8.18; S, 18.76.