Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>C1CCCCC1.CCCCCCC>[CH2:3]([C:4](=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][CH3:1]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCCCC(=O)CCC
Solvent: CCCCCCC
Solvent: C1CCCCC1
Product: CCCCCCC(CCC)=NNC(=O)OC(C)(C)C
Yield: 92.9 %

Procedure:
24.76 g (158 mmol) of 4-decanone and 20.94 g (158 mmol) of tert-butyl carbazate are heated for 90 minutes at 80° C. in 250 ml of cyclohexane/heptane mixture (1:1). After cooling, 39.71 g (93%) of a white solid are obtained by crystallization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH3:10].C(=O)([O-])[O-:28].[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:10])=[O:28]
Reactant: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1SC
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)=O
Reaction time: 1 h

Procedure:
In 150 ml of chloroform-ethanol was suspended 3.40 g of 2-(3-methoxy-4-methylthiophenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole. Thereto was added, in small portions, 1.97 g of methachloroperbenzoic acid (80%) under ice-cooling. The mixture was stirred for 1 hour. Then, the mixture was returned to room temperature and stirred overnight. Thereto was added an aqueous sodium carbonate solution. The mixture was extracted with chloroform three times. The combined extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the resulting crystals were recrystallized from dimethylformamide to obtain 0.50 g of 2-(3-methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as light yellow acicular crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34](Cl)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:38]1([C@@H:44]([CH2:46][OH:47])[NH2:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:45][C@@H:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:46][OH:47])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N[C@H](CO)c1ccccc1
Reactant: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2c(S(=O)(=O)N[C@H](CO)c3ccccc3)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a suspension of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid chloride (prepared in Example 204) (2.05 g) in chloroform (60 ml) were added (S)-2-phenylglycinol (767 mg) and diisopropylethylamine (0.99 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure and thereto were added 1N hydrochloric acid (30 ml) and ethyl acetate (60 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford (S)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-sulfonamide (813 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](=N)[NH2:34])[CH3:24]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:34][C:33]([CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH2:23][CH3:24])=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CCOc1ccccc1CC(=N)N
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccccc1Cc1nnc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)[nH]1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
50 mg (0.16 mmol) of the compound from Example 21A were taken up in 1 ml of DMF, 52 mg (0.24 mmol) of 2-(2-ethoxyphenyl)ethaneimidamide hydrochloride were added and the mixture was stirred in a microwave oven at 200° C. for 1 h. After cooling, the reaction was diluted with about 1 ml of methanol and the solution was directly separated by preparative HPLC [Method 19]. This gave 21 mg (28% of theory) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]([C:8]1[CH:13]=[CH:12][N+:11]([O-:22])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccncc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2ccccc2)cc1
Reaction time: 22 h

Procedure:
To a solution of 4-phenoxypyridine (3.0 g, 17.5 mmol) in dichloromethane (500 mL) was added 3-chloro-perbenzoic acid (5.18 g, 21.0 mmol) on an ice bath, and the solution was stirred for 22 hours. An aqueous solution of saturated sodium thiosulfate and an aqueous solution of saturated sodium bicarbonate were added to the reaction solution, the solution was stirred at room temperature for 10 minutes, then, the organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and 4-phenoxy-pyridine N-oxide (3.3 g, quantitatively) was obtained as a pale yellow solid.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].C[O-].[Na+].CO.[CH3:13][C@H:14]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:15]([C:20](OC)=[O:21])[C:16](OC)=[O:17].Cl>CO>[OH:21][C:20]1[C:15]([C@H:14]([CH3:13])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:16]([OH:17])[N:7]=[CH:5][N:6]=1
Reactant: N=CN
Reactant: COC(=O)C[C@@H](C)C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C[C@@H](C)c1c(O)ncnc1O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To the solution of formamidine acetate (1.05 eq) in methanol (5 vol) was added 29.2% NaOMe/methanol (3 eq) at 0° C. for 0.25 h and the mixture was stirred for 0.5 h. To this was added the mixture of (R)-trimethyl 2-methylpropane-1,1,3-tricarboxylate (1.1 kg, 20 L) and methanol (50% w/w) for 0.5 h. After warming to 20° C., the reaction mixture was stirred for 14 h. The reaction mixture was neutralized with 5% aq HCl at 0° C. When pH was about 7, the mixture was concentrated. To the mixture was added methanol (0.7 vol), the mixture was washed with MTBE (5 vol), acidified with HCl to pH about 2 at 2° C., and stirred for 1 h at 60° C. After cooling to 0° C., the mixture was filtered and the cake was washed with water (1 vol) and dried in vacuum at 50° C. to get the product as solid (0.8 kg, 66% yield, 96% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)NO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)NOC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4-Chlorobenzoyl chloride (1.10 mL, 8.57 mmol) is added slowly to a solution of ethyl hydroxycarbamate 6 (1.00 g, 9.52 mmol) and triethylamine (1.19 mL, 8.57 mmol) in diethyl ether (30 mL) at 0° C. then stirred at room temperature for 30 min. The reaction is quenched with HCl (1 M; 10 mL) then water (100 mL) is added and extracted with diethyl ether (100 mL). The organic layer is washed with sat. NaHCO3 (50 mL), water (50 mL), dried with MgSO4 and concentrated. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 9:1 then 8:2) to yield 7 (1.54 g) as an off-white solid. M.p. 79° C. (determined by differential scanning calorimetry, sharp onset); FTIR (neat, cm−1) 3210, 3094, 2990, 1765, 1708, 1588, 1495, 1487, 1473, 1443, 1401, 1368, 1298, 1283, 1249, 1235, 1177, 1121, 1107, 1090, 1054, 1016, 996, 876, 852, 771, 747, 728, 681; 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 8.02 (dt, J=2.1, 8.7 Hz, 2H), 7.46 (dt, J=2.1, 8.7 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.1, 156.6, 140.9, 131.3, 129.1, 125.2, 63.0, 14.3; HRMS (ES+) m/z calcd for C10H10ClNO4 (M+Na)+ 266.0191, found 266.0199.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)c(F)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(Cl)c(F)ccc2[nH]1
Reaction time: 3 h
Yield: 95.2 %

