Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[CH2:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of 9H-carbazole (1.67 g, 9.90 mmol, 1.00 equiv, 99%) in DMF (20 mL) followed by addition of NaH (400 mg, 16.50 mmol, 1.00 equiv, 99%) in small portions at 0° C. over 5 minutes. 1-(Bromomethyl)benzene (1.7 g, 9.90 mmol, 1.00 equiv, 99%) was then added drop wise at 0° C. over 5 minutes. The resulting mixture was stirred at room temperature for 16 hours. The progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the reaction was then quenched by the addition of water/ice (100 mL). The solids were collected by filtration and dried in an oven under reduced pressure to afford 9-benzyl-9H-carbazole as white solid (2.3 g, 90%). LCMS: [M+H]+: 258.
Reaction SMILES: [CH2:1]([C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:14]([C@@H:17]([CH2:22][CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])=[C:15]=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([C:8]1([O:13][C:15]([NH:14][C@@H:17]([CH2:22][CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(Cc2ccccc2)CCCC1
Reactant: CCCC[C@H](N=C=O)C(=O)OC
Solvent: Cc1ccccc1
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)OC
Temperature: 85 °C
Yield: 79 %

Procedure:
To 840.8 mg (4.77 mmol) of 1-benzylcyclopentanol in 2.4 mL of toluene was added 816.7 mg (4.77 mmol) of methyl(2S)-2-isocyanatohexanoate. The mixture was heated at 85° C. for 4 d. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 1.31 g (79%) of methyl(2S)-2-({[(1-benzylcyclopentyl)oxy]carbonyl}amino)hexanoate. Rf=0.31 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.37 (d, J=8 Hz, 1H), 7.27-7.06 (m, 5H), 4.00 (m, 1H), 3.64 (s, 3H), 3.19 (ABq, JAB=14 Hz, ΔνAB=9 Hz, 2H), 1.96-1.78 (m, 2H), 1.76-1.38 (m, 8H), 1.36-1.14 (m, 4H), 0.86 (t, J=7 Hz, 3H); ES-LCMS m/z 370 (M+Na).
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28](=[O:30])[CH3:29].[I-].[K+]>CC(C)=O.O>[CH:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH2:27][C:28]([CH3:29])=[O:30])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Yield: 73 %

