Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:18]1([CH:23]=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC.C1COCC1>[CH:18]1([CH:23]([OH:24])[C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: O=CC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC1(c2ccc(C(O)C3CCCC3)cc2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-bromophenyl)cyclopropanecarbonitrile (2.01 g, 0.00905 mol) in tetrahydrofuran (30 mL, 0.4 mol) was added 2.5 M of n-butyllithium in hexane (4.0 mL) at −78° C. and the mixture was stirred at −30° C. for 30 minutes. A solution of cyclopentanecarbaldehyde (0.972 g, 0.00990 mol) in THF (2 mL) was added to the above mixture and the resulting mixture was stirred at −78° C. for 2 hours. The reaction was then quenched with a small amount of saturated aqueous NH4Cl solution followed by extraction with ethyl acetate, drying with MgSO4, and concentrating under reduced pressure. The crude product was purified by flash chromatography, eluting with 30% AcOEt in hexanes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]1(B(O)O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:29]3[C:30]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc2ccccc12
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc4ccccc34)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 1-naphthaleneboronic acid (56 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21](Cl)(=O)[CH2:22][CH2:23][CH3:24]>>[CH2:22]([C:21]1[O:20][C:19]2[C:2]([N:1]=1)=[CH:3][C:4]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=1[CH:18]=2)[CH2:23][CH3:24]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Product: CCCc1nc2cc3c(cc2o1)CCNCC3

Procedure:
The title compound was prepared as described in General Procedure 2 from 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate and butyryl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:24]2[CH2:23][CH2:22][N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[Br:14])[CH2:26][CH2:25]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Brc1ccccc1N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccccc3Br)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-(o-bromophenyl)piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-(o-bromophenyl)piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10]N)[CH:5]=[C:6]([Br:9])[C:7]=1[Br:8].[CH3:12][CH:13]([CH3:17])[C:14](=O)[CH3:15].Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[CH:5]=[C:4]2[C:3]=1[C:13]([CH3:17])([CH3:12])[C:14]([CH3:15])=[N:10]2
Reactant: NNc1cc(Br)c(Br)c(Br)c1
Reactant: CC(=O)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1=Nc2cc(Br)c(Br)c(Br)c2C1(C)C
Yield: 56.4 %

Procedure:
1.73 g of 3,4,5-tribromophenylhydrazine and 2 mL (18.5 mmol) of 3-methyl-2-butanone were refluxed for an hour. Next, 15 mL of concentrated HCl were added and refluxed for another 3.5 h. The reaction mixture was neutralized with concentrated aqueous solution of sodium carbonate, and the product was extracted with benzene. The organic layer was dried with MgSO4 and benzene was removed under reduced pressure by a rotary evaporator to yield 1.12 g of 4,5,6-tribromo-2,3,3-trimethyl-3H-indole. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.16 (1H, s, arom.), 2.22 (3H, s, CH3), 1.35 (6H, s, C(CH3)2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCOCCCl
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1
Product: COc1cccc(N2CCOCC2)c1
Yield: 77.1 %

Procedure:
A solution of m-anisidine (11.2 mL, 0.1 mol), chloroethyl ether (11.7 mL, 0.1 mol), and diisopropylethylarine (35 mL, 0.2 mol) in toluene (100 mL) was stirred at reflux for 72 h. The precipitate was removed by filtration and washed with toluene (100 mL). The combined toluene solutions were concentrated in vacuo and purified by distillation (120–130° C., 0.2 Torr) to afford the intermediate 4-(3-methoxyphenyl)-morpholine (14.9 g, 77%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=1)[CH2:10][N:11]1[CH2:29][CH2:28][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[S:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)C>C(O)(=O)C.O>[CH3:27][C:24]1[S:23][C:22]([C:20]([N:16]2[CH2:15][C:14]3([CH2:13][CH2:12][N:11]([CH2:10][C:9]4[CH:8]=[C:7]([CH:32]=[CH:31][CH:30]=4)[O:6][CH2:5][CH:4]=[O:3])[CH2:29][CH2:28]3)[O:19][CH2:18][CH2:17]2)=[O:21])=[CH:26][CH:25]=1
Reactant: CCOC(COc1cccc(CN2CCC3(CC2)CN(C(=O)c2ccc(C)s2)CCO3)c1)OCC
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(OCC=O)c4)CC3)C2)s1
Temperature: 65 °C

Procedure:
A solution of (9-(3-(2,2-diethoxyethoxy)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (example 38, step b) (0.45 g) in a mixture of acetic acid (25 mL) and water (25 mL) was heated at 65° C. under nitrogen for 16 hours. Most of the solvents were removed under reduced pressure and the residue partitioned between ethyl acetate and excess saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and filtered, acetic acid (0.051 mL) was added and the solvent removed under reduced pressure to afford the subtitled compound. Yield 0.38 g. Used directly.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.[OH:27][CH:28]([C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[CH:28]([OH:27])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OC(COCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.9 %

