Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C1COCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:19][CH3:20])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=5[F:18])[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1F
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1F
Yield: 59.6 %

Procedure:
A solution of 2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (184.6 mg, 0.624 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (140 mg, 0.624 mmol) in THF (1095 μL) and acetic acid (1095 μL) was heated 80° C. in a capped vial overnight. The solvent was evaporated in vacuum and the residue was partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. the combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (179.6 mg, 0.372 mmol, 59.6% yield) as brown solid. LC-MS (M+H)+=483.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.97 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=1.5 Hz), 7.01-7.10 (2H, m), 7.00 (1H, d, J=1.5 Hz), 6.73-6.84 (3H, m), 4.44 (1H, s), 3.61 (3H, s), 3.11 (3H, d, J=4.9 Hz), 2.59-2.77 (2H, m), 1.95-2.05 (2H, m).
Reaction SMILES: [F:1][CH:2]([F:21])[C@@H:3]1[C@@H:11]2[C@@:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[F:20][C:14]1[C:15]([F:19])=[CH:16][C:17]([N+:27]([O-:29])=[O:28])=[CH:18][C:13]=1[C@:6]12[CH2:5][O:4][C@H:3]([CH:2]([F:1])[F:21])[C@H:11]1[CH2:10][S:9][C:8]([NH2:12])=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(4aS,5S,7aS)-5-(difluoromethyl)-7a-(2,3-difluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine, obtained in Preparation Example 1-(9), (565 mg) was dissolved in TFA (3 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 0.8 mL) was added, followed by fuming nitric acid (0.08 mL) dropwise over 20 mins. After stirring at 0° C. for 90 min, the reaction mixture carefully neutralized with NaHCO3 (sat., aq., 50 mL) and extracted with EtOAc (3×100 mL), and the combined organic portions dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (0% to 80% EtOAc in hexanes) to afford the title compound (700 mg, purity approx. 80%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 3.04 (dd, J=14.0, 3.9 Hz, 1H), 3.23-3.31 (m, 1H), 3.59 (d, J=3.0 Hz, 1H), 4.23 (d, J=9.9 Hz, 1H), 4.44-4.60 (m, 2H), 6.02 (t, J=57.6 Hz, 1H), 8.02-8.26 (m, 2H)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[CH2:14][OH:15].CCN(CC)CC.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>ClCCl.CN(C1C=CN=CC=1)C>[Si:27]([O:15][CH2:14][C@@H:3]1[C@@H:2]([OH:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a 0° C. solution of (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 equiv) and Et3N (1.05 equiv) in dichloromethane (0.5 M) was added TBSCl (1.05 equiv), followed by a few crystals of DMAP. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane, and washed with sat'd. aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (99%), which was used without further purification.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[C:30]1[CH:31]=[CH:32][C:33]([CH:36]=[O:37])=[N:34][CH:35]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:33]3[CH:32]=[CH:31][C:30]([CH:26]4[O:27][CH2:28][CH2:29][O:25]4)=[CH:35][N:34]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C2OCCO2)cn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(C2OCCO2)cn1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (4.40 g) in ethanol (50 mL) were added 5-(1,3-dioxolan-2-yl)pyridine-2-carbaldehyde (2.70 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (375 mg) and triethylamine (755 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (4.40 g, yield 67%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 528 (MH+).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:29])[C@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl.