Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:71][CH2:72][C:73]([CH3:76])([OH:75])[CH3:74]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:71][CH2:72][C:73]([OH:75])([CH3:76])[CH3:74])=[O:19])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:33])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)CN
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NCC(C)(C)O)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.080 mmol) in DMF (4 ml) was added BOP (40 mg, 0.10 mmol) and DIPEA (20 mg, 0.11 mmol), followed by 1-amino-2-methylpropan-2-ol (10 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].S(O)(O)(=O)=O.[CH3:32][N:33]([CH3:37])[C:34]([NH2:36])=[NH:35].[O-]CC.[Na+].C(O)C>C(O)C>[CH3:32][N:33]([CH3:37])[C:34]1[NH:36][C:17](=[O:18])[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:35]=1
Reactant: CN(C)C(=N)N
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(N(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
To a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (6.41 g) and N,N-dimethylguanidine sulfate (5.0 g) in ethanol (100 mL) was added 20% sodium ethoxide-ethanol solution (11 mL), and the mixture was heated under reflux for 24 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was washed with water and diethyl ether to give the title compound (2.06 g, 30%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=[O:20])[C:14]=1[CH3:22].NCC(O)CN1CCOCC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=[O:20])[C:14]=1[CH3:22]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: NCC(O)CN1CCOCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.4 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (74 mg, 0.48 mmol) to precipitate 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (65 mg, 36%). The mother liquid was evaporated to dryness and the residue was purified by flash chromatography to give additional 2N (70 mg, 39%). 1H NMR (DMSO-d6) δ 2.28 (m, 1H), 2.32 (m, 1H), 2.40 (m, 4H), 2.40, 2.42 (2×s, 6H, 2×CH3), 3.15 (s, 1H), 3.31 (m, 1H), 3.55 (m, 4H), 3.78 (m, 1H), 4.73 (brs, 1H, OH), 6.82 (dd, J=4.5, 8.4 Hz, 1H), 6.90 (td, 2J=2.8, 3J=10.0 Hz, 1H), 7.53 (m, 1H), 7.70 (s, 1H), 7.74 (dd, J=2.0, 9.6 Hz, 1H) (aromatic and vinyl), 10.87 (s, 1H, CONH), 13.66 (s, 1H, NH). LC-MS (m/z) 441.4 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](OCC)=[O:12])=[CH:5]2.[Al].[Li]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [Al]
Agent: [Li]
Product: OCc1cc2cc(Br)ccc2[nH]1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-Carboxylate and lithium aluminum in substantially the same manner, as described in step 3 of Example 1. The product was obtained as a solid; mp: 111–112° C. Mass spectrum (ESI, [M−H]−) m/z 224. 1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.27 (d, 1H, J=8.02 Hz), 7.12 (d, 1H, J=8.02 Hz), 6.25 (s, 1H), 5.29 (t, 1H, J=5.50 Hz), 4.59 ppm (d, 2H, J=5.65 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]([CH2:21][OH:22])([CH3:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:10]([CH2:21][O:22][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)([CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC1(CO)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Cl)cn2)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a stirred solution of [(3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-yl]-methanol (4.0 g, 12.7 mmol) in DMF (60 mL) at RT was added NaH (608 mg, 60%, 15.2 mmol). The reaction mixture was heated at 50° C. for 30 minutes, then cooled down to RT before 2-bromo-5-chloropyridine (3.66 g, 19.0 mmol) was added. The resulting brownish solution was stirred overnight at 60° C., then concentrated under high vacuum. The residues was taken up in EtOAc, and washed with water. The organic phase was dried over Na2SO4 and a purification by column chromatography gave 3.90 g (72%) of the title product as a viscous oil. ES-MS m/e: 427.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C)cc2SC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)S2
Temperature: 25 °C
Reaction time: 4.8 h
Yield: 10.8 %

Procedure:
The ester from Step 3 (2.02 g, 6.0 mmol) was dissolved in THF (10 mL) and ethanol (10 mL), treated with 2.5 N sodium hydroxide (5.5 mL, 13.8 mmol), and stirred at room temperature for 4.8 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl yielding a suspension. The solid was collected by filtration and was recrystallized from ethanol-water to yield the title compound as a yellow solid (0.20 g, 11%): mp 240.5–241.7° C. 1H NMR (acetone-d6/300MHz) 7.99 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 4.99 (q, 1H, J=8.5 Hz), 2.39 (s, 3H). FABLRMS m/z 307 (M−H). FABHRMS m/z 306.9831 (M−H, Calc'd 306.9807). Anal. Calc'd for C12H8ClF3O2S: C, 46.69; H, 2.61; Cl, 11.48. Found: C, 46.78; H, 2.61; Cl, 11.41.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=N/S(C2SC=CC=2)(=O)=O)/[CH:3]=1.[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:31][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21

