Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][CH2:9][C:10]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:12])[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic acid (0.20 g, 0.40 mmol) was added 4-dimethylaminopyridine (0.075 g, 0.60 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.12 g, 0.60 mmol), methanesulfonamide (0.045 g, 0.48 mmol) and triethylamine (0.12 mL, 0.84 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.10 g, LRMS: 540.2).
Reaction SMILES: [OH-:1].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:11]O>>[CH3:11][O:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10]
Reactant: Oc1ccccc1Br
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: COc1ccccc1O
Reaction time: 5 h
Yield: 8.6 %

Procedure:
Sodium hydroxide (3.16 g, 79.1 m mole) was dissolved in 60 ml of methanol and the solution was refluxed for 12 hours. To the solution were added 750 mg (4.1 m mole) of 2-bromophenol and 240 mg of anhydrous cuprous chloride. Then the reaction was carried out in the same manner as in Comparison Example 2 for 5 hours while evaporating methanol. After the reaction was completed, 43.7 mg of 2-methoxyphenol was obtained in the same manner as in Comparison Example 2. Yield: 8.6%.
Reaction SMILES: [CH3:1][C:2]([CH2:4]Cl)=[CH2:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7]>>[CH3:1][C:2]([CH3:4])=[CH:3][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=C(C)CCl
Product: CC(C)=COc1ccccc1[N+](=O)[O-]

Procedure:
3-Chloro-2-methyl propene-1 was reacted with o-nitrophenol to yield 2-(2-methyl prop-1-en-oxy)nitrobenzene; which was reduced to the corresponding aniline; reacted with N-methylol-2-pyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1)[CH:5]=[O:6]
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=Cc1ccc(O)c(F)c1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-fluoro-4-hydroxybenzaldehyde and 2-chloro-6-(trifluoromethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:19]([O:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[CH:18]=[CH2:17]
Reactant: Oc1ccc(F)cc1-c1c(Cl)cccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2′,6′-dichloro-5-fluorobiphenyl-2-ol (11.63 g, 45 mmol) in DMF (150 mL) was added allyl bromide (5.8 mL, 67.5 mmol) and potassium carbonate (18.6 g, 135 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight and poured into water. The mixture was extracted with methylene chloride and washed with water. The solvent was removed under vacuum. Chromatography with 0–30% ethyl acetate in hexanes afforded 12.7 g (94%) of 2-allyloxy-2′,6′-dichloro-5-fluorobiphenyl as a light yellow oil. MS (EI) m/z 296 (M+).
Reaction SMILES: CS(OCCCOC(C1N=C(C2C=CC=CC=2)C2C=C([Cl:29])C=CC=2N(C)C1=O)=O)(=O)=O.C1(N)CCCCC1.[CH:39]1([NH:45][CH2:46][CH2:47][CH2:48][O:49][C:50]([CH:52]2[N:58]=[C:57]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:56]3[CH:65]=[C:66]([Cl:69])[CH:67]=[CH:68][C:55]=3N(C)C2=O)=[O:51])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CC(C)=O>[ClH:29].[CH:39]1([NH:45][CH2:46][CH2:47][CH2:48][O:49][C:50]([C:52]2[NH:58][C:57]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[C:56]3[C:55]=2[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65]3)=[O:51])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CN1C(=O)C(C(=O)OCCCNC2CCCCC2)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CN1C(=O)C(C(=O)OCCCOS(C)(=O)=O)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: CC(C)=O
Solvent: NC1CCCCC1
Product: Cl
Product: O=C(OCCCNC1CCCCC1)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
A solution of 7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid 3-[(methylsulfonyl)oxy]propyl ester in 400 ml. of acetone is treated with 100 ml. of cyclohexylamine and the mixture is boiled at reflux for 2 hours. The mixture is then concentrated to dryness under reduced pressure and the residue dissolved in 300 ml. of benzene. After washing with water, the organic solution is shaken with an excess of 2-N hydrochloric acid. The clear aqueous phase is made alkaline with 2-N sodium carbonate solution and the liberated base extracted with benzene. The benzene extract is washed with water, dried over sodium sulfate and concentrated to dryness. The oily residue crystallizes upon trituration with diethyl ether, and there are obtained 22.4 g. of 7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid 3-(cyclohexylamino)propyl ester having a melting point of 109°-111° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31].ClC(OCC(C)C)=O.[CH3:40][N:41]1CCOCC1.CN>CN(C)C(=O)C.C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:41][CH3:40])=[O:14])[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: CN1CCOCC1
Reactant: CNc1nc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)OC)ccc1C
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc(C)c(-n2c(NC)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 27 %

