Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:34]1([C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[NH:41][CH2:42][CH2:43][CH2:44]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:44][CH2:43][CH2:42][NH:41][C:40]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCNC(c4ccccc4)(c4ccccc4)c4ccccc4)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1

Procedure:
360 mg (12 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a three-necked round-bottomed flask. A solution of 4.1 g (10 mmol) of methyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in 75 ml of DMF are added dropwise, under a nitrogen stream, and the mixture is stirred until the evolution of gas ceases. A solution of 42 g (11 mmol) of N-triphenylmethyl-3-bromopropylamine in 50 ml of DMF is then introduced dropwise and the mixture is stirred at room temperature for 8 h. The reaction medium is poured into water, extracted with ethyl ether, the organic phase separated after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by silica chromatography, eluted with a dichloromethane and hexane mixture (40-60). After evaporation of the solvents, 4.7 g (66%) of the expected product are recovered, which product melts at 168°-9° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:11][CH2:12][NH2:13].O>C1(C)C=CC=CC=1>[CH2:1]([NH:13][CH2:12][CH2:11][C:10]([OH:9])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC(O)(COc1ccc(Cl)cc1)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: OC(CCNCc1ccccc1)(COc1ccc(Cl)cc1)c1ccccc1
Yield: 67.9 %

Procedure:
34 g of benzaldehyde were added to a solution of 35 g (0.32 mole) of the 3-hydroxy-3-phenyl-4-(4-chlorophenoxy)-butylamine obtained as described in (b), in 700 ml of toluene, and the mixture was boiled in a water separator until the water had been removed. The solution was evaporated down, the residue was dissolved in 500 ml of methanol, and 25 g of sodium borohydride were added a little at a time. The reaction mixture was evaporated down, 2N sodium hydroxide solution was added to the residue and the mixture was extracted with 3 times 200 ml of ether. The ether was removed, and the resulting residue was dissolved in isopropanol, from which it was obtained in crystalline form. 83 g (68%) of N-benzyl-3-hydroxy-3-phenyl-4-(4-chlorophenoxy)-butylamine of melting point 84°-85° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.Br[CH2:15][CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][CH2:15][CH2:16][O:17][Si:18]([CH:22]([CH3:23])[CH3:24])([CH:19]([CH3:21])[CH3:20])[CH:25]([CH3:26])[CH3:27])[CH:6]=1
Reactant: CC(C)[Si](OCCBr)(C(C)C)C(C)C
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Product: COC(=O)Cc1cc(O)cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c1

Procedure:
A mixture of 9.39 g (51.5 mmol) of (3,5-dihydroxy-phenyl)-acetic acid methyl ester (prepared according to U. Eder, G. Sauer, G. Haffer, G. Neef, R. Wiechert, U.S. Pat. No. 4,066,674), 11.38 g (61.8 mmol) of 1-bromo-2-triisopropylsilyloxy-ethane and 14.50 g (51.5 mmol) of cesium carbonate is stirred at RT for 1 hour and at 60° C. for another hour. The reaction mixture is then treated with saturated aqueous sodium carbonate and extracted with ethyl acetate. The layers are separated and the organic layer is washed three times with saturated aqueous sodium carbonate. The aqueous layers are combined and extracted three times with ethyl acetate. The combined organic solutions are then washed with saturated brine, dried, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (85:15 hexane/ethyl acetate then 70:30 hexane/ethyl acetate and finally pure ethyl acetate) to afford above title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12](Cl)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>>[CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:22])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Clc1nc2ccccc2c2c1ncn2Cc1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2Cc1ccccc1

Procedure:
Using the method of Example 100, 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinoline (from Example 80) was reacted with ammonia to provide white solid 1-benzyl-1H-imidazo[4,5-c]quinolin-4-amine after recrystallization from N,N-dimethylformamide, m.p. 257°-259° C. Analysis: Calculated for C17H14N4: % C, 74.4; % H, 5.1; % N, 20.4; Found: % C, 74.3; % H, 5.4; % N, 20.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:14][C:12]1[N:13]=[C:8]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Nc2ccncc2)n1
Solvent: ClCCl
Product: ClCc1cccc(Nc2ccncc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 0° C., 50 mg (0.22 mmol) of the compound from example 8A and 53 mg (0.44 mmol) of thionyl chloride are initially charged in 1.5 ml of dichloromethane and, after warming to RT, stirred at this temperature for 12 h. The solvent is removed on a rotary evaporator and the product that remains is directly reacted further.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])C.Cl.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[NH:28])([O-:23])=[O:22]>>[CH2:13]([N:8]1[CH2:9][CH2:10][C:11]2[N:28]=[C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[N:29]=[C:4]([OH:5])[C:6]=2[CH2:7]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1