Procedure:
A mixed solution of 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in Reference Example 148 (1.0 g, 3.93 mmol), potassium carbonate (1.30 g, 9.44 mmol), chloroacetone (436 mg, 4.72 mmol) and potassium iodide (100 mg) in acetone (15 mL) was heated under reflux for 16 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 888 mg (yield 73%) of the title compound. Oily matter.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([O:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCCCCBr
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#CCCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure of Example 4 is followed using 4,6-diphenyl-2-pyridone (6.18 g) and 6-bromohexanonitrile (6.60 g) in place of 6-bromohexanoate, silver carbonate (6.89 g) and toluene (300 cc) and the reaction mixture is refluxed for 72 hours. The material formed is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9.5-0.5) to obtain 6-[(4,6-diphenyl-2-pyridyl)oxy]hexanonitrile as a white solid which is used directly in subsequent reactions.
Reaction SMILES: [C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:19]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)(=[O:22])[CH:20]=[CH2:21].[C:35]([O:40][CH:41]1[CH2:46][CH2:45][O:44][C:42]1=[O:43])(=[O:39])[C:36]([CH3:38])=[CH2:37].N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:8]2[CH2:16][CH:12]3[CH2:11][CH:10]([CH2:15][CH:14]1[CH2:13]3)[CH2:9]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:19]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)(=[O:22])[C:20]([CH3:35])=[CH2:21].[C:35]([O:40][CH:41]1[CH2:46][CH2:45][O:44][C:42]1=[O:43])(=[O:39])[C:36]([CH3:38])=[CH2:37]
Reactant: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Agent: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Agent: C=C(C)C(=O)OC1CCOC1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)CC(C)C
Solvent: CCCCCCC
Product: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 85 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
2-ethyl-2-adamantyl methacrylate, 3-hydroxy-1-adamantyl acrylate and α-methacryloyloxy-γ-butyrolactone were charged in a molar ratio of 2:1:1 (20.0 g:8.9 g:6.5 g), and methyl isobutyl ketone of twice weight of the total monomer weight was added to this to prepare a solution. To this was added azobisisobutyronitrile as an initiator in an amount of 2 mol % based on the total monomer amount, and the temperature was raised to 85° C. and the mixture was stirred for about 5 hours. The reaction mass was cooled, then, poured into a large amount of heptane, to cause precipitation; this operation Was repeated three times for purification. As a result, a copolymer having a weight-average molecular weight of about 8000 was obtained in a yield of 60%. This resin is called Resin AX.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:30])[NH:11][CH2:12][C@H:13]([OH:29])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH3:27])[C:20](=[O:28])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:30])[NH:11][CH2:12][C@@H:13]1[O:29][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH3:27])[C:20](=[O:28])[CH2:19]3)[CH2:14]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C(Cl)Cl
Reactant: CCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC(C)(C)C)OC3=O)cc(F)c21
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 3.58 ml, 36.7 mmol) is added to (R)-[3-(1-ethyl-7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (1.80 g, 4.89 mmol) and triethylamine (3.38 ml, 24.5 mmol) in dichloromethane (20 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a light brown solid. HPLC r.t. 4.92 min; MS for C19H24FN3O5 m/z 394.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[H-].[Na+]>C1COCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
A solution of 3,4-difluorobenzonitrile (28 g, 201 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (40.5 g, 201 mmol) in THF (500 mL) was treated with sodium hydride (4 g, 100 mmoL) and stirred at 25° C. for 16 h. The reaction mixture was washed with water, extracted with EtOAc, and the crude product purified by flash silica gel chromatography gave tert-butyl 4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylate (25 g, 39%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:17]1([N:23]2[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:27]4[N:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:24]=[N:25][N:26]=4)[CH2:29][CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: O=C(O)C(=O)c1c[nH]c2c(Br)ncc(F)c12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.0 g, 17.5 mmol) was dissolved in DMF (100 mL) and treated with 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.0 g, 17.5 mmol), Hunig's base (9.2 mL, 52.6 mmol) and TBTU (5.6 g, 17.5 mmol) and the reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A white solid precipitated out and it was collected by filtration and recrystallized twice with MeOH to afford the title compound (4.58 g) as a white solid. The mother liquid was concentrated and purified using silica gel (CH2Cl2 to 5% MeOH/CH2Cl2) to afford more title compound (1.8 g).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH3:10])[CH:8]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[ClH:2].[Cl-:1].[CH2:9]([N:7]1[CH:8]=[C:4]([CH2:3][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=[CH:6]1)[CH3:10]
Reactant: CCn1cnc(CCl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC#N
Product: CCn1cnc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Cl-]
Yield: 68.9 %

Procedure:
A mixture of 4-chloromethyl-1-ethyl-1H-imidazole hydrochloride (8.35 g), triphenylphosphine (12.1 g) and acetonitrile (200 mL) was heated under reflux for 16 hrs. After cooling, the obtained mixture was concentrated. Diethyl ether was added to the residue to allow crystallization, and the precipitated crystals were collected by filtration and washed successively with hexane and ethyl acetate. The obtained crystals were recrystallized from methanol-tetrahydrofuran to give [(1-ethyl-1H-imidazol-4-yl)methyl](triphenyl)phosphonium chloride hydrochloride as colorless crystals (14.09 g, yield 68%). melting point: 121-122° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(Cl)=[O:18]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([N:13]=[C:17]=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(CCCc2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc(CCCc2ccccc2)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 3-(3-phenylpropyl)aniline (11.6 g) in 100 ml of toluene was dropwise added a solution of phosgene (20 g) in 100 ml of toluene at 10°-20° C. The resultant mixture was gradually heated and, after refluxed for 30 minutes, allowed to cool to room temperature. The solvent was removed under reduced pressure, and the residue was distilled under reduced pressure to give 11.6 g of 3-(3-phenylpropyl)phenyl isocyanate (yield, 89%). B.P. 121°-125° C./0.2 mmHg.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]([N:9]([CH3:11])[CH3:10])=O.[C:12]([C:14]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:15]=1[NH2:16])#[N:13]>C(Cl)(Cl)Cl>[CH3:10][N:9]([CH3:11])[C:7](=[N:16][C:15]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:14]=1[C:12]#[N:13])[CH3:6]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)c(N=C(C)N(C)C)cc1OC
Reaction time: 0.08 h

