Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[C:3]([C:6]1[C:7]([CH3:28])=[C:8]([S:20][C:21]2[CH:26]=[CH:25]C(N)=[CH:23][CH:22]=2)[C:9](=[O:19])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)(=[O:5])[CH3:4].N1C(C)=CC=CC=1C.O.[CH3:38][N:39]([CH3:42])[CH:40]=O>>[C:3]([C:6]1[C:7]([CH3:28])=[C:8]([S:20][C:21]2[CH:22]=[CH:23][C:40]([N:39]([CH3:42])[CH3:38])=[CH:25][CH:26]=2)[C:9](=[O:19])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)(=[O:5])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(N)cc2)c1C
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: CI
Product: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(N(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl iodide (0.9 ml) was added to a solution of 6-acetyl-4-(4-aminophenylthio)-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (370 mg) and 2,6-lutidine (1 ml) in N,N-dimethylformamide (5 ml) at 5° C., followed by stirring at room temperature for 12 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and was crystallized from ether/hexane to obtain 6-acetyl-4-(4-dimethylaminophenylthio)-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (120 mg) (Compound No. 4-04).
Reaction SMILES: [C:1]([N:4]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1C(=O)C2=CC=CC=C2C1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.NN>C(O)C>[C:1]([N:4]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCCN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)N(CCCCN)c1ccccc1
Yield: 80.6 %

Procedure:
A mixture of N-[4-(N-acetyl-N-phenylamino)butyl]phthalimide (9.2 g), hydrazine monohydrate (10 ml) and ethanol (200 ml) was heated under reflux for 1 hour. The deposited crystals were separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 4-(N-acetyl-N-phenylamino)butylamine (4.55 g, 80.7%) as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>O=[Mn]=O.C(Cl)(Cl)Cl>[CH3:20][C:18]([CH3:21])([O:17][C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)=[O:16])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a 50 mL round bottomed flask with a stirring bar and an argon inlet was added 1-hydroxymethyl-4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)benzene, 35-1 (2.15 g, 7.35 mmol), CHCl3 (100 mL), and MnO2 (12.0 g, 138 mmol). This mixture was stirred at ambient temperature for 24 h. The salts were removed by filtration and the solvent was removed in vacuo. The residue was chromatographed on 90 g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)benzaldehyde 35-2 (2.10 g, 99%) as a crystalline solid. 1H NMR (CDCl3): δ 1.49 (s, 9H), 3.39 (m, 4H), 3.59 (m, 4H), 6.89 (d, J=9 Hz, 2H), 7.75 (d, J=9 Hz, 2H), 9.79 (s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11](Br)[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2].CC1C=C(C)N=C(C)C=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1C
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 140 °C

Procedure:
A mixture of 0.605 g. (0.0010 mole) of [1α,3β,7ξ,24R]-7-bromo-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.6 ml. of s-collidine and 18 ml. of xylene was heated at reflux (140° C.) for 0.5 hr and cooled. The mixture was diluted with 30 ml. of toluene This solution was washed with 10% aqueous sulfuric acid, and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to yield [1α,3β,24R]-24-fluorocholesta-5,7-dien-1,3,25-triol 1,3-diacetate, [α]D23 -21° (c 0.5, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:42]=[CH:41][C:23]([O:24][C:25]2[CH:26]=[C:27]([NH2:40])[CH:28]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:30]=2)=[CH:22][CH:21]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15](=[O:17])[NH:40][C:27]2[CH:28]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:30]=[C:25]([O:24][C:23]3[CH:41]=[CH:42][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[CH:26]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 65.4 %