Procedure:
To a cooled (0° C.) solution of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylamino)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 3) (0.18 g, 0.38 mmol) in N, N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.60 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.46 mmol) and 4-methylmorpholine (0.55 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.50 mmol). Stirred at 0° C. for 35 min. Added methylamine (0.29 mL of 2M solution in THF, 0.57 mmol). After 1 h, distilled DMA and purified the crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) 67.86 (m, 1H), 7.58 (m, 2H), 7.51 (d, 1H, J=8.0 Hz), 6.98 (m, 2H), 5.52 (q, 2H, J=12.8 Hz), 2.87 (s, 3H), 2.84 (s, 3H), 2.09 (s, 3H). ESHRMS m/z 493.0659 (M+H calculated for C21H20BrF2N4O3 requires 493.0681).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([OH:33])=O)[CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:15][C@H:14]1[CH3:34])=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20](=[O:21])[N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:33])[CH:29]=3)[CH2:24][CH2:23]2)[CH2:15][C@H:14]1[CH3:34])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C1CCNC1
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)O)cc32)CCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)N4CCCC4)cc32)CCN1C(=O)OC(C)(C)C

Procedure:
Starting with pyrrolidine and 1-[2-((R)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid, the title compound was prepared by using similar methods to those described in General Procedure 1. 1H NMR (Me-d3-OD): 8.31 (1H, s), 7.34 (1H, d), 7.22 (1H, dd), 4.32 (2H, t), 4.24 (1H, s), 3.83 (1H, d), 3.67-3.54 (2H, m), 3.54-3.41 (2H, m), 3.31-3.09 (5H, m), 2.93 (1H, d), 2.83 (1H, d), 2.41-2.23 (1H, m), 2.23-2.09 (1H, m), 2.02-1.98 (2H, m), 1.96-1.84 (2H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]>C(O)C.C(O)(=O)C.O.[Pd]>[NH2:2][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(CN)cc1F
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Combine a solution of methyl 4-cyano-2-fluoro-benzoate (1 g, 5.58 mmol) in absolute ethanol (42 mL) and acetic acid (1.9 mL) with a mixture of 10% Pd/C (Degussa type E101, 0.17 g, 0.078 mmol) in water (15.6 mL) at room temperature wider nitrogen. Purge with nitrogen and then with hydrogen at 55 psi and stir for 1 h. Purge the reaction with nitrogen, filter through Celite® and wash the filter cake with ethanol (100 mL), THF (100 mL) and isopropanol (100 mL). Concentrate in vacuo and purify by SCX chromatography and then chromatography on silica gel (40g RediSep® column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 9:1 gradient over 30 min; 35 mL/min) to afford the desired intermediate as a white solid (0.602 g, 59%).
Reaction SMILES: N1([C:6](N2C=NC=N2)=[O:7])C=NC=N1.[NH2:13][C:14]1[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])[C:17]([C:18]#[N:19])=[CH:16][N:15]=1.[CH3:27][O:28][CH:29]([O:57][CH3:58])[C:30]1[C:39]([CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])=[O:48])[CH2:43][C:42]2=[O:56])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:18]([C:17]1[C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:14]([NH:13][C:6]([N:33]2[C:32]3[N:31]=[C:30]([CH:29]([O:28][CH3:27])[O:57][CH3:58])[C:39]([CH2:40][N:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:55])[CH3:54])=[O:48])[CH2:43][C:42]4=[O:56])=[CH:38][C:37]=3[CH2:36][CH2:35][CH2:34]2)=[O:7])=[N:15][CH:16]=1)#[N:19]
Reactant: O=C(n1cncn1)n1cncn1
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C(=O)OCC[Si](C)(C)C)CC1=O)CCCN2
Reactant: COCCNc1cc(N)ncc1C#N
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C(=O)OCC[Si](C)(C)C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A solution of di(1H-1,2,4-triazol-1-yl)methanone (2.78 g, 15.23 mmol) in DMF (15 ml) was added to 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 2.96 g, 15.23 mmol) in anhydrous DMF (15 ml) at 0° C. After stirring for 2.5 h at room temperature a solution of 2-(trimethylsilyl)ethyl 4-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-3-oxopiperazine-1-carboxylate (intermediate 123, 2.83 g, 6.09 mmol) in DMF (20 ml) was added. The reaction mixture was stirred for 17.5 h at room temperature, then partitioned between saturated aqueous NaHCO3 solution and EtOAc, the EtOAc phase washed with brine, dried over MgSO4 and evaporated. The residue was applied to a RediSep® silica column and purified by normal phase chromatography, eluting with EtOAc then a gradient from hexane to 50% EtOAc in hexane. Product containing fractions were combined and evaporated to give the title compound as a clear pale yellow oil. (UPLC-MS 7) tR 1.28; ESI-MS 683.5 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].Br[CH2:26][CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: ClCCCBr
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, 1 mmol), (prepared as described in Example 49), 1-bromo-3-chloropropane (120 μl, 1.2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in DMF (5 ml) was stirred at ambient temperature overnight. After addition of water, the precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide at 60° C. to give 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 70%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[CH2:7](OC(OCC)OCC)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(#N)C>[O:20]1[CH2:21][CH2:22][N:17]([CH:7]=[C:3]([C:1]#[N:2])[C:4]([NH2:6])=[O:5])[CH2:18][CH2:19]1
Reactant: CCOC(OCC)OCC
Reactant: C1COCCN1
Reactant: N#CCC(N)=O
Solvent: CC#N
Product: N#CC(=CN1CCOCC1)C(N)=O

