Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[C:35]2[C:30](=[C:31](Br)[CH:32]=[CH:33][CH:34]=2)[N:29]=[N:28][C:27]=1[C:37]([NH2:39])=[O:38]>>[NH2:25][C:26]1[C:35]2[C:30](=[C:31]([C:14]3[CH:13]=[CH:12][C:11]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[CH:8]=[N:9][C:10]=4[CH:15]=3)[CH:32]=[CH:33][CH:34]=2)[N:29]=[N:28][C:27]=1[C:37]([NH2:39])=[O:38]
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CC1(C)OB(c2ccc3c(c2)ncn3C2CCCCC2)OC1(C)C
Product: NC(=O)c1nnc2c(-c3ccc4c(c3)ncn4C3CCCCC3)cccc2c1N

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 1-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 1.29 (t, J=8 Hz, 1 H), 1.44 (br s, 1 H), 1.52-1.71 (m, 2 H), 1.83 (d, J=12 Hz, 1 H), 1.88-2.08 (m, 3 H), 2.13-2.30 (m, 2 H), 7.58 (d, J=8 Hz, 1 H), 7.66-7.83 (m, 2 H), 7.83-7.96 (m, 2 H), 8.28 (d, J=8 Hz, 1 H), 8.35 (br s, 1 H), 8.62 (s, 1 H); ESI-MS m/z [M+H]+ 387.4.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3ccccc3)cc21
Reaction time: 3 h

Procedure:
7-Benzyloxy-3,4-dihydro-1(2H)naphthalenone was prepared by treating 7-hydroxy-1-tetralone (5.91 g, 36.4 mmol) and caesium carbonate (13 g, 40.0 mmol) in dry DMF (100 ml) and under N2 with benzylbromide (6.22 g, 4.33 ml, 36.4 mmol). The reaction was stirred for 3 h and the mixture then filtered and the filtrate concentrated in vacuo. The oily residue was partitioned between ethyl acetate (200 ml) and brine (200 ml), the organic layer separated, dried (MgSO4) and concentrated in vacuo. Trituration of the resultant solid with diethylether-hexane (1:1, 200 ml) gave the desired compound as a white solid (6.57 g) m.p. 86-87°0. MS (EI, 60V) 252 (M+, 100%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([CH3:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: Cc1cccc(C(=O)O)c1
Agent: Cl
Product: Cc1cccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-methylbenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give Example 60. ESI-MS m/e 341.5 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+].C(O)(=O)C>C(N(CC)CC)C>[C:16]([O:19][CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc2oc(S(N)(=O)=O)cc2c1

Procedure:
A mixture of 5-bromomethyl-2-sulfamoylbenzo[b]furan, anhydrous sodium acetate and glacial acetic acid (15 ml) is treated with a little triethylamine and the mixture is heated to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8]2[C:9]([C:19]([OH:21])=O)=[N:10][C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:12][N:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:22][NH:23][C:24]([C:26]1[N:27]([CH3:32])[N:28]=[CH:29][C:30]=1[NH2:31])=[O:25]>>[CH3:32][N:27]1[C:26]([C:24](=[O:25])[NH:23][CH3:22])=[C:30]([NH:31][C:19]([C:9]2[C:8]([NH:7][C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[N:13][CH:12]=[C:11]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[N:10]=2)=[O:21])[CH:29]=[N:28]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: O=C(O)c1nc(N2CCCC2)cnc1Nc1cncnc1
Product: CNC(=O)c1c(NC(=O)c2nc(N3CCCC3)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 3-(pyrimidin-5-ylamino)-6-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (30 mg, 94 μmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (19 mg, 123 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (10 mg, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]I.O>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(C=CC(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
To a solution of 3-(4-methylphenyl)-2-propenoic acid (10.0 g, 61.7 mmol) in THF (100 ml) were added 1,4-diazabicyclo[5.4.0]-7-undecene (11.0 mL, 73.6 mmol) and methyl iodide (4.3 mL, 69.1 mmol) under ice cooling and the mixture was stirred at room temperature for 24 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium sulfite, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 9.10 g (yield 84%) of the title compound. mp. 56–58° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)(=O)=O>>[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)=[CH:23][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)OCc1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 435 mg of indole-3-carbaldehyde and 4-benzyloxybenzyl methanesulfonate in place of the benzyl bromide used in Example 1 to give 626 mg of 1-(4-benzyloxybenzyl)indole-3-carbaldehyde as colorless crystals. The yield thereof was found to be 61%.
Reaction SMILES: C([N:4]1[CH2:16][C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[C@H:9]2[CH2:17][CH2:18][CH2:19][C@H:8]2[N:7]3[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CO>[CH2:6]1[N:7]2[C:15]3[C:10]([CH:9]4[CH2:17][CH2:18][CH2:19][CH:8]42)=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:16][NH:4][CH2:5]1
Reactant: CC(=O)N1CCN2c3c(cccc3[C@H]3CCC[C@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1cc2c3c(c1)C1CCCC1N3CCNC2

