Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:17]I>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Ethyl 2-(4-cyanophenyl)acetate (4.0 g, 21.14 mmol) in tetrahydrofuran (20 mL) was added to a suspension of 60% sodium hydride (850 mg, 21.14 mmol) in tetrahydrofuran (20 mL) at 0° C. and stirred for 30 min. Methyl iodide (1.36 mL, 21.14 mmol) was added at 0° C.; reaction mixture was then stirred at room temperature for 4 h. Reaction mixture quenched with saturated NH4Cl solution (20 mL), diluted with water (200 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and evaporated to get crude, which was purified by column chromatography (silica gel; 60-120 mesh); the product eluted with 10% ethyl acetate in pet ether to yield ethyl 2-(4-cyanophenyl)propanoate (3.2 g, 75%) as colorless liquid.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[F:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]=O)[CH2:39][CH2:38]1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1>CCOCC>[F:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[C@H:37]1[CH2:38][CH2:39][C@H:40]([CH:43]=[CH:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:41][CH2:42]1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CCC=C[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C

Procedure:
First, 25.7 g of 3-ethoxycarbonylpropyltriphenylphosphonium bromide, 10.1 g of trans-4-(2,3-difluorophenyl)cyclohexanecarbaldehyde, and 150 ml of dry tetrahydrofuran were placed in a 300 ml flask. Then, 56.3 ml of 1.0M sodium bis(trimethylsilyl)amide/tetrahydrofuran solution was added dropwise to the reaction mixture at -70° C. to -60° C. The reaction mixture was stirred while being allowed to warm to room temperature over 6 hours. Ether was added to the reaction mixture. The ether solution was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/1) to obtain 9.0 g of 2,3-difluoro-1-[trans-4-(4-ethoxycarbonyl-1-butenyl)cyclohexyl]benzene (Y: 62%). The compound thus obtained had a purity of 89.2% (mixture of E and Z isomers) by GC.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20]>>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH:24][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH3:26])[CH2:19][CH3:20])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:20]
Reactant: CCN(CC)CCN
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Product: CCN(CC)CCNc1cccc2c1C(=O)c1c(NCCN(CC)CC)cccc1C2=O
Yield: 41.6 %

Procedure:
A mixture of 5.52 g (0.02 mol) of 1,8-dichloroanthraquinone and 23.2 g (0.2M) 2-(diethylamino)ethylamine is heated under reflux for 3 hours. The reaction product is washed up as described in Example 1 except that the oily residue is only washed with water and then dried to yield 3.63 g of the title compound as the free base in the form of a purple solid, m.p. 103.5°-106.5° C.; λmax (deionised water) (E/cm/M) 236 nm (54940), 542 nm (13200).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:19]([C:23]([CH3:29])=[C:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1)=[CH:20][CH2:21][CH3:22].C1([Li])C2CC3C(=CC=CC=3)C=2C=CC=1>C1COCC1.CCCCCC.O>[C:24]1([C:23]([CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)([CH3:29])[CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCC=CC(C)=C1C=CC=C1
Agent: [Li]CCCC
Agent: [Li]c1cccc2c1Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=CCCC(C)(C1=CC=CC1)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution was prepared by dissolving 10 g of fluorene in 100 mL of THF and then this was slowly reacted with 37.6 mL of a 1.6 molar solution of n-butyllithium in hexane. This dark red solution was stirred overnight at room temperature. Then a solution was prepared by combining 8.8 g of 6-(butenyl)-6-methylfulvene with 50 mL of THF. This solution was then added dropwise over a period of one half hour to the solution of the fluorenyl lithium salt. That reaction mixture was stirred overnight at room temperature and then 100 mL of water was added. The organic phase was dried overnight over sodium sulfate and the solvent was evaporated in a vacuum. The yellow residue was dissolved in pentane and filtered using silica gel. The solvent was concentrated by means of evaporation. Crystallization took place at about -18° C. to give 5-cyclopentdienyl-5-(9-fluorenyl)-1-hexene in a form of a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:37]=[C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[S:39][CH:40]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[S:39][CH:40]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1csc(-c2ccccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2csc(-c3ccccn3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-[4-(chloromethyl)-1,3-thiazol-2-yl]pyridine (0.72 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.80 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:8]3=1.CN(C)P(=O)(N(C)C)N(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:37][CH2:38][CH2:39]I)=[CH:32][CH:31]=1>CN(C)C=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH:36]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH2:39][N:16]2[CH2:15][CH2:14][C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH2:17]2)=[C:6]2[C:2]([CH3:1])=[CH:3][S:4][C:5]2=[CH:13][CH:12]=4)=[CH:34][CH:35]=1
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCC(c1ccc(F)cc1)c1ccc(F)cc1)CC4
Temperature: 80 °C