Procedure:
The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3-nitro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.76 (s, 4H), 3.28 (s, 2H), 3.71 (s, 2H), 7.25-7.40 (m, 6H), 7.81 (t, J=8.0 Hz, 1H), 8.35-8.40 (m, 1H), 8.52 (d, J=8.0 Hz, 2H), 8.93 (s, 1H); MS: m/z (ESI) 363 (M+H).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:24][C:25]1([NH2:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:31][C:25]2([CH3:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC1(N)CCOCC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)CCOCC1
Temperature: 100 °C
Yield: 6 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (49.1 mg, 0.324 mmol, Biofine International, Blaine, Wash.), and DIPEA (141 μl, 0.810 mmol), heating at 100° C. for 20 h. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(2-methyl-3-((4-methyltetrahydro-2H-pyran-4-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6% yield). 1H NMR (400 MHz, MeOD) δ ppm 1.73 (s, 3H) 1.85-1.95 (m, 2H) 2.53 (d, J=13.50 Hz, 2H) 2.67 (s, 3H) 3.01 (t, J=7.14 Hz, 2H) 3.64 (t, J=7.14 Hz, 2H) 3.76-3.82 (m, 4H) 7.00 (s, 1H) 7.40 (t, J=7.82 Hz, 1H) 7.65 (dd, J=8.12, 1.27 Hz, 1H) 7.88 (dd, J=7.53, 1.27 Hz, 1H). MS (ESI, pos. ion) m/z: 392.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:30])[CH2:10][CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N+](=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34]([O:36][CH3:37])=[O:35])=[N-].C([O-])(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:10][CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:30][C:33]2([C:38]([O:40][CH3:41])=[O:39])[C:34]([O:36][CH3:37])=[O:35])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 82.3 %

Procedure:
{[3-(3,4-Dichlorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphenylsilane (P13, 2.25 g), dimethyl diazopropanedioate (1.2 g) (prepared in an analogous manner as reported in Synthetic Communications, 17(4), 1709-16, 1987) and rodhium (II) acetate dimer (0.060 g) were mixed together and heated at 100° C. for 40 min. After cooling, the residue was treated with DCM and the mixture was filtered. The filtrate was evaporated under reduced pressure and the crude product was purified by flash chromatography (Cy/EA from 1/0 to 95/5) to give the title compound (2.38 g) as a colourless oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].O>CN1CCCC1=O>[CH2:1]([N:15]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc(CN(c2ccccc2)c2cccc3ccccc23)cc1
Reaction time: 2 h
Yield: 65 %

Procedure:
Benzyl bromide (0.15M) was added to a stirred mixture of 1-phenylaminonaphthalene (0.1M) and KOH (0.15M) in N-methyl pyrrolidone (70 cm3) at 120° C. After 2 hours further stirring the mixture was poured in to water, the precipitate filtered off, washed and re-crystallised from methanol to give 20 g (65% yield) of a white solid mp 120°-123° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: O=C(O)c1ccc(S)nc1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(C(=O)O)cn2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 6-mercaptonicotinic acid using the procedure described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H) 7.30 (s, 1H) 7.50 (t, J=7.58 Hz, 1H) 7.72-7.82 (m, 1H) 7.99 (t, J=9.09 Hz, 2H) 8.11 (dd, J=8.34, 1.77 Hz, 1H) 8.17 (s, 1H) 8.88 (d, J=1.52 Hz, 1H); ESI-MS: m/z calc'd for C19H14N4O3S 378.08. found 379.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[C:20]([C:28]([O:30][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc(OCOC)c(C(=O)O)c3)cs2)cc1OCC
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOC(=O)c1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1OCOC
Temperature: 25 °C
Reaction time: 14 h
Yield: 43.8 %