Procedure:
(7bR, 10aR)-3-Acetyl-1,2,3,4,8,9, 10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole was treated with solid NaOH in MeOH under reflux to give 7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole mp: 57-59° C.
Reaction SMILES: C[O:2][C:3](=[O:70])[CH2:4][NH:5][C:6]([C:8]1([NH:11][C:12](=[O:69])[C@H:13]([NH:35][C:36](=[O:68])[CH2:37][NH:38][C:39](=[O:67])[CH2:40][C@H:41]([OH:66])/[CH:42]=[CH:43]/[CH2:44][CH2:45][S:46][C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:14][S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[Li+].[OH-]>C1COCC1.O>[OH:66][C@H:41](/[CH:42]=[CH:43]/[CH2:44][CH2:45][S:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:40][C:39]([NH:38][CH2:37][C:36]([NH:35][C@H:13]([CH2:14][S:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]([NH:11][C:8]1([C:6]([NH:5][CH2:4][C:3]([OH:70])=[O:2])=[O:7])[CH2:10][CH2:9]1)=[O:69])=[O:68])=[O:67]
Reactant: COC(=O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)CNC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)CNC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.92 h
Yield: 100 %

Procedure:
To 4 (157.3 mg, 0.154 mmol) in THF (2.45 mL) at 0° C. was added LiOH (9.19 mg, 0.384 mmol) in water (0.65 mL) dropwise and the reaction was stirred for 55 min. The reaction mixture was then quenched with 1M HCl (aq) (10 mL) and diluted with water (10 mL). EtOAc (30 mL) was added the layers separated and the aqueous layer was extracted with EtOAc (3×30 mL). The organic layers were combined, washed with saturated brine (20 mL), separated, dried (MgSO4) and concentrated in vacuo to give 5 (153 mg, 0.154 mmol, 100%) as a white solid, which was used without further purification [MS (ES−) 959.2 (100%, [M−H]−)].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[CH:44]=[CH:45][CH:46]=[N:47]4)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCCN2)C1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCCN2C[C@@H](O)COc2cccc3ncccc23)C1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
1-(Piperidine-2-carbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (28) (234.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 15 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, 50%→100% acetone in hexanes, then 5% ethanol in acetone) affording the desired product (250 mg) as a white solid. ESMS: MH+691.4
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)=[C:11]([Cl:16])[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (11.8 g, 32.7 mmol), prepared as described in example 1B, in toluene (200 ml) was added Pd(PPh3)4 (2.26 g, 1.96 mmol). After 5 min, 2N aqueous sodium carbonate (65 ml, 130 mmol) solution was added, followed by 4-chlorophenylboronic acid (7.16 g, 45.8 mmol). The reaction was stirred at 100° C. for 6 h. After this time, the solution was cooled RT and the reaction mixture was diluted with ethyl acetate. The resultant solution was washed with water, saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified using silica gel column chromatography eluting with a gradient of 10-20% Ethyl acetate/Hexane to give the title compounds, 2-benzyl-6-(benzyloxy)-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one and 2-benzyl-6-(benzyloxy)-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one which were obtained as a mixture.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-])=O)[CH3:2]>C1COCC1.O.[Ni]>[NH2:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[NH:3][CH2:1][CH3:2])[C:8]([OH:10])=[O:9]
Reactant: CCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc(C(=O)O)cc1N