[CH2:31]([O:38][C:39](=[O:47])[C@H:40]([CH3:46])[NH:41][C:42](=[O:45])[CH2:43][NH2:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:47])[C@H:40]([CH3:46])[NH:41][C:42](=[O:45])[CH2:43][NH:44][C:11](=[O:29])[C@H:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@H](NC(=O)CN)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A solution of 17.6 parts N-t-butoxycarbonyl-L-tyrosine 2,4,5-trichlorophenyl ester, 9.0 parts glycyl-L-alanine benzyl ester hydrochloride and 1.2 parts N-methylmorpholine in 200 parts methylene chloride is stirred for 16 hours at room temperature. Removal of the solvent under reduced pressure affords a crude product which is purified by low pressure column chromatography to give N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine benzyl ester. The purified material is dissolved in 400 parts methanol. Then, 0.4 part palladium black metal catalyst is added and the mixture shaken with hydrogen at atmospheric pressure and room temperature for about 5 hours. The catalyst is removed by filtration, and the solvent is removed by evaporation under reduced pressure. The resulting material is purified by low-pressure chromatography to give N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine. This compound is represented by the following formula
Reaction SMILES: [C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)([OH:3])=[O:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:2][C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)=[O:3]
Reactant: O=C(O)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OC1CCCCO1)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Yield: 72.6 %

Procedure:
Next, 2.1 g of the 12-carboxyhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene and 1.71 g of 3,4-dihydro-2H-pyran were dissolved in 50 ml of tetrahydrofuran, into which 0.03 g of p-toluenesulfonic acid were added. The resultant mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with 100 ml of ethyl ether, followed by the successive washing with a 3% aqueous solution of Na2CO3, 3% aqueous solution of sodium chloride, and water. An organic layer was dried over MgSO4. The ethyl ether and unreacted 3,4-dihydro-2H-pyran were distilled off under reduced pressure by an evaporator, whereby 2 g of 12-tetrahydropyranyloxycarbonylhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene were obtained as a viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[I:13])[C:5](OCC)=[O:6].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[I:13]
Reactant: CCOC(=O)c1cc(Cl)c(I)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(CO)cc(Cl)c1I
Temperature: -78 °C
Yield: 100 %

Procedure:
To a mixture of ethyl 3-chloro-4-iodo-5-methoxybenzoate (15.6 g, 45.8 mmol) and toluene (150 mL), was added diisobutyl aluminum hydride (1.01M toluene solution: 95.2 mL, 96.2 mmol) while stirring at −78° C., and the mixture was stirred while warming to −30° C. for three hours. To the mixture, an aqueous solution (400 mL) of Rochelle salt (potassium sodium (+)-tartrate tetrahydrate) (77.6 g, 275 mmol) was added, the mixture was stirred at room temperature for five hours, followed by addition of ethyl acetate. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (13.7 g, 45.8 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[CH3:11][O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].O>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:14])[CH:15]=[CH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=Cc1ccnc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 2-Methoxy-pyridine-4-carbaldehyde (1 g, 7.29 mmol, 1 eq) in 50 ml of dry DCM was added portionwise (methoxycarbonylmethylene)triphenylphosphorane (1.05 eq, 2.56 g). The mixture was stirred at room temperature for 2 hours. The mixture was then poured into 200 ml of water and the organic substances were extracted with DCM (twice, 150 ml of DCM was used in total) The gathered DCM layers were dried and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 2-20% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(2-methoxy-pyridin-4-yl)-acrylic acid methyl ester (1.3 g, yield=87.6%, purity=95%). MS: [M+H]+=194.14 1H NMR (300 MHz; CDCl3) δ/ppm 3.82(s, 3H), 3.95 (s, 3H), 6.54 (d, J=16.0 Hz, 1H), 6.80 (s, 1H), 6.97 (dd, J=5.38 Hz, J=1.31 Hz, 1H), 7.55 (d, J=16.0 Hz, 1H), 8.18 (d, J=5.38 Hz, 1H)