Procedure:
5.2.31 N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)biphenyl-4-sulfonamide (12b) was prepared according to the procedure for 12a except using 4-biphenylsulfonamide, which afforded the title compound 154 mg (37.8%) as a yellow solid. When TiCl4.2THF and THF were used instead, the reaction afforded the title compound 586.7 mg (71.9%) as a yellow solid, m.p.: 190-192° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:21])[C:7]([S:18]([CH3:20])=O)=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3].[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H](S)[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24].CC(N(C)C)=O>CN(C)C=O>[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:20]([S:18][C:7]2[C@H:6]([CH3:21])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCF
Reactant: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a mixture of allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (150 mg) and silica gel (300 mg) in N,N-dimethylformamide (1.5 ml) was added a solution of (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)-4-mercaptopyrrolidine (150 mg) i dimethylacetamide (1.45 g). The mixture was stirred for 2 hours at ambient temperature. Silica gel was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to afford allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (160 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:32])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.C(#N)C>[O:25]([C:24]([NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(NCCCOc1ccc2[nH]c(=O)ccc2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of water (50 ml) and acetonitrile (50 ml) are added 6-(3-aminopropoxy)carbostyril hydrochloride (5.0 g) and potassium carbonate (3.4 g) at room temperature. The mixture is stirred at room temperature for 2 hours, and cooled to -5° C. To the mixture is added dropwise phenyl chlorocarbonate (3.9 g) while the temperature of the mixture is kept below 0° C. The mixture is stirred at the same temperature for 1 hour, and thereto is added water (100 ml), and then the mixture is further stirred for 0.5 hour. The precipitated crystals are collected by filtration, and washed successively with water and acetone to give 6-(3-phenoxycarbonylaminopropoxy)carbostyril (6.0 g) as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[SH:10].C1(P(O[C:26]2[C@H:27]([CH3:50])[C@@H:28]3[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]3[C:30]=2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])(C2C=CC=CC=2)=O)C=CC=CC=1.[I-].[Na+].C(OCC)(=O)C>CC(C)=O.[Cl-].[Na+].O.[Ag]>[OH:48][C@@H:46]([C@H:45]1[C:44](=[O:49])[N:29]2[C:30]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])=[C:26]([S:10]/[CH:9]=[CH:8]\[C:7]3[S:6][CH:5]=[N:4][C:3]=3[CH2:2][OH:1])[C@H:27]([CH3:50])[C@H:28]12)[CH3:47]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: OCc1ncsc1/C=C\S
Agent: [Ag]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reaction time: 18 h
Yield: 54.1 %

Procedure:
The crude crystal of the silver salt of 4-hydroxymethyl-5-[(Z)-2-mercaptoethen-1-yl]thiazole (283 mg) was added to 10 ml of a solution of 599 mg of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in dry acetone under an argon atmosphere at 4° C., and 303 mg of sodium iodide was added thereto. The mixture was stirred at the same temperature for 18 hr. Ethyl acetate (20 ml) and 20 ml of semi-saturated brine were added thereto, and the mixture was filtered through Celite and was washed with ethyl acetate. The filtrate was separated, the organic layer was washed with semi-saturated brine, was dried over anhydrous magnesium sulfate, and was filtered, and ethyl acetate was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 298 mg of 4-nitrobenzyl (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[N+:9]([CH:12]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1)([O-:11])=[O:10]
Reactant: COC1=NCCCC1
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])C=C1CCCCN1

Procedure:
A solution of 33.9 g of (1A) and 36.6 g of nitromethane was refluxed for 3 days, cooled and quenched in one liter of cold ether. Filtration gave a solid crude product, m.p. 79° - 81°. Evaporation of the filtrate and trituration of the residue with cold ether give additional crude product. The crude product was continuously extracted from a Soxhlet thimble with ether for 18 hours, after which time only a small amount of dark oil remained. The solvent pot (not containing crystallized product) was cooled and the solid product was filtered, giving 2-(nitromethylene)piperidine (1B), as a pale yellow solid, m.p.: 80.5°-81°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[N:5][C:4]=1[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[N:5][C:4]=1[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)=[O:1]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(C#N)cc2)c1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(C#N)cc2)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A mixture of 4-(5-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)benzonitrile (100 mg, 0.30 mmol, 1.00 equiv) and MnO2 (260 mg, 2.99 mmol, 10.00 equiv) in dichloromethane (10 mL) was stirred at room temperature for 1 h. The solid material was removed by filtration. The filtrate was concentrated under vacuum to yield 64 mg (64%) of 4-(5-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)benzonitrile as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.94 (s, 1H), 7.93 (s, 1H), 7.76-7.56 (m, 4H), 5.75 (s, 2H), 3.66 (t, J=9.4 Hz, 2H), 0.94 (t, J=9.4 Hz, 2H), 0.04 (s, 9H) ppm. LCMS (method A, ESI): RT=1.57 min, m/z=328.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2Cl.Cl.C[OH:16]>>[Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:16]
Reactant: CO
Reactant: Oc1ccc2c(Cl)nccc2c1Br
Agent: Cl
Product: O=c1[nH]ccc2c(Br)c(O)ccc12
Temperature: 150 °C