Procedure:
2.4 g of 1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole are dissolved in 50 ml of dimethylformamide and 10 ml of hexamethylphosphoric acid triamide 4.5 g of 4,4-bis-(4-fluorophenyl)butyl iodide are added and the mixture is warmed to 80° C. under N2 for 5 hours. The solvent is then evaporated off; the residue is taken up in chloroform, the chloroform mixture is washed with water, dried and evaporated, the residue is chromatographed on Al2O3 with chloroform and the product is recrystallised from isopropanol. Melting point: 158° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH:6]=[CH:7][CH2:8]OC(=O)C.[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])CC=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: C=CCC(NC(C)=O)C(=O)OC
Reactant: COC(=O)[C@H](CC=CCOC(C)=O)NC(=O)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)C(CC=CCC(NC(=O)c1ccccc1)C(=O)OC)NC(C)=O

Procedure:
2-Acetylamino-7-benzoylamino-oct-4-enedioic acid dimethyl ester 143 was synthesised using standard solution-phase metathesis conditions (refer to Section 7.5.2): 6-Acetoxy-2-benzoylamino-4-hexenoic acid methyl ester 142 (50 mg, 0.16 mmol), dichloromethane (10 mL), second generation Grubbs' catalyst (5 mol %, 7 mg, 8 μmol), methyl-2-acetylamino-4-pentenoate 21a (168 mg, 0.98 mmol), 50° C., 18 h. The desired compound was obtained as a brown oil and purified via column chromatography (SiO2; EtOAc:hexane; 2:1). 1H NMR (500 MHz, CDCl3, mixture of isomers (1:1.2)): δ 1.95, s (major isomer) and 1.97, s (minor isomer), 3H, CH3; 2.42-2.70, m, 4H, H3, 6; 3.62, s (minor isomer), 3.64, s (major isomer), 3.78, s (minor isomer) and 3.79, s (major isomer), 6H, 2×OCH3; 4.63-4.66, m, 1H, H2; 4.85-4.91, m, 1H, H7; 5.35-5.49, m, 2H, H4, 5; 6.20, d, J=7.7 Hz (major isomer) and 6.34, d, J=7.5 Hz, 1H, NH (minor isomer); 6.87, t, J=7.55 Hz, 1H, NH; 7.44, t, J=7.1 Hz, 2H, H4′, 6′; 7.50, t, J=6.9 Hz, 1H, H5′; 7.84, t, J=7.9 Hz, 2H, H3′, 7′. 13C NMR (75 MHz, CDCl3, mixture of isomers (1:1.2)): δ 22.83, CH3; 34.84, 35.05, 35.38 and 35.73, C3, 6; 51.51 and 51.55, C2; 52.35, 52.46, 52.53, 52.60 and 52.66, C7, 2×OCH3; 127.18 and 127.22, C3′, 7′; 128.57 and 128.62, C4′, 6′; 128.88 and 129.00, C4, 5; 131.86 and 131.91, C5′; 133.71, C2′; 167.06, COPh; 170.03 and 170.11, COMe; 172.20, 172.21, 172.24 and 172.43, 2×COOMe. Mass Spectrum (ESI+, CH3OH): m/z 399.2 (M+Na+) C19H24N2O6Na.
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][N:8]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[C:17]([NH:25]C(OC(C)(C)C)=O)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:10]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[O:40][CH:41]([F:43])[F:42])=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:17]1[C:16]([C:14]([NH:13][C:11]2[C:10]([C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH:41]([F:42])[F:43])=[N:9][N:8]([CH2:7][C:6]([OH:44])=[O:5])[CH:12]=2)=[O:15])=[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:19]2[N:18]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(NC(=O)c2c(NC(=O)OC(C)(C)C)nn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nn2cccnc2c1C(=O)Nc1cn(CC(=O)O)nc1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
To a solution of [4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-acetic acid tert-butyl ester (0.91 g, 1.43 mmol) in dichloromethane (7 mL) was added TFA (15 mL) and the mixture left to stir at room temperature for 6 hours. The solvent was evaporated and the resultant residue azeotroped with dichlormethane/methanol to afford the title compound as a pale yellow solid (0.66 g, 97%). LCMS (Method 3) [M+H]+=477.8, RT=2.95 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 13.15 (br s, 1H), 9.56 (s, 1H), 8.93 (dd, 1H, J=1.5, 6.8 Hz), 8.37-8.34 (m, 1H), 8.35 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.9 Hz), 7.26 (t, 1H, J=73.4 Hz), 7.00 (dd, 1H, J=4.5, 6.8 Hz), 6.58 (br s, 2H), 5.05 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:18][CH:19]([C:27]#[CH:28])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(NC(C)C)(C)C>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>[OH:17][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:28]#[C:27][CH:19]([OH:18])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCC(O)c1ccccc1Br
Reactant: C#CC(O)CCCC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCC(O)c1ccccc1C#CC(O)CCCC(=O)OC
Yield: 129.2 %

