Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>ClCCl>[Cl:36][C:37]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:38]=1[C:39]([NH:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[F:1])=[O:40]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccc(F)cc3Cl)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To an ice-cold mixture of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (170 mg, 0.52 mmol) and N,N-diisopropylethylamine (140 mg, 1.03 mmol) in 5 mL of dichloromethane was dropwise added a solution of 2-chloro-4-fluorobenzoyl chloride (120 mg, 0.62 mmol) in 3 mL dichloromethane under nitrogen. Then the resulted mixture was stirred at R.T. for overnight. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The solvent was removed by rotary evaporation. The residue was purified by silica gel (petroleum ether/ethyl acetate=3:1) to afford 189 mg of methyl 2-(3-(2-chloro-4-fluorobenzamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid; yield: 76%. MS (ESI+APCI) M+1=485.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:37](CC)CC.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32]([NH2:37])=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.25 h

Procedure:
To a solution of the title acid of Example 2 (200 mg) in CH2Cl2 (3 mL) and CH3CN (1 mL) at 0° C. was added Et3N (120 μL) followed by 2-chloro-methylpyridinium iodide (220 mg). After stirring for 75 mins. at 0° C., an excess of NH3 was slowly bubbled into the mixture and the reaction was allowed to stir at RT for 12 h. It was then diluted with ethyl acetate and washed successively with aq. NH4OAc (×2) and brine. After drying, the organic solution was concentrated and the residue was purified on a column of silica to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:23][C:24]([O:26][CH:27]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:25])=[CH:11][C:12]([O:15][Si](C(C)(C)C)(C)C)=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:23][C:24]([O:26][CH:27]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[O:25])=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:7])=[CH:40][CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1cc(O)ccc1NC(=O)c1ccc(Cl)cc1)OC(c1ccncc1)C1CCNCC1
Reaction time: 18 h
Yield: 62.4 %

Procedure:
A solution of N1-(4-chlorobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbony]-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (97 mg, 0.16 mmol) in tetrahydrofuran (2 mL) was treated with 5 N aqueous hydrochloric acid (0.5 mL) and allowed to stand at ambient temperature for 18 h. Volatile solvents were removed in vacuo and the residue diluted with dilute sodium hydrogen carbonate solution, hexane, and methylene chloride. The mixture was sonicated 5 min then filtered. The resultant material was vacuum dried to yield 48 mg (61%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1C=C[N:8]=[C:7]1[C:11]1([OH:21])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.C(I)C.O>C1COCC1.CCOC(C)=O>[CH2:3]([C:2]1[S:6][C:7]([C:11]2([OH:21])[CH2:20][CH2:19][C:14]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:13][CH2:12]2)=[N:8][CH:1]=1)[CH3:4]
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Reactant: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cnc(C2(O)CCC3(CC2)OCCO3)s1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of n-butyllithium (5.70 mL of 1.6 M solution in hexane, 9.12 mmol) was added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.00 g, 4.14 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, ethyl iodide (0.736 mL, 9.12 mmol) was added to the lithiated compound solution via syringe at −78° C. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed using 20% EtOAc/hexane to give 0.79 g of the title compound in 71% yield. MS (EI) calcd: (M+H)+=270.1; found: 270.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S@:17](=[O:48])[C@H:12]23)=[O:9])[N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)C[S@](=O)[C@H]12)c1csc(N)n1
Yield: 69 %

