Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:8]=2[CH:32]=1)#[N:3].[C:33]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43](=O)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)(=[O:35])[CH3:34].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[C:33]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43](=[CH:12][C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:32][C:8]=3[CH:9]=2)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: CCOC(=O)C(=O)c1ccc(OC(C)=O)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cc2cc(C#N)ccc2o1)c1ccc(OC(C)=O)cc1
Reaction time: 18 h
Yield: 85.6 %

Procedure:
15.93 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride and 8.29 g of ethyl 2-(4-acetoxyphenyl)-2-oxoacetate were dissolved in a mixture solution of 80 ml of tetrahydrofuran and 80 ml of ethanol. At room temperature, 5.34 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the above solution, and the mixture was stirred for 18 hours at the same temperature. The resulting reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography using a toluene/ethyl acetate mixture as an eluant to obtain 11.28 g of ethyl 2-(4-acetoxyphenyl)-3-(5-cyano-2-benzofuranyl)acrylate in the form of light yellow crystals as a mixture of E and Z forms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[Br:17]Br>CC(O)=O>[Br:17][CH:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][C:13]1=[O:15]
Reactant: COc1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C2CC(=O)C(Br)C(=O)C2)cc1

Procedure:
To a stirred solution of 5-(4-methoxyphenyl)cyclohexane-1,3-dione (5 g, 22.6 mmol) in AcOH (40 mL) at r.t. was added bromine (3.61 g, 1.18 mL, 22.6 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound in quantitative yield as a white solid. δH (DMSO-d6) 7.24 (2H, d, J 8.6 Hz), 6.87 (2H, d, J 8.6 Hz), 3.72 (3H, s), 3.31-3.21 (1H, m), 2.88-2.82 (2H, m), 2.77-2.62 (3H, m). LCMS (ES+) 296.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I>CCCCCC.CN(C)C=O>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To sodium hydride (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3X, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3X). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5-methoxy-2 -methylpyridine.
Reaction SMILES: N[C@H](C(O)=O)CCSC.CS(O)(=O)=O.[F:15][C:16]1[CH:38]=[CH:37][C:19]2[CH2:20][CH2:21][C:22]3[C:27]([C:18]=2[CH:17]=1)=[N:26][N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)[C:24](=[O:36])[CH:23]=3>O>[F:15][C:16]1[CH:38]=[CH:37][C:19]2[CH2:20][CH2:21][C:22]3[C:27]([C:18]=2[CH:17]=1)=[N:26][N:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:24](=[O:36])[CH:23]=3
Reactant: COc1ccc(-n2nc3c(cc2=O)CCc2ccc(F)cc2-3)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Solvent: O
Product: O=c1cc2c(nn1-c1ccc(O)cc1)-c1cc(F)ccc1CC2
Temperature: 55 °C
Reaction time: 48 h
Yield: 94.1 %

Procedure:
To a solution of 5 g of methionine and 25 ml of methane-sulfonic acid is added 5 g of 9-fluoro-2-(4-methoxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one. After the mixture is heated to 55° C. and stirred for 2 days, the reaction mixture is poured into water. The resulting crystals are collected and washed with ethanol to give 4.5 g of 9-fluoro-2-(4-hydroxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, m.p. 300°-302° C. (decomposition).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(CO)COC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC1(COS(C)(=O)=O)COC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
After adding 465 g (4.0 mol) of 3-ethyl-3-hydroxymethyloxetane, 486 g (4.8 mol) of triethylamine, and 1840 ml of toluene in a glass flask having an internal volume of 5000 ml equipped with a stirrer, a thermometer, and a dropping funnel, 504 g (4.4 mol) of methanesulfonyl chloride was gently added while keeping the liquid temperature from 5° C. to 10° C. to carry out a reaction, while stirring, at the same temperature range for three hours and at room temperature for three hours. After completing the reaction, 930 ml of a saturated aqueous sodium hydrogen carbonate solution (concentration of 9.3 mass %) was added to the reaction solution to separate into a water layer and an organic layer. Then, after extracting the water layer with 930 ml of toluene, the extract was combined with the previous organic layer and washed with 465 ml of water. By concentrating the organic layer thus obtained under reduced pressure, 777 g of 3-ethyl-3-methanesulfonyloxymethyloxetane with a purity of 95 mass % (quantitative value determined by 1H-NMR) as a brown liquid was obtained (isolated yield based on 3-ethyl-3-hydroxymethyloxetane=95%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][S:9][C:7]2[NH:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=3[N:6]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: Cc1ccc2[nH]c(S)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2nc(SCCOc3ccc(Cl)cc3)[nH]c2c1
Yield: 55.4 %