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:23][CH2:22][C@H:21]4[C@@H:11]([CH:12]=[CH:13][C:14]5[C@:19]4([CH3:20])[CH:18]=[CH:17][C:16](=[O:24])[CH:15]=5)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.[OH-:25].[Na+].OO.O>CO>[CH2:1]1[CH2:10][O:9][C:3]2([CH2:8][CH2:7][C@H:6]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:4]23[CH3:5])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[C@@H:17]3[O:25][C@@H:18]32)[CH:13]=[CH:12]4)[O:2]1
Reactant: C[C@]12C=CC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@]12C(=CC(=O)[C@@H]3O[C@@H]31)C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75 %

Procedure:
A solution of 1.0 g of 17, 17-ethylenedioxy-androsta-1,4,6-trien-3-one in 40 ml of methanol is treated at room temperature with 0.28 ml of 10% methanolic sodium hydroxide and 1.8 ml of 30% hydrogen peroxide and stirred at room temperature for 4.5 hours. 50 ml of water are added dropwise to the solution, the separated product is collected by suction and chromatographed on 30 g of silica gel. Elution with hexane/ether (3:2) yields 0.793 g (75%) of crystalline 17,17-ethylenedioxy-1α,2α-epoxy-androsta-4,6-dien-3-one. The analytical sample is prepared by recrystallisation from ether; melting point 181°-186° C.; [α]D25 =+167° (c=0.5 in dioxan); UV (ethanol): λmax 291 nm (ε=19270).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC1CCCC1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCCC2C)cc1
Reaction time: 10 h
Yield: 93 %

Procedure:
2-Methylcyclopentanol (21.06 g, 0.210 mol) and p-toluenesulfonyl chloride (48.3 g, 0.252 mol) were charged into a 500 cc three-necked flask equipped with a stirrer, and then pyridine (170 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 10 hours while gradually elevating the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (200 ml×3). The organic layers were combined, washed successively with 2N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain substantially pure 2-methylcyclopentyl p-toluenesulfonate as a colorless transparent oily substance (49.7 g, 0.195 mol, 93% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2>CN(C=O)C.C(OCC)(=O)C>[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:51][CH2:52][N:53]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)[CH2:54][CH2:55]1)(=[O:48])=[O:49])[CH:41]=[CH:40]2
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
4-(4-Pyridyl)benzoic acid (238 mg, 1.2 mmol) was suspended in DMF (5 mL) with triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 15 minutes then cooled to 5° C. Carbonyldiimidazole (194 mg, 1.2 mmol) was added and the reaction mixture allowed to warm slowly to room temperature over one hour. 4-(6-Bromonaphth-2-ylsulphonyl)piperazine hydrochloride (470 mg, 1.2 mmol) was added as a solid in one portion and the reaction mixture stirred for 2 days at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed twice with saturated aqueous sodium hydrogen carbonate solution (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was subjected to chromatography (SiO2; 2%, 4%, 6%, 8%, 10% methanol/ethyl acetate) to yield 1-(6-bromonaphth-2-ylsulphonyl)4-[4-(4-pyridyl)benzoyl]piperazine as a white solid (90 mg), 1H NMR (DMSO-d6) δ=3.07 ppm (s,4H), δ=3.59 ppm (s,4H), δ=7.27 & 7.46 ppm (dd,4H), δ=7.18 & 8.64 ppm (dd,4H), δ=7.34 ppm (m,2H), δ=8.17 ppm (dd,2H), δ=8.39 ppm (d,1H), δ=8.47 ppm (s,1H); MS (M+H)+ 536.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10](O)=[O:11])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([N:24]=[N+:25]=[N-:26])=[O:11])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOc1cc(C=CC(=O)O)ccc1OC(C)=O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CCOc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