Procedure:
Into a heavy walled pyrex test tube was added 130 mg (0.43 mmol) of 1-(0-bromophenyl)-1-nonanol, 67 mg (0.43 mmol) of methyl 5-hydroxy-6-heptynoate prepared according to the procedure of Nicolaou et al., J.A.C.S., 106, 2748 (1984), 25 mg (0.02 mmol, 5 mole%) of Pd(PPh3)4, and 4 ml (93.0 mg) of diisopropylamine. The reaction was run and worked up according to the procedure of Example 11 to yield 208 mg of a yellow-brown oil. The oil was chromatographed on a silica gel column which was eluted with 70% diethyl ether/hexane to produce the titled product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8](Br)[CH2:9][CH2:10]Cl)=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[I-].[K+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:9][CH2:10][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C(Br)CCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C(c1ccc(F)cc1)C(CCN1CCOCC1)N1CCOCC1

Procedure:
A solution of 10 g. of 1-p-fluorobenzoyl-1-bromo-3-chloro-propane, 12.5 g. of morpholine and a catalytic quantity of potassium iodide in 100 cc. xylene is made to reflux for 12 hours and then cooled. The resulting solid is filtered and the filtrate extracted with dilute HCl. The separated aqueous phase is filtered hot using animal charcoal, cooled, made alkaline with dilute soda solution, and extracted with diethyl ether. The organic phases are combined, washed with water, dried and evaporated, m.p. : 82°C (from hexane).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([CH2:18]O)=[N:16][N:15]=[N:14]2)=[N:11][CH:12]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:18][C:17]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([F:21])([F:20])[F:5])=[CH:12][N:11]=2)[N:14]=[N:15][N:16]=1
Reactant: OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-n2nnnc2CCl)nc1
Reaction time: 2 h
Yield: 27.8 %

Procedure:
Thionyl chloride (0.22 g, 1.85 mmol) was added at room temperature to a solution of {1-[5-(Trifluoromethyl)-2-pyridinyl]-1H-tetrazol-5-yl}methanol (Intermediate 58, 0.20 g, 0.82 mmol) in toluene, and the reaction mixture was stirred for 2 hr at reflux. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and washed with ice-water, saturated NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 mesh silica gel) eluting with 0-20% ethyl acetate/pet ether to give the title compound (60 mg) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[CH3:27][N:28]([CH2:30][C:31](O)=[O:32])[CH3:29]>>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:31](=[O:32])[CH2:30][N:28]([CH3:29])[CH3:27])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CN(C)CC(=O)O
Product: Cc1ccc(NC(=O)Nc2nc(CCNC(=O)CN(C)C)cs2)c(C(=O)C2CCCC2)c1
Yield: 62.2 %

Procedure:
N-(2-{-2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl)-2-dimethylamino acetamide (37 mg, 61%) was prepared from 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol), dimethylamino acetic acid (0.02 g, 0.13 mmol) following the general procedure K.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH2:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc(NC2CCCNC2)nc1N