Procedure:
4-Methoxybenzyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (see example 7) (250 mg, 0.44 mmol) in ethyl acetate (25 ml) was stirred in an ice bath and a solution of m-chloroperbenzoic acid (75 mg, 0.44 mmol) in ethyl acetate (5 ml) was added. After 10 min the reaction mixture was washed with dilute aqueous sodium hydrogen carbonate then water followed by drying (magnesium sulphate) and evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with acetone/ethyl acetate mixtures to give the title compound as a white solid (179 mg, 69%); νmax (CHCl3) 1800, 1730, 1680 and 1610 cm-1 ; δH (CDCl3) 1.48-1.64 (1H,m), 1.89-2.00 (2H,m), 2.33-2.47 (1H,m), 3.29 and 3.75 (2H, ABq, J 19 Hz), 3.82 (3H,s), 3.84-3.96 (2H,m), 4.09 (3H,s), 5.06 (1H,dd, J 7, 9 Hz), 5.22 (2H,s), 5.55-5.8 (1H, br s, exch), 6.16 (1H,dd, J 4.5, 10 Hz), 6.91 (2H,d, J 7.9 Hz), 6.98 (1H,s), 7.35 (2H,d, J 9 Hz) and 7.55-7.65 (1H,br, exch). [Mass spectrum: +ve ion (thioglycerol) MH+ (590)].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A mixture of 0.040 g (0.1 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.029 g (0.11 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.030 g (0.15 mmole) of p-toluenesulfonic acid monohydrate and 2 mL of isopropanol was stirred in a pressure tube at 140 degrees overnight. The mixture was cooled, diluted with dichloromethane and saturated sodium carbonate and extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-50:50) gave 0.033 g of give 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-137) as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:12]#[C:13]/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])[CH:7]([CH3:8])[CH2:6][C:5](=[O:9])[CH2:4][C:3]1([CH3:11])[CH3:10]>[O-2].[O-2].[Mn+4].CC(C)=O>[OH:1][C:2]1([C:12]#[C:13]/[C:14](/[CH3:18])=[CH:15]/[CH:16]=[O:17])[CH:7]([CH3:8])[CH2:6][C:5](=[O:9])[CH2:4][C:3]1([CH3:10])[CH3:11]
Reactant: C/C(C#CC1(O)C(C)CC(=O)CC1(C)C)=C\CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: C/C(C#CC1(O)C(C)CC(=O)CC1(C)C)=C\C=O
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A mixture of (±)-E-4-hydroxy-4-(5-hydroxy-3-methylpent-3-en-1-ynyl)-3,3,5-trimethylcyclohexanone (2.0 g, 8.0 mol), manganese dioxide (14 g, 160 mmol), and acetone (50 mL) were combined and strred for 1.5 h. The mixture was filtered, the solvent removed by evaporation, and the residue chromatographed over silica eluting with 75% ether and 25% hexane to afford 1.17 g (±)-E-4-hydroxy-4-(5-oxo-3-methylpent-3-en-1-ynyl)-3,3,5-trimethylcyclohexanone (58%), as an oil, that gave ir: 3600 (strong), 220 (weak), 1710, 1660, 900 cm-1; gc/eims: 248 (M+, 15%) 233 (9), 219 (19), 205 (16), 192 (42), 163 (95) and 121 (100); 1H nmr -∥: 0.99 and 1.20 (s, gem CH3, 6H), 1.14 (d, J=5.9 Hz, HCCH3, 3H), 2.11 (dd, J=14.3, 2.3 Hz, H-2 eq, 1H), 2.18 (m, H-6eq, 1H), 2.3 (m, 2H), 2.32 (d, J=1.5 Hz, =CCH3, 3H), 2.60 (d, J=14.3 Hz, H-2ax, 1H), 6.22 (dq, J=7.7, 1.5 Hz, =CH, 1H), and 10.03 (d, J=7.7 Hz, CHO, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:20][CH3:21])=[N:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]2)=[CH:7][CH:6]=1)=[O:4].O>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:20][CH3:21])=[N:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCc1nn(C2C=CCCC2)c2cc(C(=O)OC)ccc12
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCCC2)c2cc(C(=O)OC)ccc12
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
A mixture of 417 mg (1.47 mmol, 1.0 equiv) 1-cyclohex-2-enyl-3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 50 mg of 10% Pd/C, 50% water wet in 20 mL ethyl acetate was placed on a Parr® hydrogenation appartus and shaken under 45 psi H2 for 45 minutes. The reaction mixture was filtered through Celite®, and the filtrate concentrated on a rotary evaporator and dried at high vacuum, room temperature to give 399 mg (95%) of a clear oil: HRMS calcd for C17H22N2O2+H: 287.1759. Found: 287.1783.
Reaction SMILES: [C:1](O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>OS(O)(=O)=O>[Br:11][C:12]1[C:17]2[C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[S:4][C:16]=2[C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1S
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=c1c2ccccc2sc2c(O)ccc(Br)c12
Reaction time: 48 h
Yield: 60.8 %

