Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:7]=[C:3]1C(O)=O.CCOCC>N1C2C(=CC=CC=2)C=CC=1>[N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:3][C:2](=[O:1])[NH:10][CH:9]=2)=[N:12][CH:13]=1
Reactant: O=C(O)c1cc(-c2ccncn2)c[nH]c1=O
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: O=c1ccc(-c2ccncn2)c[nH]1
Reaction time: 0.5 h

Procedure:
A solution of 90.8 g of 1,2-dihydro-2-oxo-5-(4-pyrimidinyl) nicotinic acid in 900 ml of quinoline is refluxed overnight. The reaction mixture is cooled, poured into 1800 ml of anhydrous ether, stirred for 30 minutes, filtered and the filtered solid washed with 2 l of ether. The solid is dried, recrystallized from 100 ml of hot dimethylformamide and dried to yield 5-(4-pyrimidyl)-2(1H)-pyridone, M.P. >250° C.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]([NH:28][C:29](=[O:31])[CH3:30])([CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])(C)(C)C>C(O)=O>[C:29]([NH:28][C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:8][CH2:7][C:6]([OH:32])=[O:5])(=[O:31])[CH3:30]
Reactant: CC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Solvent: O=CO
Product: CC(=O)NC(CCC(=O)O)(CCC(=O)O)CCC(=O)O
Reaction time: 4 h
Yield: 93 %

Procedure:
1.5 g of triester 63 (3.28 mmol) was added to 20 ml formic acid (96%) and stirred for 4 hours. After this time the formic acid was removed by azeotropic distillation with 5×20 ml portions of toluene. The crude residue was recrystallised from EtOH and petroleum spirit to give 0.9 g of off white crystals in 93% yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].Cl>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(C=C2CCCCC2=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C=C2CCCCC2O)cc1
Temperature: 0 °C
Yield: 17.4 %

Procedure:
2.0 g of (+)-2-[4-(2-oxocyclohexylidenemethyl)phenyl]propionic acid and 0.6 g of sodium cyanoborohydride were dissolved in 50 ml of methanol. The pH of the mixture was adjusted to a value of 3 with 6N hydrochloric acid, whilst ice-cooling. The mixture was then stirred, with heating, for 40 minutes. Ice-water was added to the reaction mixture, which was then extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulphate, and the solvent was distilled off, to give 350 mg of (±)-2-[4-(2-hydroxycyclohexylidenemethyl)phenyl]propionic acid as crystals [compound of formula (VI)]. These crystals were dissolved in 10 ml of ethyl acetate, 50 mg of palladium chloride were added, and the mixture was subjected to catalytic reduction whilst bubbling hydrogen through the mixture. After the theoretical amount of hydrogen had been absorbed, the catalyst was removed by filtration and the solvent was distilled off, to give 330 mg of a mixture of the cis- and trans-isomers. This mixture was treated in the same manner as in Example 1, affording crystals of the cis- and trans-isomers of the title compound, having the same properties as the product of Example 1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[N:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1>[C:19]([N:17]([C:15](=[O:16])[CH2:14][N:4]1[C:5]2[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[N:3]1)[NH2:18])(=[O:21])[CH3:20]
Reactant: NNC(=O)Cn1nc(Br)c2c([N+](=O)[O-])cccc21
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N(N)C(=O)Cn1nc(Br)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 2-(3-bromo-4-nitro-1H-indazol-1-yl)acetohydrazide (0.865 g) in anhydrous toluene (20 mL) was treated at ambient temperature with 1 equivalent of acetic anhydride. The reaction mixture was stirred at ambient temperature for 16 hours and concentrated under reduced pressure to afford the product (0.98 g) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[CH2:33]([NH:40][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A suspension of 29.4 mg (0.10 mmol) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 18.4 mg (0.11 mmol) 1.1′-carbonyl-diimidazole in 3 ml dimethylformamide was stirred at room temperature for one hour. 12.1 μl (0.11 mmol) benzylamine were added, stirring was continued and after 20 hours 15 ml water were added. Extraction with ethyl acetate and chromatography on silicagel with dichloromethane/ethyl acetate 95/5 yielded 31.2 mg (41%) of yellow 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid benzylamide with mp.: 156-158° C., MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:5]=1[C:6]#[N:7])([O-])=O>C(O)C(F)(F)F.FC(F)(F)C(O)C(F)(F)F>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(OCCN2CCCC2=O)cccc1[N+](=O)[O-]
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: OCC(F)(F)F
Product: N#Cc1c(N)cccc1OCCN1CCCC1=O
Yield: 100 %