Procedure:
Analogously to the preparation of Example 38A, 150 mg (0.39 mmol) of tert-butyl 3-{[4-amino-5-(methoxycarbonyl)-1,3-thiazol-2-yl]amino}piperidine-1-carboxylate and 20 ml of hydrochloric acid in dioxane (4M) gave 130 mg (99% of theory) of the product as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[O:35])[CH:29]=1>>[OH:35][CH:34]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([O:26][CH3:25])=[O:36])[CH:29]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Agent: [Li]CCCC
Product: CCCCCCCCC(O)/C=C/c1cccc(C(O)c2cccc(C(=O)OC)c2)n1
Yield: 25.5 %

Procedure:
Under the conditions of example 1B, 326 mg of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine is reacted with 1.38 ml of n-butyllithium (1.6 molar in hexane) and 181 mg of 3-formylbenzoic acid methyl ester (J. Org. Chem. 31, 1966, 2585), worked up and chromatographed on silica gel with hexane/ethyl acetate 8/2. 105 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][S:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[S:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: Cc1c(SCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CSc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution 2-[4-(4-hydroxy-butyl)-benzylsulfanyl]-3-methyl-chromen-4-one (300 mg, 0.85 mmol) dissolved in anhydrous dichloromethane (8.0 mL) was added TsCl (194 mg, 1.01 mmol), DMAP (124 mg, 1.01 mmol) and TEA (0.213 mL, 1.52 mmol). The reaction mixture continued stirring at room temperature. After 3 hours the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (1:1 pentane:ethyl acetate) to yield toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-chromen-2-ylsulfanylmethyl)-phenyl]-butyl ester (280 mg, 0.55 mmol) in moderate yield (65%). 1H (CDCl3, 600 MHz): δ 8.18 (1H, dd, J=7.9,1.3 Hz), 7.77 (2H, d, J=8.2 Hz). 7.62 (1H, m), 7.39 (2H, t, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz), 7.30 (2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz), 4.37 (2H, s), 4.02 (2H, t, J=5.8 Hz), 2.55 (2H, t, J=7.3 Hz), 2.05 (3H, s), 1.65 (4H, m); 13C (CDCl3, 150 MHz): δ 175.5, 162.2, 156.7, 144.9, 141.5, 134.1, 133.4, 133.0, 130.0, 129.1, 129.0, 128.1, 126.5 125.3, 122.9, 117.5, 117.0, 70.5, 35.3, 34.9, 28.6, 27.2, 21.8, 10.8.; HRMS calcd for C28H28O5S2 509.1450. found 509.1441.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][CH:9]([CH2:14][CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Yield: 55.1 %

Procedure:
A mixture of 0.058 g (0.00019 mole) of (rac)-2-chloro-9-cyclopentyl-7-ethyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-12), 0.038 g (0.00023 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.046 g of (rac)-4-(9-cyclopentyl-7-ethyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-12) as an off-white solid.
Reaction SMILES: [CH2:1]([NH:8][S:9]([CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][C@@H:19]1[CH2:36][C:35]2[CH:34]=[C:33]([OH:37])[CH:32]=[CH:31][C:30]=2[C@@H:29]2[C@@H:20]1[C@H:21]1[C@@:25]([CH2:27][CH2:28]2)([CH3:26])[C@@H:24]([OH:38])[CH2:23][CH2:22]1)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][S:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]1[CH2:36][C:35]2[CH:34]=[C:33]([OH:37])[CH:32]=[CH:31][C:30]=2[C@@H:29]2[C@@H:20]1[C@H:21]1[C@@:25]([CH2:27][CH2:28]2)([CH3:26])[C@@H:24]([OH:38])[CH2:23][CH2:22]1)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNS(=O)(=O)CCCC=CCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCNS(=O)(=O)CCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
A solution of N-heptyl-7-(3,17β-dihydroxy-oestra-1,3,5(10)-trien-7α-yl)hept-4-enesulphonamide (Example 36; 0.04 g.) in ethyl acetate (10 ml.) was stirred with a 10% palladium-on-charcoal catalyst (0.01 g.) at laboratory temperature for 90 minutes and then filtered, and the filtrate was evaporated to dryness. There was thus obtained as residual oil N-heptyl-7-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)heptanesulphonamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.