Procedure:
Thiosalicylic acid (20.0 g, 129.71 mmol) and 4-bromophenol (35.9 g, 207.53 mmol) were suspended in conc. H2SO4 (200 ml) and stirred for 48 hours. The red solution was slowly poured onto ice (500 ml) with vigorous stirring. The resulting yellow precipitate was filtered, and dried in a vacuum oven (50° C.) to give the title compound (24.23 g, 61%) as a yellow amorphous solid. m/z (LC-MS, ESP), RT=4.39 min, (M−−1)=305–307.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:16]3[N:24]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:19]4=[N:20][CH:21]=[CH:22][CH:23]=[C:18]4[CH:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:8][C:7]=1[O:35][CH3:36].[I-:37].[Na+].C1CCCCC1.C(OCC)(=O)C>C(C(C)=O)C.ClCCl>[I:37][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:16]3[N:24]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:19]4=[N:20][CH:21]=[CH:22][CH:23]=[C:18]4[CH:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:8][C:7]=1[O:35][CH3:36]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCI
Yield: 75.3 %

Procedure:
A solution of 2-[6-(3-chloropropoxy)-5-methoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.415 g; 792 μmol) in methyl ethyl ketone (10 ml) is placed in a 50 ml single-necked flask and sodium iodide (0.178 g; 1.18 mmol) is then added. The reaction mixture is refluxed for 16 hours. Analysis by thin layer chromatography (50/50 cyclohexane/ethyl acetate) shows that the starting compound is still present. Additional sodium iodide (0.178 g; 1.18 mmol) is introduced and the reflux is maintained for 3 hours. After returning to 20° C., the precipitate is dissolved in dichloromethane (200 ml) and then washing with water (50 ml) and drying over magnesium sulfate are carried out. After evaporation, the residue is taken up in ethyl acetate (20 ml); the insoluble material is removed and the filtrate is then evaporated under reduced pressure. 2-[6-(3-Iodopropoxy)-5-methoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.367 g; 75%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.[BH4-].[Na+].O.Cl>C(O)(C)C>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CSc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C(O)CSc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a stirred suspension of ethyl 3-(4-biphenylylthio)-2-oxopropionate (1.44 g, 0.0048 mole) in isopropanol (24 ml) was added sodium borohydride (0.18 g, 0.0048 mole). After 2 hrs., water (75 ml) and 2 N HCl (0.5 ml) were added. The mixture was extracted with methylene chloride (2×150 ml). The contents of the combined extracts, after drying (Na2SO4) and concentration, were chromatographed on silica gel (120 g) using 1,1,1-trichloroethane as eluting solvent to obtain 0.35 g (24%) of ethyl 3-(4-biphenylylthio)lactate, m.p. 101.5°-102° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35]Br)/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:38][SH:39]>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][S:39][CH3:38])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CS
Agent: [Na]
Product: CSCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
N.m.r. in solvent C: 1.44 (s, 9H), 4.75 (d, 2H), 5.92 (m, 1H), 6.56 (s, 1H), 6.7-6.9 (m, 2H), 7.29 (s, 15H). 2. N.m.r. in solvent C: 3.4 (m, 2H), 3.9 (d, 1H), 4.45 (d, 1H), 4.9 (m, 2H), 5.02 (d, 1H), 5.7 (m, 1H), 5.95 (d, 1H), 6.83 (s, 1H), 6.9 (d, 1H), 7.32 (s, 15H). 3. The starting material was prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-bromoethoxyimino)acetate (UK Patent Application 2017702A) with the sodium salt of methyl mercaptan and hydrolysis of the resulting ester to give 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-methylthioethoxyimino)acetic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6]([Cl:16])[N:5]=[C:4]([NH2:17])[N:3]=1.[CH3:18][O-:19].[Na+]>>[Cl:16][C:6]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:2]([O:19][CH3:18])[N:3]=[C:4]([NH2:17])[N:5]=1
Reactant: CC(=O)N1CCN=C1c1c(Cl)nc(N)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(N)nc(Cl)c1C1=NCCN1
Reaction time: 3 h