Procedure:
A stirred mixture of cyanoacetamide (63 g.), triethylorthoformate (134 g.), morpholine (82.5 g.) and acetonitrile (37.5 ml.) was heated under reflux for 4 hours. The initial reflux temperature was 117° C. and the final reflux temperature was 82° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[C:16]([O:20][CH3:21])(=[O:19])[C:17]#[CH:18].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[F:12][C:11]([F:14])([F:13])[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH:18]=[C:17]([C:16]([O:20][CH3:21])=[O:19])[O:1][N:2]=2)=[CH:5][CH:6]=1
Reactant: ON=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C#CC(=O)OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To a mixture of N-hydroxy-4-(trifluoromethoxy)benzimidoyl chloride (1.2 g, 5 mmol) and methyl propiolate (0.9 mL, 10 mmol) in toluene (12 mL) was added Et3N (0.73 mL, 5.3 mmol) dropwise over 10 minutes. The resulting reaction mixture was heated at 80° C. for 2.5 h and then diluted with EtOAc (20 mL). The organic layer was washed with 0.1 M aq. HCl, H2O, and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was crystallized from CHCl3 and petroleum ether to afford the title compound (1.1 g, 77%). MS (ES+) C12H8F3NO4 requires: 287. found: 288 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=6.8 Hz, 2H), 7.33 (d, J=6.8 Hz, 2H), 7.25 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=4)[O:25][CH:24]=3)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1>>[CH3:35][O:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:36][CH3:37])[O:25][CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][N:13]([C:9]3[CH:8]=[C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])[CH:12]=[CH:11][CH:10]=3)[CH2:18][CH2:17]1)[C:32]2=[O:33]
Reactant: COc1cc2occ(CCCCN3CCN(c4cccc(N)c4)CC3)c(=O)c2cc1OC
Reactant: COC(=O)Cl
Product: COC(=O)Nc1cccc(N2CCN(CCCCc3coc4cc(OC)c(OC)cc4c3=O)CC2)c1

Procedure:
In a similar manner to Example 13, but using methyl chloroformate and 3-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-6,7-dimethoxychromen-4-one obtained in Example 12, methyl (3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-carbamate is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]2)[CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:22][C:18]1[CH:19]=[C:20]([CH3:21])[N:16]([CH2:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:9][CH2:10]2)=[O:23])[N:17]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3N)CC2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3NC(=O)c3ccccc3)CC2)n1
Reaction time: 60 h
Yield: 100 %