Procedure:
In 5 ml of dimethylformamide was dissolved 600 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-methoxymethoxyphenyl)thiazole. Thereto was added 56 mg of sodium hydride and 290 mg of 1-bromononane. The mixture was stirred at room temperature for 14 hours. The solvent was removed by distillation. To the residue were added 80 ml of dichloromethane and 30 ml of a 10% aqueous sodium hydroxide solution, and phase separation was conducted. The dichloromethane portion was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was subjected to silica gel column chromatography. There was obtained, from the dichloromethane layer, 340 mg of 2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazole as a colorless oily substance.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:23]([CH3:25])[CH3:24])[S:14]2)[C@H:10]1[O:26]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[CH3:25][N:23]([CH3:24])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH2:18][C:19]([F:22])([F:20])[F:21])[C@@H:9]([OH:8])[C@H:10]([OH:26])[C@H:11]2[N:12]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CC(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CC(F)(F)F)O[C@@H]2S1
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A solution of compound 112 (300 mg, 0.6 mmol) in dichloromethane (10 mL) was added BCl3 (3 mL, 3 mmol, 1M in dichloromethane) at −78° C. The resulting solution was kept at −20° C. for 1 hour, then quenched by the addition of methanol (10 mL). Volatiles were distilled out under vacuum to give a residue, which was dissolved into methanol (5 mL) and neutralized by Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give the title compound as a white solid (94.2 mg, 49%). (ES, m/z): [M+H]+ 300.9; 1H NMR (D2O, 300 MHz) δ 6.16 (d, J=6.3 Hz, 1H), 4.11-4.15 (m, 1H), 3.93-3.97 (m, 1H), 3.77-3.83 (m, 1H), 3.44-3.48 (m, 1H), 2.91 (s, 6H), 2.52-2.68 (m, 1H), 2.37-2.49 (m, 1H).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([N:22]1[C:28]2[CH:29]=[CH:30][S:31][C:27]=2[C:26](=[O:32])[NH:25][CH2:24][CH2:23]1)[CH3:21].C(O[B:37]1[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)(C)C.Cl>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([N:22]1[C:28]2[CH:29]=[C:30]([B:37]3[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]3)[S:31][C:27]=2[C:26](=[O:32])[NH:25][CH2:24][CH2:23]1)[CH3:21]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(c1ccccc1Cl)N1CCNC(=O)c2sccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(c1ccccc1Cl)N1CCNC(=O)c2sc(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
HNiPr2 (246 μL, 1.74 mmol, 3.0 Eq) was dissolved in anhydrous THF (10 mL) and cooled to −78° C. under nitrogen. 2.5 M BuLi in hexanes (700 μL, 1.74 mmol, 3.0 Eq) was added dropwise and the reaction stirred at −78° C. for 15 minutes then warmed to 0° C. for 30 minutes. The reaction was cooled to −78° C. and 1-[1-(2-chloro-phenyl)-ethyl]-1,2,3,4-tetrahydro-thieno[3,2-e][1,4]diazepin-5-one (178 mg, 0.58 mmol, 1.0 Eq) was in anhydrous THF (5 mL) was added dropwise. The reaction was stirred at −78° C. for 2 hours. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (355 μL, 1.74 mmol, 3.0 Eq) in anhydrous THF (5 mL) was added and the reaction stirred at −78° C. for 20 minutes them warmed to ambient temperature for 1.5 hours. 1M HCl (20 mL) was added and the mixture extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. The yellow oil obtained was used without further purification; 1H NMR (DMSO D6) 1.28 (12H, s), 1.51 (3H, d), 2.93-2.99 (1H, m), 3.03-3.13 (2H, m), 3.20-3.26 (1H, m), 5.32 (1H, dd), 6.19 (1H, br s), 7.20-7.28 (3H, m), 7.33-7.36 (2H, m); LC/MS M+1 (obs.) 433.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH2:21][CH2:20]3)=[C:15]([O:31][CH3:32])[CH:14]=1)[CH2:6][CH2:5]2.CS([CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>>[CH3:32][O:31][C:15]1[CH:14]=[C:13]([N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:37][C@H:38]4[CH2:42][CH2:41][CH2:40][O:39]4)[CH:3]=3)[C:8]2=[O:12])[CH:18]=[CH:17][C:16]=1[N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH2:21][CH2:20]1
Reactant: CS(=O)(=O)C[C@H]1CCCO1
Reactant: COCC(C)N1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2OC)CC1
Product: COCC(C)N1CCCN(c2ccc(N3CCc4cc(OC[C@H]5CCCO5)ccc4C3=O)cc2OC)CC1

