Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:33][NH2:34]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9]([NH:34][CH3:33])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CN
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Reaction time: 8 h

Procedure:
5-Cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (40 mg, 83 μmol) was dissolved in THF (5 ml), a 2 M solution of methylamine in THF (208 μl, 415 μmol; 5 eq.) was added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (14.3 mg, 36% of theory).
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.[CH2:7]([C:9]([CH2:14][OH:15])([CH2:12][OH:13])[CH2:10][CH3:11])[OH:8].CCCCCC(=O)CCCCC.CC(C)=O>CCCCCC>[OH:8][CH2:7][C:9]1([CH2:10][CH3:11])[CH2:14][O:15][C:3]([CH3:5])([CH3:2])[O:13][CH2:12]1
Reactant: OCC(O)CO
Reactant: CCC(CO)(CO)CO
Agent: CCCCCC(=O)CCCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCC1(CO)COC(C)(C)OC1

Procedure:
The same procedures as in Production Example 3 are carried out except that glycerol is replaced with 292.1 g (2.18 mol) of trimethylolpropane, 6-undecanone is replaced with 474.0 g (8.17 mol) of acetone, and the amount of paratoluenesulfonic acid monohydrate is changed to 6.0 g (0.0315 mol) and the amount of hexane is changed to 900 ml to give 5-hydroxymethyl-5-ethyl-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Cl)cc4)CC3)nn12

Procedure:
A mixture of 1-[(4-chlorophenyl)methyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C.CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cn1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Temperature: 140 °C

Procedure:
Method 1. A mixture of methyl 4-methyl-5-nitropyridine-2-carboxylate (3.5 g, 17.8 mmol), dimethylformamide dimethylacetal (DMF-DMA) (3.6 ml, 1.5 eq) in acetonitrile (35 mL) was heated in a microwave at 140° C. for 20 min. The solvent was removed. The residue (5.1 g) was carried onto the next step without further purification. Method 2. A mixture of methyl 4-methyl-5-nitropyridine-2-carboxylate (39.5 g, 0.19 mol) and DMF-DMA (30.6 g, 0.26 mol, 1.35 eq) in DMF (470 mL) was heated to 90° C. for 30 min. The solvent was removed in vacuo. The residue (78 g) was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:27][CH:26]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)COc3ccc(F)cc3)CC2)CS1

Procedure:
Compound 206 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=189-191° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (dd, J=1.5, 6.8 Hz, 3H), 6.98 (d, J=3.5 Hz, 1H), 4.90 (d, J=4.7 Hz, 1H), 4.05-3.92 (m, 2H), 3.87 (s, 3H), 3.06 (s, 2H), 2.87-2.72 (m, 2H), 2.57-2.32 (m, 4H), 2.01-1.90 (m, 2H), 1.86-1.73 (m, 2H). LCMS: 500 [M+H].
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:3][C:4]2[C:5]3[C:10]([N:11]=[C:12]4[C:17]=2[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]4)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:22][CH:21]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3ccc(F)cc3)c21

Procedure:
In 300 ml of toluene and 200 ml of 30% potassium hydroxide were added 8.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 1.92 g of tetrabutylammonium hydrogen sulfate catalyst. The mechanically stirred biphasic solution was heated to reflux and 9.4 ml of 4-fluorobenzyl bromide in 50 ml of toluene was added dropwise. Reflux was continued for a total of 2 hours. The reaction was poured onto ice and the toluene layer was separated. The aqueous phase was extracted with ethyl acetate. The organics were combined, washed with saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated to a solid. The solid was recrystallized from 1:1 ethyl acetate/hexane to yield 5.89 g of product, mp 158°-159° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:22][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[CH:12]=[C:7]([CH:25]=[O:26])[CH:8]=[N:9][CH:10]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: Fc1ccc(C#Cc2cncc(Br)c2)cc1F
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
Add a 2.5 M solution of butyllithium in hexanes (3.18 mL, 7.96 mmol) to anhydrous toluene (11 mL) at −78° C. Allow the internal temperature to return to −78° C., then add 3-bromo-5-(3,4-difluorophenylethynyl)-pyridine (1.56 g, 5.30 mmol), (prepared essentially as described in EXAMPLE 100), dissolved in anhydrous toluene (11 mL) at such a rate to maintain the reaction temperature below −60° C. Stir for 5 min, add N,N-dimethylformamide (0.47 g, 6.37 mmol) dropwise at a rate so as to maintain the reaction temperature below 60° C. Stir for 20 min, warm to 0° C. and add an aqueous saturated solution of ammonium chloride and ethyl acetate. Stir for 5 min and separate the layers. Dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes to give the title compound as a white solid (0.780 g, 61%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].NC1N=C(O)C=C(O)N=1.Br[C:26]1[S:30][C:29]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=1>O.CN1C(=O)CCC1>[N:1]1([C:26]2[S:30][C:29]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCCCC(=O)c1ccc(Br)s1
Reactant: c1ccc2[nH]cnc2c1
Agent: Nc1nc(O)cc(O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCC(=O)c1ccc(-n2cnc3ccccc32)s1
Temperature: 157.5 °C