Procedure:
5-Bromo-1-chloro-6-hydroxyisoquinoline (108 mg, 0.42 mmol) was mixed with hydrochloric acid (5M, 2 ml) and heated under microwave conditions at 150° C. for 40 minutes. The cooled residue was mixed with methanol and azeotroped to dryness under reduced pressure to give 5-bromo-6-hydroxy-2H-isoquinolin-1-one El-MS: m/z=240 and 242[M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19](=[S:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.N1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CC#N.C(OCC)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19]1[S:21][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1nc(-c2ccccc2)cs1
Reaction time: 2 h
Yield: 39 %

Procedure:
A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butyl ester, 2, (0.343 g, 1.05 mmol), 2-bromo-acetophenone (0.231 g, 1.15 mmol), in CH3CN (5 mL) is refluxed 1.5 hour. The solvent is removed under reduced pressure and the residue re-dissolved in CH2Cl2 then pyridine (0.24 mL, 3.0 mmol) and Boc2O (0.24 mL, 1.1 mmol) are added. The reaction is stirred for 2 hours and diethyl ether is added to the solution and the precipitate which forms is removed by filtration. The organic layer is dried (Na2SO4), filtered, and concentrated to a residue which is purified over silica to afford 0.176 g (39%) of the desired product ESI+ MS 426 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][CH:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[NH:9]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(n1-c1ccccc1)CCCC2
Product: ClC1NC2=C(CCCC2)N1c1ccccc1
Yield: 32.2 %

Procedure:
A mixture of 2.3 g (0.0107 mol) of 1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazol-2-one and 30 ml of POCl3 is stirred under reflux for 6 hours. The excess POCl3 is evaporated under vacuum and the residue is hydrolyzed with water and concentrated ammonium hydroxide. The mixture is extracted twice with methylene chloride, evaporated and the residue is purified by flash chromatography on silica with an 80:20 heptane/ethyl acetate eluent. 0.8 g of product is recovered. Yield=32.2%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1)[CH3:2]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CCOCCOCCO
Product: CCOCCOCCOc1nc(Nc2cc(C)[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from 2-(2-ethoxy-ethoxy)-ethanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give {-[2-(2-ethoxy-ethoxy)-ethoxy]-isoquinolin-3-yl}-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 357(MH+).
Reaction SMILES: OO.[F:3][C:4]1[C:18]([F:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1.C([O-])([O-])=[O:23].[K+].[K+].CS(C)=O>O>[F:3][C:4]1[C:18]([F:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([NH2:12])=[O:23])=[CH:9][N:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Reaction time: 1 h
Yield: 148.1 %

Procedure:
Add 30% aq. H2O2 (7.95 ml) to a suspension of 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinonitrile (2.07 g, 7.95 mmol), K2CO3 (550 mg, 3.98 mmol) and DMSO (20 ml) stirring in an ice/water bath. After one hour, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide (1.64 g) as a white solid. 1HNMR (DMSO-d6): 10.14 (s, 1H), 8.58 (s, 1H), 8.33 (d, 1H), 8.07 (s, 1H), 7.74 (t, 1H), 7.55 (s, 1H), 7.33 (d, 1H), 7.27 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
A solution of ethyl 6-chloro-4-(phenylamino)nicotinate (19 g, 89 mmol) in anhydrous THF (40 mL) was added dropwise to a 0° C. suspension of LiAlH4 (8.5 g, 223 mmol) in anhydrous THF (80 mL). After complete addition, the reaction mixture was stirred at RT for 3 h. The mixture was quenched by the addition of 10% aq NaOH (8.5 mL) and water (8.5 mL). The solids were removed by filtration and the organic phase was concentrated in vacuo to provide (6-chloro-4-(phenylamino)pyridin-3-yl)methanol (12 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1 H), 8.08 (s, 1 H), 7.39-7.10 (m, 5 H), 6.73 (s, 1 H), 5.37 (s, 1 H), 4.52 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:28]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[OH:36])[CH2:29]1>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:33]1[CH2:34][CH2:35][C:30]2([CH2:28][CH2:29]2)[C@H:31]([OH:36])[CH2:32]1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2ccc(C(F)(F)F)cc2)CCC1=O
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(C(F)(F)F)cc2)CCC1=O
Yield: 75 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-[7-oxo-4-(4-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 75% yield as light yellow foam. MS: 484.4 (MH+).