Procedure:
Following the procedure of Example 9(e) cis-4-tert-butoxycarbonylamino-cyclo-hexanecarboxylic acid 1.0 g (4.15 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (1.34 g, 4.15 mmol) were used to afford 1.5 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 2.3 (4H, m), 2.81 (1H, m), 3.15 (4H, m), 3.5 (1H, m), 6.71 (1H, s), 6.81 (1H, brs), 7.21 (6H, m), 7.92 (4H, d), 10.0 (1H, brs).
Reaction SMILES: [C:1]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:9]1[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:3][C:2]2=[O:10].BrC1C=NC=CC=1/C(=[CH:30]\[N:31]([CH3:33])[CH3:32])/C(C1CCCC1)=O.CC([O-])(C)C.[Na+].C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][N:31](/[CH:33]=[C:3]1\[C:2](=[O:10])[C:1]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4]\1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:32]
Reactant: CN(C)/C=C(/C(=O)C1CCCC1)c1ccncc1Br
Reactant: O=C1Cc2ccccc2C12CCCC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: Cc1ccccc1
Product: CN(C)/C=C1\C(=O)C2(CCCC2)c2ccccc21
Temperature: 110 °C

Procedure:
(3′Z)-3′4(Dimethylamino)methylidene)spiro[cyclopentane-1,1′-inden]-2′(3′H)-one (123) To a degassed solution of 2-(3-bromopyridin-4-yl)-1-cyclopentyl-3-(dimethylamino)prop-2-en-1-one (122) (4.738 g, 14.63 mmol) and sodium 2-methylpropan-2-olate (4.23 g, 44 mmol) in 20 ml of anhydrous toluene was added Pd2(dba)3 (0.806 g, 0.879 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.603 g, 1.757 mmol) under an atmosphere of nitrogen. The reaction was heated to 110° C. for 1.5 hours before it was cooled to 20° C. and concentrated under vacuum to give mainly (3′Z)-3′-((dimethylamino)methylidene)spiro[cyclopentane-1,1′-inden]-2′(3′H)-one (123). LCMS-ESI (POS), M/Z, M+1: Found 243.1.
Reaction SMILES: CI.[CH3:3][C:4]1[N:9]2[N:10]=[C:11]([CH2:13][S:14][C:15]3[NH:16][N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:3][C:4]1[N:9]2[N:10]=[C:11]([CH2:13][S:14][C:15]3[N:16]([CH3:26])[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc2nc(CSc3nc(-c4ccccc4)n[nH]3)nn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cccc2nc(CSc3nc(-c4ccccc4)nn3C)nn12
Reaction time: 3 h

Procedure:
Methyl iodide (142 mg, 1.00 mmol) dissolved in DMF (0.5 ml) was added to a stirred suspension of 5-Methyl-2-(5-phenyl-2H-1,2,4-triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyridine (322 mg, 1.00 mmol) and Potassium carbonate (276 mg, 2.0 mmol) in N,N-Dimethylformamide (3.5 mL) at rt, under Ar. The solution was stirred at 3 h and then quenched by adding Sat bicarbonate sol and extracting with EtOAc. The Organic phase was dried (MgSO4) and was rotovaped. The crude product was purified by HPLC. This afforded 10 mg of the title compound. LC-MS: m/z=337.1 (MH+), tR=0.63 min, Method B. 1H NMR (600 MHz, DMSO-d6): δ 7.96 (d, 2H), 7.63 (d, 1H), 7.60 (t, 1H) 7.50-7.40 (m, 3H), 7.07 (d, 1H), 4.68 (s, 2H), 2.66 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([OH:31])[CH:11]=[C:10]1[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:60][C:61]1[CH:66]=[CH:65][C:64](O)=[C:63]([CH2:68][C:69]2[CH:74]=[CH:73][C:72]([CH2:75][CH3:76])=[CH:71][CH:70]=2)[CH:62]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:34]([O:33][CH2:32][C:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([O:31][C:64]2[CH:65]=[CH:66][C:61]([Cl:60])=[CH:62][C:63]=2[CH2:68][C:69]2[CH:70]=[CH:71][C:72]([CH2:75][CH3:76])=[CH:73][CH:74]=2)[CH:11]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCc1ccc(Cc2cc(Cl)ccc2O)cc1
Reactant: O[C@H]1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2C=C(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 48 h
Yield: 22 %