Procedure:
Charged Benzimidazole (12.11 mmoles), cesium carbonate (14.11 mmoles), cuprous oxide (0.4 mmoles), 2-Amino-4,6-dihydroxypyrimidine (1.5 mmoles), PEG (catalyst), keto thiophene (XXI) and NMP (5 ml) to the RB flask fitted with thermo well and condenser. The reaction mixture was heated to 155-160° C. and the temperature was maintained for 10-12 hrs at 155-160° C. After completion of reaction, cooled to room temperature, added water (25 ml), extracted with ethyl acetate (2×100 ml), washed with 10% brine solution, dried the ethyl acetate layer over sodium sulfate and distilled off the solvent completely at reduced pressure to get crude compound. The crude compound was purified by using silica gel 60-120 silica gel column chromatography and DCM: methanol: 100-5% as mobile phase to get the pure compound (84).
Reaction SMILES: C(OC([NH:11][CH:12]([CH:23]([CH3:25])[CH3:24])[C:13](=[O:22])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH:23]([CH:12]1[NH:11][C:15](=[O:16])[C:14]([CH3:21])([CH3:20])[C:13]1=[O:22])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)C(=O)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C1NC(=O)C(C)(C)C1=O
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2,5-trimethyl-3-oxohexanoate (7.2 g) in methanol (80 mL) was added 10% palladium carbon (containing 50% water, 3.0 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound as a colorless solid (yield: 2.64 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH:14]2[CH2:13][O:12][CH2:11][C:10](=[S:16])[NH:9]3)[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](O)=[O:25])=[N:22][CH:23]=1>>[S:16]=[C:10]1[CH2:11][O:12][CH2:13][CH:14]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:24]([C:21]4[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][N:22]=4)=[O:25])[CH:7]=[CH:6][CH:5]=3)([CH2:15]2)[NH:9]1
Reactant: Nc1cccc(C23CC2COCC(=S)N3)c1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: O=C(Nc1cccc(C23CC2COCC(=S)N3)c1)c1ccc(Cl)cn1

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (1SR,7RS)-1-(3-amino-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13B) (230 mg, 0.98 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS-no 86873-60-1] (172 mg, 1.09 mmol). The title compound was obtained as a light yellow foam (310 mg, 76%). MS (ISP): m/z=374.1 [(M+H)+]and 376.0 [(M+2+H)+].
Reaction SMILES: C(N(CC)CC)C.ClCCl.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1.C(OCC)(=O)C.[NH2:23][C:24]1[S:28][N:27]=[C:26]([Br:29])[C:25]=1[C:30](=[O:32])[CH3:31]>>[C:30]([C:25]1[C:26]([Br:29])=[N:27][S:28][C:24]=1[NH:23][C:14]([CH:11]1[CH2:13][CH2:12]1)=[O:15])(=[O:32])[CH3:31]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)c1c(Br)nsc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(Br)nsc1NC(=O)C1CC1
Temperature: 16 °C
Yield: 60 %