Procedure:
A suspension of 6.3 g of ethyl 4-chloro-5-fluoroindole-2-carboxylate in 260 ml of ethanol was treated with 130 ml of 2N sodium hydroxide solution and stirred for 3 hours. Ethanol was evaporated and the reaction solution was adjusted to pH 1 with 25% hydrochloric acid. The precipitate was washed with water and dried. There were obtained 5.3 g (96%) of crude 4-chloro-5-fluoroindole-2-carboxylic acid which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Brc1ccc2c(N3CCCCC3)nncc2c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCCCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A mixture of 6-bromo-1-(piperidin-1-yl)phthalazine (0.12 g, 0.40 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.12 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol) and 2M potassium carbonate (0.6 mL, 1.2 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was transferred directly to silica gel and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give the title compound (0.13 g) as yellow solid. Found MS (ES+): 387(M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]O.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[Br:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][C:15]#[N:17]
Reactant: CCN(CC)CC
Reactant: COCOc1cc(Cl)c(Br)cc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COCOc1cc(Cl)c(Br)cc1CC#N
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 5-bromo-4-chloro-2-methoxymethoxybenzyl alcohol (137.9 g) and triethylamine (105 ml) in dichloromethane (500 ml) was added at 0° C. methanesulfonyl chloride (45.5 ml) over a period of 30 minutes. The mixture was stirred overnight (13 hours), while warming up to room temperature. The reaction mixture was poured into water, to which was added dichloromethane for extraction. The extract solution was dried (anhydrous magnesium sulfate) and concentrated. To a suspension of the concentrate and sodium cyanide (51.4 g) in dichloromethane (40 ml) was added dropwise at 0° C. DMSO (300 ml). The mixture was then stirred for 3 hours at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous magnesium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-4-chloro-2-methoxymethoxybenzyl cyanide (86.4 g) (Compound B-35). The physical properties are shown in [Table 6].
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[S:10][C:11]([C:15]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[C:12]([CH3:14])[N:13]=1>>[CH3:14][C:12]1[N:13]=[C:9]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])[S:10][C:11]=1[C:15]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: O=c1cccc[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-n2ccccc2=O)sc1C(=O)NCc1cccnc1
Yield: 21 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 21% yield: mp 218-220° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.6 Hz, 1H), 8.71 (dd, J=7.3, 1.3 Hz, 1H), 8.56-8.43 (m, 2H), 7.71 (d, J=7.3 Hz, 1H), 7.68-7.59 (m, 1H), 7.38 (br s, 1H), 6.74 (d, J=9.2 Hz, 1H), 6.60-6.55 (m, 1H), 4.42 (d, J=5.7 Hz, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 160.2, 153.8, 150.8, 149.3, 148.4, 141.4, 135.5, 131.5, 124.2, 120.9, 108.7, 41.0, 17.5; MS (ES+) m/z 327.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560 mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 as a white powder: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J=13 Hz, 1H), 5.04 (t, J=11 Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.21 (s, 1H), 7.02 (s, 1H), 7.22 (d, J=10 Hz, 1H), 7.45 (s, 1H), 7.99 (d, J=10 Hz, 1H), 10.82 (broad s, 1H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5](=[C:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:5](=[C:12]1[CH2:16][CH2:15][N:14]([C:1]([Cl:4])=[O:2])[C:13]1=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1NCCC1=Cc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(Cl)N1CCC(=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g (20.5 mmols) of phosgene are added to a suspension of 3.0 g (18.6 mmols) of 3-benzylidene-2-pyrrolidinone 50 ml in abs. ethyl acetate at -20°. A solution of 3.8 g (20.5 mmols) of tri-n-butylamine in 20 ml of abs. ethyl acetate is added dropwise to this mixture at 0° to 5°. After stirring for 4 hours at room temperature, dry nitrogen is passed through the mixture for 30 minutes and the mixture is then concentrated. Water is added to the oily residue, whereupon the acid chloride precipitates in the solid form. It is filtered off and dried over P2O5 and KOH is a desiccator. 3.5 g (84.5%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:13])[CH:10]=[N+]=[N-])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22].O1CCOCC1>CCOCC>[Cl:22][CH2:10][C:9](=[O:13])[C@@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)C=[N+]=[N-]
Reactant: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)CCl