Procedure:
Prepared as in example 254b from 2-nitro-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrile (Example 257c) using trifluoroethanol/hexafluoroisopropanol (1:1) as solvent in 100% yield MS 246 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][N:3]=1.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N+:22]([O-:24])=[O:23])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(Cc2cnc(N)nc2N)c2cccnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2cccnc2c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a cold (5°) solution of 2,4-diamino-5-(7-methoxy-5-quinolylmethyl)pyrimidine (0.28 g, 1.0 mmol) in concentrated sulfuric acid (2 mL) was added dropwise 90% nitric acid (0.10 g, 1.4 mmol). After stirring at 5° for 30 min, the reaction was poured onto ice and the resulting solution taken to pH 3 with 5N sodium hydroxide. The tan solid that separated was collected then boiled in water and filtered to remove insolubles. The filtrate was taken to pH 8 with 1M sodium carbonate to precipitate the title compound (0.14 g, 42%); mp>270° dec. Anal. Calcd for C15H14N6O3 : C, 55.21; H, 4.32; N, 25.75. Found: C, 55.02, H, 4.10; N, 25.41.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:21][CH2:20][C:13]2([CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25].Cl>CN(C)C=O>[C:4]([Si:1]([O:8][CH2:9][CH:10]1[CH2:21][CH2:20][C:13]2([CH2:14][CH2:15][CH:16]([O:19][CH3:25])[CH2:17][CH2:18]2)[CH2:12][CH2:11]1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC2(CCC(O)CC2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC2(CCC(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-ol (309 mg) obtained in Step 4 in N,N-dimethylformamide (5 mL) was added 60% sodium hydride (60 mg) under ice-cooling, followed by stirring the reaction mixture at room temperature for 5 minutes. To the reaction mixture was added iodomethane (0.19 mL), followed by stirring at room temperature for 15 minutes. To the reaction mixture were further added 60% sodium hydride (120 mg) and iodomethane (0.38 mL), followed by stirring at room temperature for 15 minutes. To the reaction mixture was added 1N aqueous hydrochloric acid solution under ice-cooling, followed by extraction with diethyl ether three times. The organic layer was dried and then concentrated to give tert-butyl-(9-methoxyspiro[5.5]undec-3-ylmethoxy)-dimethylsilane (393 mg) as a crude product.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:18]=[C:17]3[C:12]([C:13](=[O:26])[C:14]([C:23]([OH:25])=[O:24])=[CH:15][N:16]3[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][C:10]=1[F:27])[CH2:2]2.[CH3:28][S:29]([O-:32])(=[O:31])=[O:30]>>[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].[CH3:28][N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][N:3]([C:9]1[N:18]=[C:17]3[C:12]([C:13](=[O:26])[C:14]([C:23]([OH:25])=[O:24])=[CH:15][N:16]3[C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:11][C:10]=1[F:27])[CH2:4]2
Reactant: CS(=O)(=O)[O-]
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC(C3)N4)nc21
Product: CN1C2CCC1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C(C)(C)C)C2
Product: CS(=O)(=O)O

Procedure:
7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[CH2:1]([O:11][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCO
Reactant: O=C(Cl)OCc1ccccc1
Product: C=CCCCCCCCCOC(=O)OCc1ccccc1