Procedure:
A suspension of 5-methyl-1H-benzoimidazole-2-thiol (492 mg, 3 mmol), 1-(2-bromo-ethoxy)-4-chloro-benzene (777 mg, 3.3 mmol) and K2CO3 (828 mg, 6 mmol) in acetone (1.0 ml) is refluxed for 3 h. It is cooled down and filtered on filter paper. The solvent is removed in vacuo and the crude purified by flash chromatography on silica-gel (AcOEt/heptane, 3:7), yielding the title compound (530 mg) in 55% as an off-white solid: tR=2.02 min (LC-2), ESI-MS (pos.): m/z 319.21 [M+H]+, ESI-MS (neg.): m/z 317.23 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 2.36 (s, 3H, Me), 3.59 (t, 2H, SCH2), 4.23 (t, 2H, CH2O), 6.75 (d, 2Harom), 6.97 (d, 1Harom), 7.13 (d, 2Harom), 7.18 (s, 1Harom), 7.34 (d, 1Harom).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c3) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: O1CCCC1.[OH-].[Li+].C([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[Br:23])=[O:12])C>O>[Br:23][C:16]1[CH:17]=[C:18]([F:22])[CH:19]=[C:20]2[C:15]=1[NH:14][C:13]([C:11]([OH:12])=[O:10])=[CH:21]2
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(F)cc(Br)c2[nH]1