Procedure:
Add triethylamine (234.5; mL, 1.68; mol) to a cooled suspension of 1-(5-amino-3-bromo-isothiazol-4-yl)-ethanone (310; g, 1.40; mol) in dichloromethane (2.79; L, 43.53 mol) at 0° C. under nitrogen and then add slowly a solution of cyclopropanecarbonyl chloride (137.5; mL, 1.47; mol) in dichloromethane (310; mL, 4.84; mol) at 0° C. over 1 hour. Warm to 16° C. over 2; hours and then cool to 10° C., add water (1; L) and separate the layers. Extract the aqueous layer once with dichloromethane (500; mL). Combine the organic layers, concentrate and purify by silica gel chromatography eluting with n-hexane:dichloromethane 30:70. Triturate the recovered solid with hexanes to give the title compound as a white solid (256.1; g, 60%). MS (m/z): 289, 291; (M+1).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][O:4][C:5]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([NH2:18])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[N:35]=[C:36]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])=[CH:23][C:22]=1[NH:35][C:36]1[N:16]([CH3:17])[C:14]2[CH:15]=[C:5]([O:4][CH2:3][CH:2]([F:1])[F:19])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][C:13]=2[N:18]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)n(C)c2cc1OCC(F)F

Procedure:
The sub-title compound was prepared from ethyl 2-(2,2-difluoroethoxy)-4-methylamino-5-amino-benzoate and N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethylpropionamide with DIC in DMF at r.t. in analogy to example 72a. The crude material was directly used in the next step.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f6) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([F:23])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]>>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[F:23][C:17]1[CH:16]=[C:15]2[C:14]3=[C:19]([C:20]4[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=4[N:13]3[CH2:25][CH2:26][C:27]2=[O:28])[CH:18]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(F)cc3c2CC1
Agent: O=C(O)/C=C\C(=O)O
Product: O=C1CCn2c3c(c4cc(F)cc1c42)CCNCC3

Procedure:
Following the general procedure of Example 41, making non-critical variations but starting with 3-benzoyl-9-fluoro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and using maleic acid for the salt formation, the title compound was obtained (mp 242-244° C. [dec.]). 1H NMR (d-DMSO) δ 9.18, 7.67, 7.21, 4.40, 3.33, 3.25, 3.12, 3.04; IR (drift) 3358, 2970, 2959, 2830, 2792, 2785, 2752, 1681, 1593, 1490, 1464, 1383, 1330, 1216, 907 cm−1.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH:4]([CH3:23])[C:3]([NH2:26])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C(N)=O)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-malonamic acid methyl ester and ammonium hydroxide. Colorless solid. Mp=206° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][C:8]1[N:13]=C(C=O)C=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C:2]1[CH:1]=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[N:13]=1)=[CH2:4]
Reactant: COc1cccc(C=O)n1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(OC)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (7.07 g, 19.8 mmol, 1.1 eq) in dry THF (50 ml) at 0° C. is added n-butyl lithium (1.6M in cyclohexane, 12.5 ml, 19.8 mmol, 1.1 eq). After stirring at 0° C. for 20 minutes, a solution of 6-methoxypyridine-2-carbaldehyde a1-50 (2.5 g, 18 mmol, 1 eq) in dry THF (10 ml) is added dropwise to the mixture. The reaction mixture is warmed to room temperature for 30 minutes. The reaction mixture is quenched with 3 drops of water, and Rochelle salt is added (10 g). The mixture is filtered on Celite and MgSO4. The crude residue is distilled to afford 400 mg of pure 2-ethenyl-6-methoxypyridine a1-51.
Reaction SMILES: [CH3:1][C:2]([CH3:38])=[CH:3][C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C@@:9]([O:36]C)([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2)[CH2:8]1)=[O:5].CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1][C:2]([CH3:38])=[CH:3][C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:10][C@@:9]([OH:36])([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[NH:22]2)[CH2:8]1)=[O:5]
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H](OC(=O)C=C(C)C)C[C@@H](CCc3ccccc3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CC(C)=CC(=O)O[C@@H]1C[C@@H](CCc2ccccc2)O[C@@](O)([C@@H]2CSC(=O)N2)C1

Procedure:
Application of the method shown in Example 46, with the modification that (2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl 3-methylbut-2-enoate is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([O:28]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6].FC(F)(F)C([O-])=O.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([OH:28])=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: O=C([O-])C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 4 h