Procedure:
Starting Material: dec-9-en-1-ol and benzyl chloroformate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:32])[C:15]=2[C@H:16]2[O:22][CH2:21][C@@H:20]([F:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:33].[Cl:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[NH2:24][C@H:19]1[C@H:20]([F:23])[CH2:21][O:22][C@H:16]([C:15]2[N:14]([CH3:32])[N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:33])=[C:2]([C:36]3[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:35]=3[Cl:34])[N:7]=2)[CH2:17][CH2:18]1
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3cccc(F)c3Cl)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 103), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-3-fluorophenyl)boronic acid gave 227. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.28 (dd, J=8.6, 3.9 Hz, 1H), 8.12 (t, J=8.9 Hz, 1H), 7.89 (s, 1H), 7.64-7.45 (m, 3H), 4.81 (dd, J=10.3, 3.8 Hz, 1H), 4.20 (ddt, J=49.1, 5.7, 2.7 Hz, 1H), 4.05-3.80 (m, 2H), 3.75 (s, 3H), 3.09-2.95 (m, 1H), 2.10-1.99 (m, 1H), 1.82-1.64 (m, 1H), 1.66-1.56 (m, 2H), 1.53 (br, 2H). LCMS (ES+) m/z 480 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][CH2:33][CH3:34]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:32][CH2:33][CH3:34])[N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:27][CH:28]=1
Reactant: CCCBr
Reactant: O=C(NCC=C1CCN(Cc2ccc(F)cc2)CC1)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1nc(C(=O)NCC=C2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
N-[2-(1-p-Fluorobenzyl-4-piperidylidene)ethyl]-1H-indazole-3-carboxamide (0.33 g) obtained in Example 9 was dissolved in DMF (5 ml), 60% sodium hydride (0.05 g) and 1-bromopropane (0.21 g) were successively added under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 ml), washed with water (20 ml×4), dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (0.15 g). Yield=41%.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[CH2:10][C@@H:9]2[N:11]2[C:19](=[O:20])[C@@H:14]3[CH2:15][NH:16][CH2:17][CH2:18][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([N:28]2[C:32]([NH:33][C:34](=O)[O:35]C3C=CC=CC=3)=[CH:31][CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[O:20]=[C:19]1[C@@H:14]2[CH2:15][N:16]([C:34]([NH:33][C:32]3[N:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:29]=[CH:30][CH:31]=3)=[O:35])[CH2:17][CH2:18][N:13]2[C:12](=[O:21])[N:11]1[C@H:9]1[CH2:10][C@@H:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Reactant: O=C(Nc1ccnn1-c1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccnn1-c1ccccc1)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
Example 4, D2 (1 eq) was dissolved in DCM (0.1M), F3 (1.5 eq) and TEA (1.5 eq) were added and the reaction was stirred at RT 6 h. The reaction was diluted with DCM and washed with water and brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtOAc/petroleum ether to afford the title compound in 85% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.91 (1H, s), 7.62 (1H, d, J=1.7 Hz), 7.54-7.47 (4H, m), 7.37 (1H, m), 7.30 (2H, m), 7.22-7.20 (3H, m), 6.31 (1H, d, J=1.7 Hz), 4.24 (1H, m), 4.02-3.96 (2H, m), 3.87 (1H, m), 2.97 (1H, m), 2.84 (2H, m), 2.67 (1H, m), 2.38 (1H, m), 1.52-1.48 (1H, m), 1.40 (1H, m). MS (ES+) C25H24N6O3 requires 456, found: 457 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C1COCC1>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:10][N:11]=1)[C:38]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=1)=[O:39]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCCN(C)C)nc3)cc2n(CCC)c1=O
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CCN(C)C)C(=O)Nc4ccc(F)cc4)nc3)cc2n(CCC)c1=O
Temperature: 85 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
9c (35 mg) was suspended in THF (3 ml) in a pressure tube, 4-fluorophenyl isocyanate (130 mg) was added and the mixture was stirred at 85° C. for 3 days. After cooling to room temperature, the mixture was evaporated and the solid was stirred with ether and filtered The mother liquid contained most of the product. After removal of the solvent, the residue was purified by column (14 g silica gel, RT Scientific) (CH2Cl2: MeOH=100:0 to 95:5) to give the product (11c) (22 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=7.20 min. 1H NMR (DMSO, d6): 0.83-0.93 (m, 6H), 1.53-1.71 (m, 4H), 2.28 (s, 6H), 2.50 (s, 4H), 3.87 (m, 4H), 4.14 (t, 1H, J=5.4 Hz), 6.83 (s, 1H), 7.15 (t, 2H, J=8.7 Hz), 7.52 (m, 3H), 8.24 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.92 (d, 1H, J=2.4 Hz), 11.54 (s, 1H). MS: m/z 536 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C@H:9]([C:17](=[O:19])[NH2:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[NH:15])=[O:7])=[CH:4][C:3]=1[O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>>[C:17]([C@@H:9]([NH:8][C:6]([C:5]1[CH:20]=[CH:21][C:2]([NH:1][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:3]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH:4]=1)=[O:7])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[NH:15])(=[O:19])[NH2:18]
Reactant: O=C1CCC(=O)O1
Reactant: N=C(N)NCCC[C@H](NC(=O)c1ccc(N)c(OCCc2ccc(Cl)cc2Cl)c1)C(N)=O
Product: N=C(N)NCCC[C@H](NC(=O)c1ccc(NC(=O)CCC(=O)O)c(OCCc2ccc(Cl)cc2Cl)c1)C(N)=O