Procedure:
Tetrahydrofuran (35.2 ml), water (23.5 ml), lithium hydroxide (2.61 g, 10.9 mmol), and 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (3.11 g, 10.9 mmol) were added to a round bottom flask and mixed with a magnetic stirrer. This mixture was refluxed for 1 hour. The THF was removed via rotary evaporator, and the aqueous solution was acidified with 1M HCL, and extracted with ethyl acetate. 1H NMR (DMSO-d6): δ 13.206 (bs, 1H), δ 11.876 (s, 1H), δ 7.498-7.445 (m, 2H), δ 7.19 (d, J=2.0 Hz, 1.0H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[SH:10][CH2:11][C:12](O)=[O:13]>C(#N)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([O:6][CH2:7][CH:8]1[S:10][CH2:11][C:12](=[O:13])[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CS
Reactant: CCCC(=O)OCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCCC(=O)OCC1OC(=O)CS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A solution of 24 (3.90 g, 0.030 mol), mercaptoacetic acid (3.32 g, 0.036 mol) and p-TsOH.H2O (0.28 g, 1.5 mmol) in acetonitrile (600 ml) was heated at reflux for 3.5 hours. During the period of reflux, four portions of 25 ml each were drained from a Dean-Stark trap (to remove the water-acetonitrile azeotrope). Analysis of the reaction solution by TLC (6:1 hexane:AcOEt) revealed one major new component and no unreacted aldehyde (visualized by PMA and 2,4-DNP stains). The reaction solution was allowed to stir at room temperature for 16 hours, and then evaporated to dryness. The residue was partitioned between concentrated NaHCO3 (50 ml) and AcOEt (75 ml); the aqueous portion was extracted with additional AcOEt (2×75 ml). The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude material (6 g) was purified by flash chromatography (125 grams silica gel with 20% ethyl acetate in hexane). Compound 25 (3.27 g, 16 mmol, 53%) was obtained as an oil: TLC (3:1 hexane:AcOEt)—one spot with Rf=0.41; 1H-nmr (CDCl3)—compatible with structure; mass spectrum (FAB)—m/z=205.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[NH:43]1[CH2:48][CH2:47][S:46](=[O:49])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:43]1[CH2:48][CH2:47][S:46](=[O:49])[CH2:45][CH2:44]1)=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: O=S1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCS(=O)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and thiomorpholine-1-oxide with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=O)([O:11]C)[O:9][CH3:10])([O-:3])=[O:2].S(Cl)([Cl:32])=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8]([Cl:32])(=[O:11])[O:9][CH3:10])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: COP(=O)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC
Solvent: c1ccccc1
Product: COP(=O)(Cl)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonate (0.5 g) in benzene (10 ml) is added thionyl chloride (8 ml) at RT. The mixture is allowed to return to RT and is stirred for 6 hours. The solvent and any excess thionyl chloride are then distilled off, yielding methyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonochloridate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][SH:13]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[NH:10][CH2:11][CH2:12][S:13]2)=[CH:4][N:3]=1
Reactant: NCCS
Reactant: O=Cc1ccc(Cl)nc1
Solvent: c1ccccc1
Product: Clc1ccc(C2NCCS2)cn1
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution composed of 6-chloronicotinaldehyde (14.2 g), 2-aminoethanethiol (7.7 g) and benzene (80 ml) was heated with stirring for 5 hours while removing water as an azeotrope. After the reaction, benzene was distilled off under reduced pressure, and further volatile materials were removed at 1 mmHg and 70° C. to give 2-(2-chloro-5-pyridyl)thiazolidine (18 g) as a residue. Ten grams of 2-(2-chloro-5-pyridyl)thiazolidine was dissolved in 100 ml of ethanol, and sodium borohydride was added. With stirring, the mixture was gradually heated and thereafter refluxed for 1 hour. Ethanol was distilled off under reduced pressure, and chloroform was added to the residue. Insoluble materials were separated by filtration and the chloroform layer was washed with water and dehydrated. Chloroform was distilled off under reduced pressure to give the desired N-(2-chloro-5-pyridylmethyl)2-aminoethanethiol (8.3 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1[C:14]2[C:13]3[C:15]([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=4)=[C:16]4[C:21](=[CH:22][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:20]=[CH:19][CH:18]=[CH:17]4.O>C(Cl)Cl.N1C=CC=CC=1>[CH:6]1[C:14]2[C:13]3[C:15]([C:23]4[CH:24]=[CH:25][C:26]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:27][CH:28]=4)=[C:16]4[C:21](=[CH:22][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:20]=[CH:19][CH:18]=[CH:17]4
Reactant: Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Reaction time: 36 h
Yield: 114.3 %

Procedure:
Methylsulfonyl chloride (0.63 mL, 8.14 mmol) was added dropwise to a cold (ice bath) solution of 4-benzo[b]naphtho[2,3-d]thiophen-11-yl-phenol (2.00 g, 5.43 mmol) in dry methylene chloride (10 mL) and pyridine (2.08 mL). After stiring at ambient temperature for ca. 36 h. the reaction mixture was combined with water (100 mL). The organics were extracted with ether (100 mL), washed with 10% HCl (100 mL) and concentrated to give the title compound as a white solid (2.51 g, 100%); mp 136-139° C.; NMR (CDCl3); δ 8.38 (s, 1H), 7.97-7.95 (m, 1H), 7.80-7.78 (m, 1H), 7.60-7.50 (m, 6H), 7.43-7.35 (m, 2H), 7.07 (ddd, J=8, 7, 1 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 3.33 (s, 3H); MS (EI): [M+] 404 (100%); Anal. calc. for C23H16O3S2+0.07 C6H14, C, 68.52, H, 4.17, N, 0.03. Found: C, 67.91, H, 3.85, N, 0.06.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][C:20]3[C:21]([CH3:36])=[N:22][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:36][C:21]1[C:20]([CH2:19][CH2:18][O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]([OH:37])=[O:5])[CH:9]=[CH:10]3)=[CH:25][CH:24]=[C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=2)[N:22]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCOc1ccc2c(ccn2CC(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCOc1ccc2c(ccn2CC(=O)O)c1