Procedure:
In a argon stream, (1S,4R,5S,6S)-4,5,6-tris(benzyloxy)-3-(benzyloxymethyl)cyclohex-2-enol (0.5 g, 0.933 mmol) and triphenylphosphine (367 mg, 1.400 mmol) were added to a THF (6 mL) solution of 4-chloro-2-(4-ethylbenzyl)phenol (345 mg, 1.400 mmol) at room temperature. DIAD (0.276 mL, 1.400 mmol) was added thereto at the same temperature. The reaction mixture was stirred for 48 h. The reaction mixture was concentrated under reduce pressure, and the obtained residue was purified by prepared LC-MS to obtain 157 mg of ((1S,2S,3R,6R)-4-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohex-4-ene-1,2,3-triyl)tris(oxy)tris(methylene)tribenzene (27).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>[Pd].Cl.CCO>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2ccnc2cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1cn2c(n1)CNCC2
Reaction time: 16 h

Procedure:
Imidazo[1,2-a]pyrazine (250 mg, 2.1 mmol) and palladium on carbon (10%) (55.8 mg, 0.53 mmol) were placed in a pressure resistant bottle and suspended under nitrogen in 0.5M HCl/EtOH. The mixture was stirred under at 45 psi H2 for 16 hrs. LC/MS showed completion. The next day, the reaction mixture was passed through celite cake. The filtrate was concentrated under reduced pressure to afford a tan solid. This was used directly without further purification. MS: [N+H]=124.2; Calc'd for C6H9N3: 123.2.
Reaction SMILES: [C:1]([C:3]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27]3)[C:21]=2[CH3:37])=[N:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:39]>>[CH3:19][O:18][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:7]3[C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[C:35](=[O:36])[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:28]=[CH:27]5)[C:21]=4[CH3:37])=[N:5][CH:4]=[C:3]([C:1](=[O:39])[NH2:2])[C:8]=3[NH:9][C:10]=2[CH:11]=1)=[O:17]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cnc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 60 °C

Procedure:
A stirred mixture of methyl 4-cyano-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate (0.192 g, 0.395 mmol) and 90% aqueous Sulfuric acid (2.000 ml, 36.8 mmol) was heated at 60° C. for 15-30 minutes. HLC-MS showed complete conversion to the desired product plus the corresponding carboxylic acid. The reaction mixture was cooled to 0° C. and neutralized to approx. pH=5-6 with 50% NaOH solution then stirred overnight. The reaction mixture was filtered and the residue dried overnight under vacuum to give methyl-4-carbamoyl-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate a tan/brown solid [0.111 g, 0.220 mmol, 56% yield]. The product had an HPLC Retention Time=2.798 minutes[mixture of isomers] [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC Comb screen ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 504.4
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]1[C:19]2[CH2:18][CH2:17][C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[NH:9][C:8]=1Br)=[O:6])[CH3:3].[Li+].[Cl-]>CCO.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:2]([O:4][C:5]([C:7]1[C:19]2[CH2:18][CH2:17][C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[NH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(Br)[nH]c2c1CCc1cnccc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c[nH]c2c1CCc1cnccc1-2
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 2-bromo-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid ethyl ester F1 (0.5 mmol), LiCl (1.49 mmol), Na2CO3.10H2O (1.74 mmol) and (Ph3P)2PdCl2 (0.005 mmol) in EtOH (4 mL) and toluene (4 mL) was heated with microwave irradiation to 150° C. for 20 min. The solvents were removed, DCM was added and the mixture washed with water. The organic layer was dried (Na2SO4), filtered and the solvent evaporated. The crude obtained was purified by chromatography on silica gel (DCM/MeOH 95:5). The title compound was obtained in 50% yield. ESI (+) MS: m/z 243 (MH+). 1H NMR: 1.29 (t, J=7.07, 3H), 2.83-3.00 (m, 4H), 4.20 (q, J=7.07, 2H), 7.42 (d, J=5.00, 1H), 7.59 (d, J=3.17, 1H), 8.29-8.42 (m, 2H), 12.22 (bs, 1H).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]#[N:30])[CH:25]=[CH:26][CH:27]=1.ClC1C=CC=CC=1CSC#N>C1C=CC=CC=1.C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]([CH:28]([C:1]#[N:4])[C:29]#[N:30])[CH:25]=[CH:26][CH:27]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: N#CSCc1ccccc1Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: c1ccccc1
Product: N#CC(C#N)c1cccc(Br)c1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 113.7 %