Procedure:
The third part of the resin obtained in Example 2 (116 mg) was coupled with 160 mg of succinic anhydride analogously to the procedure described in Example 3. The resin was washed and dried, and the final product was cleaved off and processed as described in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8]([CH2:10][CH2:11][OH:12])=[O:9])[CH:2]=1.[CH3:13]C(C)([O-])C.[K+].C=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[S:8](=[O:9])[CH2:10][CH2:11][O:12][CH2:13]2)[CH:2]=1
Reactant: O=S(CCO)Cc1cccnc1
Reactant: CC(C)(C)[O-]
Agent: C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1CCOCC1c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 338 %

Procedure:
A stirred solution of 2-(3-pyridylmethylsulphinyl)ethanol (0.25 g, 1.35 mmol) in dimethylformamide (25 ml) at 0° C. was treated portionwise with potassium tert-butoxide (0.15 g, 1.35 mmol) and stirred for 10 mins. Formaldehyde gas [generated by heating paraformaldehyde (45 mg, 1.5 mmol) at 150° C.] was passed into the reaction mixture in a rapid stream of argon whilst cooling in an ice bath. When addition of the formaldehyde was completed the cooling bath was removed and the mixture allowed to warm to room temperature over 15 mins. The solution was poured into ethanol (30 ml), neutralised with concentrated hydrochloric acid and filtered to give a clear solution which was evaporated in vacuo and the residue was purified by flash chromatography on silica, eluting with 7% methanol in dichloromethane, to give 3-(3-pyridyl)-1,4-oxathiane 4-oxide (900 mg), as a colourless crystalline solid, m.p. 74°-76° C.
Reaction SMILES: C(C(O)=O)(F)(F)F.C([O:12][C:13](=[O:41])[CH2:14][N:15]([S:23]([C:26]1[CH:35]=[C:34]2[C:29]([C:30]([Cl:40])=[CH:31][N:32]=[C:33]2[NH:36][C:37]([NH2:39])=[NH:38])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(C)(C)C>C(Cl)Cl>[ClH:40].[ClH:40].[Cl:40][C:30]1[C:29]2[C:34](=[CH:35][C:26]([S:23]([N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][C:13]([OH:41])=[O:12])(=[O:24])=[O:25])=[CH:27][CH:28]=2)[C:33]([NH:36][C:37]([NH2:39])=[NH:38])=[N:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1cccnc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3cccnc3)cc12
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 129 %

Procedure:
CF3CO2H (1.0 mL) was added to a stirred solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine t-butyl ester (100 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) and the mixture was stirred at 23° C. for 3.5 h. The solvents were evaporated in vacuo, azeotroping with PhMe and CH2Cl2. The oily residue was dissolved in EtOAc and a solution of EtOAc saturated with HCl (3.0 mL) was added which gave a precipitate. The white solid was collected by filtration and dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine dihydrochloride (48 mg, 0.086 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:13]2[N:14](C=C)[CH:15]=[CH:16][N:17]=2)[OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+]>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)[OH:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cn1ccnc1C(O)(c1ccccc1)c1ccc(C(C)(C)C)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(O)(c2ccccc2)c2ncc[nH]2)cc1