Procedure:
N-(tert-Butoxycarbonyl)-L-proline (2.93 g), HOBt (4.55 g) and water-soluble carbodiimide hydrochloride (2.88 g) were added to a methylene chloride suspension (30 ml) of (S)-2-[1-hydroxy-2(phenylmethyloxy)ethyl]pyrrolidine (3.00 g) obtained in Example 5a), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with 5% citric acid, saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (4.99 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:13])[CH:11]=[CH2:12])=[CH:2]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:12][CH2:11][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:13])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: C=CC(=O)c1c[nH]c2ccccc12
Reactant: c1c[nH]cn1
Product: O=C(CCn1ccnc1)c1c[nH]c2ccccc12
Yield: 56.2 %

Procedure:
By a similar procedure to that described in Example 1, 1-(1H-indol-3-yl)-1-prop-2-enone (0.4 g) was reacted with imidazole (0.8 g) to give the title compound (0.314 g), m.p. 194°-197°; λmax (EtOH) 242.5 nm (ε12,900) λinf 259 nm (ε9,090) λmax 299.5 nm (ε12,390).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34].[Na+].[Cl-]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylate (1.0 g, 2.8 mmol) in dry THF (40 mL) cooled to 0° C. NaH 60% (1.342 g, 3.36 mmol) was added portion wise and the reaction mixture stirred for 30 min. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.417 mL, 3.36 mmol) was added drop wise. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 2 h. Saturated aqueous NaCl (30 mL) was added at 0° C. and the mixture was extracted with EtOAc (2×35 mL). The separated organic phase was dried over sodium sulfate and the solvent evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 98/2) to afford the title compound as an orange oil (0.80 g, 57%).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)=[N+]=[N-].O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
111.6 mg (0.50 mmol) of 4-azidobenzophenone (5), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction product, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 87.7 mg (0.45 mmol) of 4-aminobenzophenone (6). The yield was 89%. The reaction is expressed by the following scheme.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH3:38])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)=[O:16]>>[CH2:32]([O:31][CH:30]([O:34][CH2:35][CH3:36])[C@@H:29]([N:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH3:38])[CH3:37])[CH3:33]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 73 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:9][CH:10]=1)=[O:5])[CH3:2].C1(S([NH:26][C:27]2[C:32](I)=[CH:31][C:30]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)(=O)=O)C=CC=CC=1.C([O-])(=O)C.[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[NH:26][C:27]3[C:28]([CH:12]=2)=[CH:29][C:30]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:31][CH:32]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)o1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of the compound obtained in Example 29 (2) (0.1 g) in N,N-dimethylformamide (1 ml), 2-benzenesulfonylamino-3-iodo-5-methanesulfonylbenzene (0.0925 g), bistriphenylphosphine palladium dichloride (0.015 g), cuprous iodide (0.004 g) and potassium acetate (0.04 g) were added successively and the mixture was stirred in a sealed tube at 100° C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.0462 g of the desired product as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:27]=[CH:28][C:23]([C:20](=[O:22])[CH3:21])=[CH:24][CH:25]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: COc1ccc2c(-c3ccc(C(C)=O)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-acetyl-phenylboronic acid to give 1-{4-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 359(MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:4].[H-].[Na+].I[CH3:18].O>CC(N(C)C)=O>[F:1][C:2]([F:13])([F:14])[C:3]([N:5]([CH:6]1[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]1)[CH3:18])=[O:4]
Reactant: CI
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C(=O)C(F)(F)F)C1CCC(O)CC1
Temperature: 0 °C