26.2 g (0.1 mol) of 3-allyloxy-4-acetoxy-cinnamic acid are suspended in 90 ml of benzene and 14.6 ml (0.2 mol) of thionyl chloride are added. The reaction mixture is heated to the boil under reflux for 30 minutes. Thereafter the solvent and the excess thionyl chloride are removed by distillation under reduced pressure. The crude 3-allyloxy-4-acetoxy-cinnamic acid chloride which is left is dissolved in 100 ml of absolute dimethoxyethane, 19.5 g (0.3 mol) of sodium azide are added and the reaction mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by addition of ether. 3-Allyloxy-4-acetoxy-cinnamic acid azide of melting point 83°-84° C is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([SH:7])([CH3:6])[CH3:5].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH2:18][CH3:19])=[C:11]([CH3:20])[N:10]=1>CN(C)C=O>[C:4]([S:7][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH2:18][CH3:19])=[C:11]([CH3:20])[N:10]=1)([CH3:6])([CH3:5])[CH3:3]
Reactant: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc([N+](=O)[O-])c(SC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
To a suspension of sodium hydride (0.23 g, 9.8 mmol) in dimethylformamide (DMF, 20 mL) under an atmosphere of nitrogen, 2-methyl-2-propanethiol (1 mL, 8 mmol) was added. After stirring at room temperature for 15 minutes, a clear solution was obtained. Then a solution of 2-chloro-5-ethyl-6-methyl-3-nitropyridine (1.5 g, 7.5 mmol) in DMF (2 mL) was added, and the reacting mixture turned dark green to black in color. After addition was completed, the mixture was stirred for an additional 15 minutes, and then concentrated under reduced pressure (0.1 torr). The residue was subjected to column chromatography on silica gel, eluted with 60% chloroform in hexane. Collection and concentration of appropriate fractions yielded 0.5 g (26%) of the corresponding 2-tert-butylthiopyridine as a bright yellow solid.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:32]=[C:33]([N:36]2[CH2:39][CH:38]([OH:40])[CH2:37]2)[S:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[CH:1]1([O:5][C:6]2[C:15]([C:31]3[N:32]=[C:33]([N:36]4[CH2:39][CH:38]([OH:40])[CH2:37]4)[S:34][CH:35]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CN(c2nc(Br)cs2)C1
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3csc(N4CC(O)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.080 g, 0.20 mmol), 1-(4-bromothiazol-2-yl)azetidin-3-ol (0.056 g, 0.24 mmol), sodium carbonate (0.042 g, 0.40 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.081 g, 0.10 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was stirred for 4 h at 80° C. The reaction mixture was cooled to room temperature and filtered through a short pad of Celite. The filtrate was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (eluting with 2:1, ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, XBridge Prep C18 OBD Column, 5 um, 19×150 mm; mobile phase, water (0.03% aqueous ammonia) and acetonitrile (16.0 to 34.0% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV 254&220 nm. This afforded (S)-methyl 5-cyclobutoxy-6-(2-(3-hydroxyazetidin-1-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.030 g, 34%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.17 (d, J=6.40 Hz, 3H), 1.32-1.41 (m, 1H), 1.42-1.54 (m, 1H), 1.55-1.67 (m, 1H), 2.04-2.18 (m, 4H), 2.21-2.29 (m, 1H), 2.45-2.55 (m, 1H), 2.91-3.00 (m, 1H), 3.78 (s, 3H), 3.90-3.96 (m, 2H), 4.15-4.21 (m, 1H), 4.32-4.39 (m, 2H), 4.53-4.59 (m, 1H), 4.73-4.80 (m, 1H), 6.99 (s, 1H), 7.28-7.30 (m, 1H), 7.53-7.55 (m, 1H). MS (ESI, pos. ion) m/z 430 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2)[OH:29]
Reactant: CC(C=O)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(-n2ncc3cc(Br)ccc32)cc1
Product: COc1ccc(-n2ncc3cc(C(O)C(C)c4ccc(Cl)cc4Cl)ccc32)cc1

Procedure:
In analogy to Example 186, 5-bromo-1-(4-methoxy-phenyl)-1H-indazole was reacted with 2-(2,4-dichloro-phenyl)-propionaldehyde to give 2-(2,4-dichloro-phenyl)-1-[1-(4-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-ol which was oxidized to 2-(2,4-dichloro-phenyl)-1-[1-(4-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-one and converted further to the title compound. Off-white foam. MS (m/e)=495.1 [M+H+].
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1cccnc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2cccnc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (38 mg, 50%), MS (ISP) m/z=303.5 [(M+H)+], mp 252° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).