Procedure:
This compound was prepared by the procedure described in Example XXI B using 22.6 g. (0.068 mol) of α-(p-tert.-butylphenyl)-α-phenyl-1-vinylimidazole-2-methanol, 820 ml. of 4% aqueous potassium permanganate and 11 g. of solid potassium permanganate (total permanganate 0.214 mol). After the manganese dioxide had been filtered off, the excess of potassium permanganate in the filtrate was reduced to manganese dioxide by addition of sodium bisulphite. The precipitate was filtered off and the organic solvents were distilled off. The remainder of the filtrate was poured into water and the oil thus obtained was dissolved in diethyl ether. The solution was washed four times with water and dried over sodium sulphate and the solvent was distilled off. The resulting oil was taken up in as little acetone as possible and brought to crystallisation by adding petroleum ether (boiling range 28°-40° C.). Melting point 166°-166° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][C:11]=2[C:12]=1[CH3:13].[CH2:24](Br)[C:25]#[CH:26]>CC(C)=O>[CH2:26]([N:21]1[CH2:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:10]3[O:9][C:8]([CH3:7])=[C:12]([CH3:13])[C:11]=3[CH:14]=2)[CH2:19][CH2:20]1)[C:25]#[CH:24]
Reactant: Cc1oc2ccc(C3CCNCC3)cc2c1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCC(c2ccc3oc(C)c(C)c3c2)CC1
Temperature: 25 °C

Procedure:
4.15 g (0.030 mol) of anhydrous potassium carbonate are added to a solution of 2.29 g (0.010 mol) of 4-(2,3-dimethyl-5-benzofuranyl)-piperidine (c.f. Example 1) in 25 ml of acetone, and a solution of 1.3 g (0.011 mol) of 2-propynyl bromide in 11 ml of acetone is added dropwise in the course of 10 minutes, with stirring. The reaction mixture is heated to 40° for 4 hours and then cooled to room temperature and the inorganic salts are filtered off. The filtrate is evaporated in a rotary evaporator. The brown oil which remains has, in the thin layer chromatogram (silica gel/5% methanol/chloroform), a main spot at an Rf value of about 0.7, in addition to 4 secondary spots. The resulting oil is chromatographed on 50 g of silica gel using chloroform as the solvent and eluting agent, whereupon 1-(2-propynyl)-4-(2,3-dimethyl-5-benzofuranyl)-piperidine is obtained, as the main fraction, as a yellowish oil with an Rf value of about 0.7. This base is dissolved in about 3 ml of methanol and converted into the hydrochloride by acidifcation with hydrogen chloride solution and the hydrochloride is made to crystallise by adding about 20 ml of ether and is filtered off with suction. The hydrochloride thus obtained as white crystals melts at 224°-225°.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1O)#[C:11][CH2:12][CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Br:1][C:2]1[C:3]([CH2:8][O:9][C:19]2[CH:18]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=2[C:10]#[C:11][CH2:12][CH3:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC#Cc1ccc(F)cc1O
Reactant: OCc1ncccc1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC#Cc1ccc(F)cc1OCc1ncccc1Br
Yield: 63.7 %

Procedure:
A solution of (3-bromo-pyridin-2-yl)-methanol (3.09 g, 16.43 mmol), 2-but-1-ynyl-5-fluoro-phenol (2.70 g, 16.43 mmol), and triphenylphosphine (6.46 g, 24.64 mmol) in dichloromethane (162 mL) is cooled to −5 to 0° C. Diisopropyl azodicarboxylate (DIAD) is added (4.85 mL, 24.64 mmol) dropwise over a 15 min period. After 1 h the solvent is evaporated and the crude material directly purified by flash chromatography (SiO2; 4% hexane: AcOEt) to give 3.5 g (64%) of the title compound. LCMS m/e 334 [M+H]+.