Procedure:
To a flame dried 5L 3-neck flask equipped with a mechamical overhead stirrer under nitrogen was added diisopropylamine (78.60 mL, 0.56 mol, 2.2 eq) and 2 L of benzene. After cooling to 0-5° C., 1.6 M n-BuLi (351.0 mL, 0.56 mol, 2.2 eq) was added dropwise via addition funnel while keeping the temperature at 0-5° C. The LDA was stirred for 45 min. at 0-5° C. 3-Bromophenylacetonitrile (50.0 g, 0.26 mol, 1.0 eq) dissolved in 200 mL of benzene was added dropwise via addition funnel keeping the temperature at 0-5° C. The mixture was stirred an additional 15 min at this temperature. 2-Chlorobenzylthiocyanate (J. Am. Chem. Soc., 1954, 76, 585) (103.0 g, 0.56 mol, 2.2 eq) dissolved in 200 mL benzene was added dropwise via addition funnel keeping the temperature at 0-5° C. During the addition, a precipitate formed. The reaction was allowed to warm to room temperature and the mixture stirred overnight. The reaction was quenched by adding water and 200 mL 10% NaOH. The layers were separated, and the benzene layer extracted with 10% NaOH (3×1 L). The basic layers were collected and acidified with conc. HCl to pH 1-2. A precipitate formed. Methylene chloride was added to dissolve the precipitate. The layers were separated and the aqueous layer reextracted with methylene chloride (2×). The methylene chloride layers were collected, dried (MgSO4) and the solvent removed in vacuo to yield 65.32 g of 2-(3-bromophenyl)malononitrile as a yellow solid. Recrystallization from methylcyclohexane yielded two crops: crop 1, 42.86 g of orange crystals, m.p. 99.5-101.5° C.; crop 2, 2.18 g of orange crystals, m.p. 97.0-99.0° C. Combined yield 79.9%. 1H-NMR (CDCl3) δ: 7.67 (s, 1H); 7.63 (d, 1H, J=7 Hz); 7.47 (d, 1H, J=7 Hz); 7.39 (t, 1H, J=7 Hz); 5.08 (s, 1H).
Reaction SMILES: C(O[CH:4]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5]1)C.S(=O)(=O)(O)O.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:4]2[NH:9][C:7](=[O:8])[CH2:6][CH2:5]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC1CCC(=O)N1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C1CCC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
At 0° C., 6.45 g of γ-ethoxy-γ-butyrolactam and 50 ml of concentrated sulphuric acid were charged initially, and 18.8 ml of benzene were added. After thawing, the mixture was stirred at room temperature for 4 days. For work-up, the mixture was poured onto ice, extracted three times with ethyl acetate and the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution, dried and evaporated. 8.1 g (100% of theory) of γ-phenyl-γ-butyrolactam were obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C:13]([CH2:16][OH:17])=[CH:14][CH2:15][C@@H:11]2[C:10]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][O:8]1)[CH3:5])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C:13]([CH2:16][O:17][CH3:24])=[CH:14][CH2:15][C@@H:11]2[C:10]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][O:8]1)[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CO)[C@@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(COC)[C@@H]12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Methyl (1S, 4aS, 7aS)-1-[1-(ethoxy)ethoxy]-7-(hydroxymethyl)-1, 4a, 5, 7a-tetrahydrocyclopenta[c]-pyran-4-carboxylate (2.0 g, 0.0067 mol) obtained in Example 16 was dissolved in 30 ml of dimethylformamide, and 540 mg (0.013 mol) of sodium hydride (in 60% oil) was added while the reaction mixture was being cooled by ice and stirred. After the reaction mixture was stirred at the same temperature