Procedure:
A solution of 1.56 g (7.4 mmol) of the title A compound 4-ethylamino-3-nitro-benzoic acid in 60 mL of THF/water (2:1) is hydrogenated at 20 psi over 300 mg of Raney nickel for 18 h. The catalyst is removed by filtration through Celite and the solvent is removed under reduced pressure to give 3-amino-4-ethylamino-benzoic acid as a dark solid. This material is used as such in the next step.
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[CH3:5][C:6]1[N:11]=[C:10]([NH:12][C:13](=[S:15])[S-:14])[CH:9]=[CH:8][CH:7]=1.C([NH+](CC)CC)C.C(O)C>O>[OH:4][CH:3]1[CH2:2][S:15][C:13](=[S:14])[N:12]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[N:11]=1
Reactant: O=CCCl
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: CCO
Solvent: O
Product: Cc1cccc(N2C(=S)SCC2O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A 50% aqueous solution of chloroacetaldehyde (28.4 g) is added, at between 20° and 30° C., to a solution of triethylammonium 6-methylpyrid-2-yldithiocarbamate (51.5 g) in distilled water (225 cc). The reaction mixture is stirred for 2 hours at 25° C. The crude product is filtered off, washed five times with distilled water (total 125 cc) and dried in air. The product obtained (37.0 g; m.p. 128° C.) is dissolved in boiling ethanol (250 cc). After filtering the boiling solution and cooling the filtrate for 2 hours at 2° C., the resulting crystals are filtered off, washed three times with ice-cooled ethanol (total 30 cc) and dried under reduced pressure (0.2 mm Hg) at 40° C. 4-Hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (29.8 g), melting at 128° C., is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5]
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4.44 g (28 mmol) of 2-fluorobenzoyl chloride are added to 30 ml of anhydrous pyridine at 0° C. while the temperature is maintained below 5° C. 3 g of 3-amino-2-chloropyridine in 20 ml of pyridine are added with stirring using a pressure equalizing funnel. After being left overnight at room temperature, the reaction medium is poured into an ice/water mixture. The solid obtained is filtered off and washed several times with water.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[S:27])=[O:24]>C1COCC1>[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([NH:25][C:26](=[S:27])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:24]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: O=C(N=C=S)c1ccccc1F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2F)sc2c1CC(C)(C)OC2
Temperature: 60 °C
Yield: 48.9 %