Procedure:
3.5 g 4,6-dichloro-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are introduced into 30 ml 1% sodium methylate solution. After three hours, the precipitate is vacuum dried, washed with water, and recrystallized from nitromethane. 2.1 g of 4-chloro-6-methoxy-5-(2-imidazolin-2-yl)-aminopyrimidine (melting point 212° C.), is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][OH:27].[CH2:28]([O:30][C:31]([C:33]1[O:34][C:35]2[CH:41]=[CH:40][C:39](O)=[CH:38][C:36]=2[CH:37]=1)=[O:32])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:28]([O:30][C:31]([C:33]1[O:34][C:35]2[CH:41]=[CH:40][C:39]([O:27][CH2:26][C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]5[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]6[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=6)[CH2:14]5)[C:6]=4[C:2]=3[CH3:1])=[CH:38][C:36]=2[CH:37]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Reactant: Cc1c(CO)oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCC5CCCN(Cc6cccnc6)C5)c4c3C)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
[3-Methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-yl]-methanol (107 mg), 5-hydroxybenzofuran-2-carboxylic acid ethyl ester (60 mg), triphenylphosphine (100 mg) and azodicarboxylic acid diethyl ester (70 μl) were dissolved in THF (7 ml). The solution was stirred overnight at room temperature. A white precipitate separated out. The precipitate was filtered out and the filtrate was evaporated to dryness. The residue was separated by silica gel column chromatography developed by dichloromethane-methanol to give 5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-carboxylic acid ethyl ester (48 mg) as a colorless oil. FAB-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 1.25-2.23 (7H, m), 1.43 (3H, t, J=7 Hz), 2.24 (3H, s), 2.78 (1H, m), 2.95 (1H, m), 3.47 (1H, d, J=13 Hz), 3.57 (1H, d, J=13 Hz), 3.89 (2H, m), 4.44 (2H, q, J=7 Hz), 5.10 (2H, s), 6.55 (1H, d, J=8 Hz), 7.04 (1H, d, J=8 Hz), 7.14 (1H, dd, J1=9 Hz, J2=2 Hz), 7.23 (3H, m), 7.47 (1H, m), 7.48 (1H, s), 7.66 (1H, br d, J=7 Hz), 8.48 (1H, br d, J=5 Hz), 8.53 (1H, br s).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH2:11][CH:12]=O)=[CH:4][CH:3]=1.Cl.[N:15]1([C:21](=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.N1ON=C2C=C(CCN3CCN(C(=O)CC4C=CC(N5C=NN=N5)=CC=4)CC3)C=CC=12>>[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH2:11][CH2:12][N:18]2[CH2:17][CH2:16][N:15]([C:21](=[O:34])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH:33]=[N:32][N:31]=[N:30]4)=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: Cc1c(CC=O)ccc(F)c1C#N
Agent: Cl
Agent: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCN(CCc2ccc3nonc3c2)CC1
Product: Cc1c(CCN2CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC2)ccc(F)c1C#N

Procedure:
6-Fluoro-2-methyl-3-[2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]benzonitrile was prepared from 6-fluoro-2-methyl-3-(2-oxoethyl)benzonitrile and 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride in an analogous fashion to that described for 1-{4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazin-1-yl}-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (General Method C). 1H-NMR (400 MHz, CD3OD) δ 9.89 (s, 1H), 7.76˜7.78 (m, 2H), 7.51˜7.55 (m, 1H), 7.40˜7.42 (m, 2H), 7.21˜7.25 (m, 1H), 4.44˜4.45 (m, 1H), 4.16˜4.17 (m, 1H), 3.84 (s, 2H), 3.38˜3.56 (m, 2H), 2.98˜3.01 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(N3CCOCC3)ccc21
Product: CC1c2ccc(N3CCOCC3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][C:15]1[CH:16]=[C:17]([C:21](=[O:37])[CH2:22][C:23]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)(O)[C:24]([F:27])([F:26])[F:25])[S:18][C:19]=1[CH3:20]>C(N(CC)CC)C>[Br:14][C:15]1[CH:16]=[C:17]([C:21](=[O:37])[CH:22]=[C:23]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[C:24]([F:27])([F:25])[F:26])[S:18][C:19]=1[CH3:20]
Reactant: Cc1sc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1sc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 12 h
Yield: 89.9 %

Procedure:
Triethylamine (53 ml) and trifluoracetic anhydride (38 ml) are added to a solution of -(4-bromo-5-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butan-1-one (110 g, 77% purity) at 0° C. After 12 hours at room temperature, the reaction is quenched with water (200 ml) and a saturated aqueous solution of NaHCO3. The aqueous phase is separated and further extracted with two times dichloromethane. The organic phases are combined, washed with water, dried over MgSO4 and concentrated in vacuo to yield 1-(4-bromo-5-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (95 g, 71% purity) as a brown oil. The crude product is used without further purification.