Procedure:
To a solution of the crude (S)-tert-butyl 1-cyclohexyl-4-diazo-3-oxobutan-2-ylcarbamate (7 g, ˜65% pure) in anhydrous ether (150 mL) at 0° C. was added dropwise a solution of 3.65 N HCl in dioxane (4.1 mL, 0.015 mmol). The mixture was stirred until tlc showed the starting material had been consumed. Satd aq NaHCO3 was added and the organic layer was separated, washed with satd aq NaHCO3 and brine, and concentrated to afford a solution of crude (S)-tert-butyl 4-chloro-1-cyclohexyl-3-oxobutan-2-ylcarbamate (5.8 g), which was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:18])=[N:10][N:9]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]1>CS(C)=O>[Cl:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:19]2[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]2)=[N:9][N:10]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OC1CCCN(c2nnc(Cl)c3ccccc23)C1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A resealable pressure bottle was charged with potassium carbonate (273 mg, 2.0 mmol), 1,4-dichlorophthalazine (590 mg, 3.0 mmol), piperidin-3-ol (200 mg, 2.0 mmol) and methylsulfinylmethane (10 mL, 0.2M). The vessel was sealed and the mixture stirred at 90° C. for 24 hrs. Next day the reaction was cooled to RT and diluted with 5 ml of DMSO. The solution was purified by Gilson reverse phase liquid chromatography (10% to 90% CH3CN/H2O/0.1% TFA) to afford 1-(4-chlorophthalazin-1-yl)piperidin-3-ol. MS m/z=264 [M+1]+. Calculated for C13H14ClN3O: 263.7.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32]C(C(O)=O)=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 4 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol) was added dropwise to a solution of 3-(tert-butyloxycarbonyl)-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.0 g, 3.7 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J. Org. Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.5 ml, 10 mmol) in 10 ml of anhydrous CH2Cl2. After 4 hrs, CH2Cl2 was removed by evaporation at reduced pressure. Flash chromatography (4×20 cm, hexane-ethyl acetate, 1:2) afforded 1b as a yellow crystalline solid (1.25 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.39 (d, 1H, J=1.4 Hz, NH), 8.02 (m, 1H, C6F4H), 7.9 (br s, 1H, C4—H), 7.45 (d, 1H, J=1.4 Hz, C8—H), 7.33 (d, 1H, J=9 Hz, C5—H), 4.02 (t, 2H, J=9 Hz, NCH2CH2), 3.26 (t, 2H, J=9 Hz, NCH2CH2), 1.51 (s, 9H, C(CH3)3). Anal. Calcd. for C22H18N2O4F4: C, 58.67; H, 4.03; N, 6.22. Found: C, 58.45; H, 4.09; N, 6.13.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH2:14][CH3:15])[CH:11]([OH:16])[C:10]([CH2:18][CH3:19])([CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:18]([C:10]1([CH3:17])[CH:11]([OH:16])[CH:12]([CH2:14][CH3:15])[CH2:13][NH:8][CH2:9]1)[CH3:19]
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCC(C)(CC)C1O

Procedure:
A mixture of 1-benzyl-3,5-diethyl-4-hydroxy-3-methylpiperidine (1.8 g, 6.89 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred in hydrogen atmosphere (4 atm.) for 3 hr at 45° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to give 3,5-diethyl-4-hydroxy-3-methylpiperidine as oil. Yield 1.1 g (94%), C12H2,NO, m/z 172 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1cccc(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#Cc1cccc(OCCOC)c1
Yield: 70.1 %

Procedure:
3-Hydroxyphenylacetylene (237 mg, 2 mmol) was heated with 2-bromoethylmethylether (0.23 mL, 2.4 mmol) and potassium carbonate (322 mg, 2.4 mmol) in acetone (5 mL) to 110° C. in a microwave oven (CEM Discover) for 45 minutes. Water (1 mL) was added to the mixture and the whole was extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a brown oil. The oil was purified by column chromatography (SiO2, dichloromethane) to afford 3-(2-methoxyethoxy)phenylacetylene as a colourless oil (247mg, 70% yield).