for 30 minutes, 1.9 g (0.013 mol) of methyl iodide was added dropwise. After the temperature was raised up to the room temperature and the reaction mixture was stirred for 2 hours, the reaction mixture was extracted by adding 50 ml of 2N hydrochloric acid solution and 200 ml of ethyl acetate. The organic layer was washed with water (100 ml×2), saturated sodium bicarbonate solution (100 ml) and saturated sodium thiosulfate (100 ml), it was dried by adding magnesium sulfate and was then filtered, and thereafter concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=7:3 eluent was distilled off. A colorless oily substance was thus obtained, i.e., methyl (1S, 4aS, 7aS)-1-[1-(ethoxy)ethoxy]-7-(methoxymethyl)-1, 4a, 5, 7a-tetrahydrocyclopenta[c]pyran-4-carboxylate (1.71 g, yield=81.8%). This methyl (1S, 4aS, 7aS)-1-[1-(ethoxy)ethoxy]-7-(methoxymethyl)-1, 4a, 5, 7a-tetrahydrocyclopenta[c]pyran-4-carboxylate had the following physicochemical properties:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1([CH3:31])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16](C(OC(C)(C)C)=O)[C:15]1=[O:30].[ClH:32]>>[ClH:32].[NH2:3][CH2:12][CH2:13][C:14]1([CH3:31])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(CCN2C(=O)c3ccccc3C2=O)c2ccccc21
Agent: Cl
Product: CC1(CCN)C(=O)Nc2ccccc21
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 3-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-methyl-2-oxoindoline-1-carboxylate (600 mg, 1.43 mmol) and hydrochloric acid (5 mL) in a sealed tube was stirred at 100° C. for 72 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The aqueous layer was concentrated to dryness to give a crude product (350 mg, crude) as a yellow solid, which was used directly for next step without further purification. MS (ESI) m/z 191.1 [M+H]+
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:11]([C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[OH-].[Na+]>Cl>[NH2:5][C:6]1[C:11]([C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C(=O)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncccc1C(=O)c1cccnc1
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-N-[3-(pyridine-3-carbonyl)-pyridin-2-yl]-propionamide (0.225 g, 0.79 mmol) in 3M HCl (10 ml) is heated at reflux for 4 hours. The reaction mixture is allowed to cool to room temperature and the pH adjusted to basic with 2M NaOH. The product is extracted into DCM, dried (MgSO4), and concentrated in vacuo to afford a yellow solid. Drying in vacuo at 45° C. overnight yields (2-Amino-pyridin-3-yl)-pyridin-3-yl-methanone [M+H]+ 200.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:25](=[O:27])/[CH:24]=[CH:23]/[C:11]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid (Example 100, step B) and 1,2-diaminobenzene analogous to Example 131, step C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:14]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:15]#[N:16].[OH-:30].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:12])[CH3:13])=[CH:4][C:3]=1[CH:14]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[C:15]([NH2:16])=[O:30]
Reactant: COc1cc(Br)c(C(C#N)CCCc2ccc(OC(C)C)cc2)cc1OC(C)C
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(Br)c(C(CCCc2ccc(OC(C)C)cc2)C(N)=O)cc1OC(C)C
Reaction time: 6 h

Procedure:
α-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylethoxy)benzene pentane nitrile (30.0 g, 65.2 mmol) in ethanol (600 ml) is mixed with potassium hydroxide (60.0 g, 1.07 mol) in water (100 ml) and stirred for 6 hours at boiling temperature.