Procedure:
5 g of 2,2,2-trifluoro-N-(4-hydroxy-cyclohexyl)-acetamide (148) were dissolved in 25 mL of dimethyl acetamide, 625 mg of 95% sodium hydride were added and the reaction mixture was cooled to 0° C. 1.64 mL of iodomethane were added slowly and the reaction mixture was allowed to warm to room temperature. Upon completion, the reaction mixture was poured into water, extracted three times with methyl tert. butyl ether and the combined organic layer was extracted once with brine, dried over sodium sulfate and evaporated to dryness. The residue was taken up in water and lyophilized to remove remainders of dimethyl acetamide to yield 4.0 g of product. Rt=0.95 min (Method C). Detected mass: 226.2 (M+H+).
Reaction SMILES: [C:1](/[C:3](=[C:9]1/[CH2:10][CH2:11][C:12]2[C:17]/1=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)/C(OCC)=O)#[N:2].[C-:19]#[N:20].[K+]>C(O)C.O>[C:1]([CH2:3][C:9]1([C:19]#[N:20])[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCc2cc(F)ccc21
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCc2cc(F)ccc21
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of (E)-ethyl 2-cyano-2-(5-fluoro-2,3-dihydro-1H-inden-1-ylidene)acetate (Prep11, 100 g, 0.408 mol) in ethanol (800 ml) a solution of KCN (67 g, 1.02 mol) in water (240 ml) was added, and warmed to 65° C. The mixture was stirred for 24 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:22]2[C:21]3[CH:20]=[C:19]([OH:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:26])[C:11]1=[O:27])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[CH:40]=[CH:39][S:38][CH:37]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:22]2[C:21]3[CH:20]=[C:19]([O:23][CH2:35][C:36]4[CH:40]=[CH:39][S:38][CH:37]=4)[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:26])[C:11]1=[O:27])[C:5]#[N:6]
Reactant: ClCc1ccsc1
Reactant: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc3c(c2cc1OCc1ccsc1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (80 mg, 220 μmol) was dissolved in N,N-dimethylformamide (4.0 ml) under a dry argon atmosphere. Potassium carbonate (85 mg, 618 μmol) and 3-chloromethylthiophene (112 mg, 845 μmol; prepared from 3-thiophenemethanol using SOCl2 in CH2Cl2) were subsequently added. The reaction mixture was stirred at 50° C. for 18 h overnight. When the reaction was complete, the mixture was poured into water (60 ml), stirred for 30 min and extracted twice with ethyl acetate (75 ml each time). The combined organic phases were washed with water (25 ml), subsequently dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue chromatographed over flash silica gel (solvent gradient ethyl acetate/0-17% by vol. of ethanol), giving 3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (64 mg, 139 μmol), as solid. MS: 461.1 (M+H+), TLC (HPTLC): Rf=0.33 (ethyl acetate/ethanol 5:1, parts by volume).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][OH:7])[NH:4][C:3]1=[O:8].C(=O)([O-])O.[Na+].Cl.[Cl:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23](/[C:25](=[N:29]/[O:30][CH3:31])/[C:26](Cl)=[O:27])[N:24]=1)=[O:18]>O1CCCC1.O>[Cl:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25](=[N:29][O:30][CH3:31])[C:26]([NH:1][C@H:2]2[C@@H:5]([CH2:6][OH:7])[NH:4][C:3]2=[O:8])=[O:27])[N:24]=1)=[O:18]
Reactant: N[C@@H]1C(=O)N[C@@H]1CO
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CO)c1csc(NC(=O)CCl)n1

Procedure:
In a mixture of 2 ml of tetrahydrofuran and 2 ml of water is dissolved 75 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine as obtained in Reference Example 53C and, under ice-cooling and stirring 168 mg of sodium hydrogen carbonate and then 332 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride are added. The mixture is stirred under ice-cooling for one hour and the reaction mixture is made neutral with aqueous sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran (2:1). The extract is washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and, after addition of ethyl acetate-ether (1:2), the crystalline residue is recovered by filtration to give cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-hydroxymethyl-2-oxoazetidine (syn-isomer) as colorless crystals, m.p. 238°-241° C. (decomp.).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:11][N:10]=1)=[O:8]>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:11][N:10]=1)=[O:8]
Reactant: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Reaction time: 0.25 h

Procedure:
To the stirred mixture of 8 g of sodium borohydride and 350 ml of methanol, cooled to -2°, the solution of 20 g of 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester in 60 ml of dimethylformamide sufficiently warm for dissolution is added all at once and the container of the latter is washed with 15 ml dimethylformamide and 20 ml methanol containing 0.5 g of sodium borohydride. The mixture warms to about 20°, is cooled to 0° for 40 minutes and stirred at 25° for 15 minutes. It is cooled again to 0° and 9 ml of 12 N hydrochloric acid, 2 ml of acetic acid and 200 ml of ice water are added in this order. The resulting solution is diluted with crushed ice to about 1,000 ml, extracted with ethyl acetate and diethyl ether, the extract dried and evaporated. The residue is first recrystallized from diethyl ether/hexane and then from ethyl acetate/diethyl ether, to yield the 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester of the formula ##STR9## melting at 111°-113°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([OH:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:16][S:28]([CH3:27])(=[O:30])=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(OS(C)(=O)=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Hydroxy-(4-trifluoromethyl-phenyl)-acetic acid ethyl ester (I101) (440 mg, 1.77 mmol) and DIPEA (0.43 mL, 2.48 mmol) are dissolved in dry DCM (17 mL) and cooled at 0° C. under N2. Methansulfonyl chloride (0.18 mL, 2.30 mmol) is added dropwise to the solution and the resulting mixture is allowed to warm to RT and stirred for 3 hours. The mixture is diluted with DCM and washed with sat. NaHCO3, water and brine. The organic layer is dried (Na2SO4), filtered and evaporated to obtain intermediate I150 as a yellow oil (578 mg, quantitative yield), which is used in the next step without any further purification.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[C:12]([CH2:14]P(=O)(OCC)OCC)#[N:13].[O:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[CH:14]/[C:12]#[N:13])[CH2:25][CH2:24]1
Reactant: O=CC1CCOCC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#C/C=C/C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (9.20 mL, 0.00920 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (1.56 mL, 0.00965 mol) in tetrahydrofuran (11.73 mL, 0.1447 mol). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was added a solution of tetrahydro-2H-pyran-4-carbaldehyde (1.0 g, 0.0088 mol) in tetrahydrofuran (2.35 mL, 0.0289 mol). The reaction was allowed to warm up to room temperature and stirred overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was used directly in next step. LCMS (M+H) 138.0.