Procedure:
6-Hydroxy-2-{3-methoxy-4-[4-(2-methoxy-1-methyl-ethyl)-[1,4]diazepan-1-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one and (R)-2-methanesulfonylmethyl-tetrahydrofuran were reacted according to Method K1. In this way the product was obtained with molecular weight 523.68 (C30H41N3O5); MS (ESI): 524 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH:10]=O)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>CO.O>[CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH:10]=[N:22][OH:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a mixture of 2-butyl-1-benzofuran-3-carbaldehyde (25 g, 0.124 mol) and sodium acetate (12.2 g, 0.124 mol) in methanol (100 mL) was added hydroxylamine hydrochloride (10.3 g, 0.149 mol) in water (25 mL) at 0° C. The mixture was stirred at rt for 2 h. Water (300 mL) was added to the reaction mixture and the product was extracted with EtOAc. The organic layer was dried and concentrated under vacuum to give crude 2-butyl-1-benzofuran-3-carbaldehyde oxime (25 g, 93%) as a light brown liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:28]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:22]3[O:23][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCCC3)C2)cc1
Reactant: NC(=NO)c1ccccc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
73 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-carboxylic acid (Example 41A) and 33 mg (0.24 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 32 mg (33% of theory)
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([S:25][CH3:26])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6].C(O)(=[O:29])C.OO>O>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([S:25]([CH3:26])=[O:29])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6]
Reactant: CSc1cc(C)c(-c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)cn1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: Cc1cc(S(C)=O)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of (1S,2S)-2-fluoro-N-(7-(4-methyl-6-(methylthio)pyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.3674 mmol) and acetic acid (4.0 mL) was treated with hydrogen peroxide (35 mass % in water, 0.16 mL, 1.8 mmol) at room temperature. After 3 hours, additional hydrogen peroxide was added (35 mass % in water, 0.03 mL; 0.3 mmol). After an additional 30 minutes, the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified via preparatory reverse-phase HPLC and lyophilized to yield 63.1 mg (45%) of the title compound. LCMS (ESI): RT (min)=4.013, M+H=384.2, method=E; 1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.22 (s, 1H), 8.61 (s, 1H), 8.54 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 4.96 (m, 1H), 2.86 (s, 3H), 2.46 (s, 3H), 2.35-2.24 (m, 1H), 1.78-1.63 (m, 1H), 1.29-1.12 (m, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[CH:17]([C:30]([CH:27]1[CH2:28][CH2:29][CH:24]([CH3:23])[CH2:25][CH2:26]1)=[O:31])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cc1c(F)cccc1Cl
Reactant: CC1CCC(C(=O)Cl)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCC(C)CC1)c1c(F)cccc1Cl
Temperature: -70 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
Lithium diisopropylamide (0.18 mol) in tetrahydrofuran (270 ml) is added to a mixture of ethyl (2-chloro-6-fluorophenyl)acetate (38.1 g, 0.175 mol) and THF (200 ml) at -70° C. The reaction mixture is stirred for 2 hours at about -70° C. 4-Methylcyclohexanecarboxylic acid chloride (28.25 g, 0.175 mol) is added and the reaction mixture is allowed to warm up to room temperature over night. The reaction mixture is then quenched with hydrochloric acid (5N, 60 ml) and most of the organic solvent is distilled off under reduced pressure. From the remainder the product is extracted with light petroleum (200 ml). The organic layer is separated, washed with water, dried with magnesium sulphate and concentrated in vacuo to yield a yellow oil (63.5 g). This is filtered through silica (light petroleum, 3% ethyl acetate) to yield a pale yellow oil (27.2 g). The product is used in the next step without further purification.