Procedure:
To a solution of tert-butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (50 mg, 0.18 mmol) in THF (3 mL) was added 2-fluorobenzoyl isothiocyanate (35.2 mg, 0.19 mmol) and the mixture heated at 60° C. for 16 h. The solvent was removed in vacuo. The residue was sonicated (1 min) with cold EtOH, filtered and the resulting solid rinsed with cold EtOH to yield tert-butyl 2-(3-(2-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (41 mg, 0.088 mmol, 50% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 14.70 (s, 1H), 9.69 (s, 1H), 8.25-8.11 (m, 1H), 7.63-7.49 (m, 1H), 7.36-7.26 (m, 1H), 7.23-7.17 (m, 1H), 4.72 (s, 2H), 2.73 (d, J=6.3, 2H), 1.58 (d, J=2.4, 9H), 1.29 (d, J=1.7, 6H). 13C NMR (101 MHz, CDCl3) δ 173.27, 164.59, 161.79, 161.21, 161.18, 159.30, 147.36, 135.67, 135.57, 132.79, 129.15, 125.37, 125.34, 124.64, 119.06, 118.96, 118.06, 116.70, 116.46, 82.42, 70.79, 59.81, 38.24, 28.49, 26.48.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[C:10]([Cl:18])[CH:9]=1.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([Cl:18])[CH:9]=1
Reactant: [H][H]
Reactant: C=CCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Reaction time: 5 h
Yield: 19.9 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-glycine methyl ester (see Example 6; 3.0 g) was dissolved in absolute ethanol (100 ml) and Adams catalyst (20 mg) was added. Hydrogenation was carried out in an atmospheric pressure hydrogenator for 5 hrs. until hydrogen (310 ml) had been taken up. The catalyst was removed from the reaction mixture by filtration, the solvent was evaporated at reduced pressure, and light petroleum (b.p. 40°-60° C.) was added to the residue; a solid product (600 mg) of m.p. 76°-80° C. was obtained. After recrystallisation from chloroform/light petroleum (b.p. 40°-60° C.), the above-named product (200 mg), m.p. 79°-82° C., was obtained.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CO>[OH:13][N:12]=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([I:1])=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(C#N)ccc1I
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(N)=NO)ccc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a mixture of 4-iodo-3-methylbenzonitrile (3.59 g, 14.8 mmol) and hydroxylamine hydrochloride (2.05 g, 29.5 mmol) in methanol (75 mL) under nitrogen was added sodium bicarbonate (4.96 g, 59.1 mmol). The reaction mixture was stirred at room temperature for 5 min. and then immersed in an oil bath and heated at reflux for 2 h. The heterogeneous mixture was filtered, the solid was washed with methanol, and the filtrate was concentrated under reduced pressure. The white solid residue was diluted with ethyl acetate (300 mL) but remained heterogeneous. The mixture was sonicated for 5 min and filtered under reduced pressure. By HPLC, the solid appeared to be inorganic. The filtrated was washed with (50 mL), and washed with a 10% aqueous solution of lithium chloride (50 mL), and washed with brine (50 mL). The combined aqueous layers were extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded N′-hydroxy-4-iodo-3-methylbenzimidamide (3.87 g, 14.0 mmol, 95% yield) as a white solid. The compound had an HPLC ret. time=0.993 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=276.8. 1H NMR (500 MHz, CDCl3) δ ppm 2.46 (s, 3H), 4.85 (br. s., 2H), 7.13 (dd, J=8.32, 2.22 Hz, 1H), 7.51 (d, J=1.66 Hz, 1H), and 7.84 (d, J=8.32 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([NH:47]C(OC(C)(C)C)=O)[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C@H:41]([CH2:43][CH3:44])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[ClH:55]>C(#N)C>[ClH:55].[CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]([NH2:47])[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C@H:41]([CH2:43][CH3:44])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:19][CH:20]=2)=[N:11]1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1

Procedure:
Under a nitrogen atmosphere, 317 mg (0.43 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane in 15 ml of acetonitrile and 15 ml of 2N HCl are stirred at 50° C. for 20 hours and worked up analogously to Example 25h to form the title compound: HPLC20-100: tRet=14.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:14]([CH3:13])(=[O:16])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)aniline (10 g) in pyridine (50 ml) was added methanesulfonyl chloride (5.73 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (13.4 g, yield quant.) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH:9]=[C:8]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](OCC3C=CC=CC=3)=[O:26])[CH2:20]2)[C:3]=1C(OC)=O>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:3]2[C:25](=[O:26])[N:21]3[CH2:20][CH:19]([CH2:24][CH2:23][CH2:22]3)[C:8]=2[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:11]=1
Reactant: COC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)cc(-c2ccccc2O)nc1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(-c2ccccc2O)cc2c1C(=O)N1CCCC2C1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 41.7 %

Procedure:
To a solution of methyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinate (60 mg, 0.130 mmol) in methanol (2.0 mL) and THF (1.0 mL) was added 10% Pd—C (200 mg). The mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 6.5 hrs. The mixture was filtrated on Celite®, and washed with MeOH and THF successively. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate, 2:1) to give 6-amino-4-(2-hydroxy-phenyl)-5,9-diazatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-8-one as a yellow solid (16 mg, yield; 40%).