Procedure:
In analogy to the procedure described in example 5 g], (5-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (5-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-indol-1-yl)-acetic acid as light brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:35])([CH3:34])[CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[N:18][C:19]([Cl:33])=[CH:20][N:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:35])([CH3:34])[CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[N:18][C:19]([Cl:33])=[CH:20][N:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(NCC(C)(C)NC(=O)OC(C)(C)C)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NCC(C)(C)N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1

Procedure:
Formula 202 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl; W and Z are —N═; X and Y are —C═: To a solution of (±)-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (1.63 g, 3.16 mmol) in dichloromethane (40 mL) is added trifluoroacetic acid (10 mL). The resultant solution is maintained at ambient temperature overnight and concentrated under reduced pressure. The residue is dissolved in dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (40 mL). The aqueous layer is extracted with dichloromethane (50 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-pteridin-4-one which is used in the subsequent step without purification.
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1>C(O)(C)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH:36][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=3)[N:3]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2nc(Cl)n(C)c(=O)c2c1
Reactant: NCCc1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(NCCc3ccc(Cl)cc3)n(C)c(=O)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of methyl 2-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylate (77.0 mg, 0.30 mmol) in isopropyl alcohol (5 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) and 2-(4-chlorophenyl)ethanamine (0.11 mL, 0.76 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% MeOH/DCM) to afford methyl 2-{[2-(4-chlorophenyl)ethyl]amino}-3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylate (106 mg, 94%). LC-MS: (FA) ES+ 372.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:13]1[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCCC2)N1CC(C)C

Procedure:
1-Amninocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. 1-(Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.5]decane.
Reaction SMILES: [N:1]([C:4]1([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:58])([P:50]([O:55][O:56][CH3:57])([O:52][O:53][CH3:54])=[O:51])[P:42]([O:47][O:48][CH3:49])([O:44][O:45][CH3:46])=[O:43])=[O:35])[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>>[N:1]([C:4]1([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:58])([P:50]([O:55][O:56][CH3:57])([O:52][O:53][CH3:54])=[O:51])[P:42]([O:44][O:45][CH3:46])([O:47][O:48][CH3:49])=[O:43])=[O:35])[C:32](=[O:33])[N:6]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]
Reactant: COOP(=O)(OOC)C(O)(CCCCNC(=O)C1(N=[N+]=[N-])C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@@H]21)P(=O)(OOC)OOC
Solvent: O=C(O)C(F)(F)F
Product: COOP(=O)(OOC)C(O)(CCCCNC(=O)C1(N=[N+]=[N-])C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21)P(=O)(OOC)OOC

Procedure:
Cleavage of benzhydryl 7-azido-7-{[5-hydroxy-5,5-bis(dimethoxyphosphono)-1-pentylamino]-carbonyl}-3-acetoxymethyl-3-cephem-4-carboxylate, prepared as described in Example 30, with trifluoroacetic acid gives 7-azido-7-{[5-hydroxy-5,5-bis(dimethoxyphosphono)-1-pentylamino]-carbonyl}-3-acetoxymethyl-3-cephem-4-carboxylic acid.
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])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([CH:13]2[CH2:14][CH2:15]2)[C:11]1=[O:16])[CH3:23]
Reactant: O=c1[nH]cc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reaction time: 8 h

Procedure:
740 mg (3.15 mmol) of 5-(4-chlorophenyl)-1-cyclopropyl-1,3-dihydro-2H-imidazol-2-one from Example 118A are dissolved in 15 ml acetonitrile and treated with 386 mg (3.15 mmol) of ethyl chloroacetate and 872 mg (6.31 mmol) of potassium carbonate. The mixture is stirred overnight under reflux. It is then concentrated, the residue is partitioned between dichloromethane and water, the organic phase is separated, and this is dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1→100:1) and thus yields 602 mg (57% of theory) of the target compound.