Procedure:
The 1-[4-(2-amino-phenyl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (0.042 g, 0.136 mmol) is dissolved in 1.5 mL of CH2Cl2. To this is added diisopropylethyl amine (0.046 mL, 0.250 mmol) and benzoyl chloride (0.018 mL, 0.150). The mixture is stirred for 60 h. The reaction is quenched with 2 mL of saturated NH4Cl and extracted in the reaction vial with 2×2 mL of CH2Cl2. The organic phase is concentrated. The residue is purified using a SiO2 prep plate eluting with (75% EtOAc/hexanes) to give 58.1 mg of N-(2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-phenyl)-benzamide in 100% Yield. MS: MH+=418.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:16]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:15])[CH:9]([CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:16]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C)CCC(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)CC1Cc2cccc(Cl)c2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
101.8 g (453 mmole) 1-(2-Chloro-phenyl)-4,4-dimethyl-pentan-1-one, 133.4 g (2.1 eq.) urotropine and 124.7 g (2.7 eq.) of acetic anhydride were placed in a 1000 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 200 ml water and 200 ml 2M NaOH were added and the mixture was extracted two times with 250 ml dichloromethane each. The organic layer was washed two times with 150 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 250 ml volume and the solution was added dropwise over a period of 2.5 h to 1000 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was poured onto approx. 800 g of ice and extracted three times with 250 ml dichloromethane each. The organic layer was washed twice with 250 ml of a saturated sodium bicarbonate solution and once with 200 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 1:1) to yield 79.4 g (74%) of the desired product as a slightly off-white oil, which slowly crystallized. 1H-NMR (400 MHz, CDCl3): δ=7.44 (t, 1H, aromatic), 7.30 (d, 1H, aromatic), 7.27 (d, 1H, aromatic), 3.38 (dd, 1H, COCH), 2.79, 2.60 (2×m, 2H, benzylic), 2.10, 1.21 (2×m, 1H, CH2-t-Bu), 0.90 (s, 9H, t-Bu) ppm.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(N2CCCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and pyrrolidine.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].Cl.[CH3:9][NH:10][O:11][CH3:12].C(N(CC)CC)C>ClCCl>[CH3:12][O:11][N:10]([CH3:9])[C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1]
Reactant: CC(C)=CC(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,3-Dimethylacryloyl chloride (28.2 mL, 0.253 mol) was slowly added to a mixture of N,O-dimethylhydroxylamine hydrochloride (27.2 g, 0.278 mol) and triethylamine (75 mL, 0.519 mol) in dichloromethane (300 mL) at 0° to 30° C. and stirred 1 h at 0° C. The resultant mixture was washed with 1 N hydrochloric acid and then with 1 N sodium hydroxide and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue vacuum distilled (60° to 70° C. at 0.2 mm Hg) to give the product, 26.8 g (74%) as a colorless oil; IR(neat): 2938 and 1660 cm-1 : MS: m/z 144 (MH+); 1H NMR(CDCl3): δ 1.91 (d, J=1.2 Hz, 3H), 2.14 (d, J=0.9 Hz, 3H), 3.20 (s, 3H), 3.68 (s, 3H), and 6.12 (bs, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(OC(C)(C)C)=O)=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:45]2[CH:46]=[C:41]([F:40])[CH:42]=[CH:43][C:44]=2[F:47])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH3:31])[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][NH:18][CH2:17][CH2:16]1)=[O:8]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: OB(O)c1cc(F)ccc1F
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3F)sc2N)c1N1CCNCC(F)(F)C1
Yield: 28 %

Procedure:
Following the procedure for Example 105, reacting tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate and 2,5-difluorophenylboronic acid gave 106 as a beige solid (57 mg, 28% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.88-7.81 (m, 2H), 7.18-7.10 (m, 1H), 7.06-6.99 (m, 1H), 6.16 (s, 2H), 3.78 (s, 3H), 3.70-3.56 (m, 2H), 3.44 (t, J=14.0 Hz, 2H), 3.35 (t, J=5.5 Hz, 2H), 3.11-3.05 (m, 2H), 1.95 (s, 1H). LCMS (ES+) m/z 470 (M+1).
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][N+:8]([O-])=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:14])=O>O1CCOCC1>[Cl:14][C:7]1[N:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3][S:2][C:6]=12
Reactant: [O-][n+]1ccc2ccsc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nccc2ccsc12

Procedure:
(adb) 671.5 g of thieno[2,3-c]pyridine 6-oxide hydrochloride were suspended in 4000 ml of dioxane under argon and 655 ml of phosphorus oxychloride are added. The mixture was heated on an oil-bath until the exothermic reaction set in. After the exothermic reaction faded away, the mixture was heated to reflux for an additional 10 minutes. The mixture was concentrated in vacuo and the residue was taken up in 2000 ml of toluene. The solution was then treated with 300 ml of water while cooling slowly. The mixture was neutralized by the portionwise addition of sodium carbonate. The organic phase was separated and the aqueous phase was extracted with 1000 ml of toluene. After washing with water, the combined organic solutions were dried over sodium sulfate, filtered and evaporated, whereby crude 7-chloro-thieno[2,3-c]pyridine was obtained as a brown oil.