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate.trifluoroacetate (syn isomer) (1.4 g ) in methylene chloride (30 ml) were added anisole (1.4 ml) and trifluoroacetic acid (1.83 ml) with stirring under ice-cooling and the stirring was continued for 4 hours at 5° C. The reaction mixture was evaporated and the residual oil was pulverized in diethyl ether, collected by filtration and then dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.trifluoroacetate (syn isomer) (1.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.ClCCl.CO>C(O)C>[N:9]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:15][CH:14]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(CN2CCCC2)cc1
Yield: 36.9 %

Procedure:
To a solution of 1-(4-nitro-benzyl)-pyrrolidine (1.37 g) in ethanol (66 mL) tin(II)-chloride dihydrate (9.0 g) was added portionwise and the resulting mixture refluxed for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (432 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)/C=C/C1(c2ccc(F)c(F)c2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C1(c2ccc(F)c(F)c2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)acrylate (Preparation 5C, 53 mg, 0.180 mmol) in MeOH (1 mL) was added 1M NaOH (0.216 mL, 0.216 mmol), and the mixture was stirred at room temperature overnight. The mixture was acidified by the addition of 0.3 mL of 1N HCl, and the product was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and evaporated to give the (E)-3-(1-(3,4-difluorophenyl)cyclohexyl)acrylic acid as an oil. 1H NMR (400 MHz, CCl3D) δ ppm 11.94 (1H, br. s.), 7.11 (2H, m), 7.02 (1H, d, J=15.82 Hz), 6.98-7.06 (1H, m), 5.62 (1H, d, J=15.82 Hz), 1.83-2.06 (4H, m), 1.37-1.65 (6H, m).
Reaction SMILES: N1C2C=CC=CC=2C=NC=C1.O[CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[NH:15][C:14]1=[O:30]>CC(O)=O>[C:20]1([C:18]2[C:17]3[C:16](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]=[C:13]([CH:14]=[O:30])[N:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1O
Agent: C1=CNc2ccccc2C=N1
Solvent: CC(=O)O
Product: O=Cc1nc(-c2ccccc2)c2ccccc2n1
Yield: 35 %

Procedure:
The conversion of benzo[e][1,4]diazepine derivatives into 4-phenyl-quinazolines, such as the refluxing of 3-hydroxy-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one in AcOH to give 35% of 4-phenyl-2-quinazolinecarbaldehyde [30], thermolysis of 7-chloro-3-(2-methylimidazol-1-yl)-5-phenyl-3H-1,4-benzodiazepin-2-amine in 50% H2SO4 that afforded about 15% of 6-chloro-4-phenyl-2-quinazolinecarbaldehyde [31], thermolysis of 7-bromo-3-hydroxy-5-pyridin-2′-yl-3H-1,4-benzodiazepin-2(1H)-one at 220° C. to give 6-bromo-4-pyridin-2′-yl-2-quinazolinecarbaldehyde [32], sublimation of 7-chloro-5-phenyl-1,3-dihydro-2,1,4-benzothiadiazepine 2,2,4-trioxide at 160° C. under vacuum (at 10−3 mmHg) to give 6-chloro-4-phenylquinazoline [33], acidic hydrolysis of 8-chloro-6-phenyl-3,4-dihydro-1,5-benzodiazocin-2-amine in refluxing methanolic hydrogen chloride for 2.5 hours to afford 53% of 2-α-aminoethyl-6-chloro-4-phenylquinazoline [34], treatment of 8-chloro-3-methyl-6-phenyl-3H-4,1,5-benzoxadiazocin-2(1H)-one with sodium methoxide for 20 hours to yield 50% of 2-acetyl-6-chloro-4-phenylquinazoline [35], oxidation of N-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-3-carboxamide with CrO3 in AcOH to give 29% of N-methyl-6-nitro-4-phenyl-2-quinazolinecarboxamide [36], and hydrogenation of 8-chloro-6-phenyl-3H-4,1,5-benzoxadiazocin-2(1H)-one oxime over Raney-nickel to afford 50% of 6-chloro-2-hydroxymethyl-4-phenylquinazoline [37];