Procedure:
Phosphorous oxychloride (1.0 ml) was added to a stirred solution of dimethylacetamide (2.8 ml) in chloroform (10 ml) at room temperature. The mixture was stirred for 5 minutes, 2-cyano-4,5-dimethoxyaniline (1.78 g) added and the reaction stirred under reflux for 4 hours. The mixture was cooled, poured onto ice and extracted with chloroform and the organic phase discarded. The aqueous layer was basified (solid NaOH) extracted with chloroform, the combined extracts washed with water, dried (Na2SO4) and evaporated in vacuo. A sample of the brown oily residue (2 g) was crystallised from diisopropylether to give N,N-dimethyl-N'-(2-cyano-4,5-dimethoxyphenyl)acetamidine, m.p. 94°-96°.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[S:22][N:21]=[C:20]([CH3:23])[N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][C:30]=1[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[S:22][N:21]=[C:20]([CH3:23])[N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1nsc(N2CCC(Nc3nc4c(Br)cccn4n3)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5cc(C(F)(F)F)ccc5Cl)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 66c employing (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine and 2-chloro-5-(trifluoromethyl)-phenyl boronic acid. The title compound was obtained as light yellow foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([NH2:34])=[O:33])[N:27]=1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][C:32]([C:28]3[N:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC(=O)c1cccnn1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)c3cccnn3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and pyridazine-3-carboxamide. MS obsd. (ESI+) [(M+H)+] 460, 1H NMR (400 MHz, CD3OD) δ ppm 9.52-9.48 (d, J=8 Hz, 1 H), 8.68 (s, 1 H), 8.62-8.58 (d, J=7.6 Hz, 1 H), 8.10-8.02 (m, 3 H), 7.94 (s, 1 H), 7.88-7.82 (d, J=8 Hz, 1 H), 7.75-7.68 (t, J=7.6 Hz, 2 H), 7.60-7.52 (t, J=7.2 Hz, 1 H), 5.36 (s, 2 H), 4.80-4.55 (m, 2 H), 3.83-3.78 (t, J=2.8 Hz, 2 H), 2.56 (s, 3 H).
Reaction SMILES: [CH2:1]([C:3]1([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[C@@H:19]([CH2:22][CH:23]=[O:24])[CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH3:2].C[Mg+].[Br-].[CH2:36]1COCC1>O1CCCC1>[CH2:1]([C:3]1([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:4][CH2:5][CH:6]([O:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[C@@H:19]([CH2:22][C@H:23]([OH:24])[CH3:36])[CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:7][CH2:8]1)[CH3:2].[CH2:1]([C:3]1([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:4][CH2:5][CH:6]([O:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[C@@H:19]([CH2:22][C@@H:23]([OH:24])[CH3:36])[CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:7][CH2:8]1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Agent: C[Mg+]
Agent: [Br-]
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](C)O)CC4)CC1
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](C)O)CC4)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %
Yield: 20 %

Procedure:
Into a 100-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-(1-ethyl-4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate (330 mg, 0.72 mmol, 1.00 equiv) in 10 mL of distilled tetrahydrofuran. This solution was cooled to 0° C. Then CH3MgBr-THF (1 M, 1.5 mL) was added dropwise via syringe. The resulting solution was stirred for 2 h at this temperature. The reaction was then quenched by the addition of 10 mL of NH4Cl (aq.) and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give 160 mg (47%) of tert-butyl N-(1-ethyl-4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate 199.2 as a white solid and 70 mg (20%) of tert-butyl N-(1-ethyl-4-[[(3R)-3-[(2S)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate 199.1 as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[O:9]=[C:10]1[C:16]2[CH:17]=[CH:18][C:19]([C:21](OCCN(C)C)=[O:22])=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:29]=[CH:30][CH:31]=[CH:32][C:11]1=2>>[O:9]=[C:10]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:22])=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:29]=[CH:30][CH:31]=[CH:32][C:11]1=2
Reactant: CN(C)CCOC(=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CCN(CC)CCO
Product: CCN(CC)CCOC(=O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
In similar manner substituting diethylethanolamine for the dimethylethanolamine, there is obtained β-N,N-diethylaminoethyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)carboxylate.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[S:3]([O:6]C)(=[O:5])=[O:4].[CH2:10]([O:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[F:1][C:2]([F:9])([F:8])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:10]([O:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[CH3:2])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: c1ccc(CON=C(c2ccccc2)c2ccccn2)cc1
Solvent: CCOCC
Product: C[n+]1ccccc1C(=NOCc1ccccc1)c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
17.4 ml (120 mmol) of methyl trifluoromethanesulphonate are added dropwise and at 0° C. to a suspension of 35 g (120 mmol) of phenyl(pyridin-2-yl)methanone O-benzyloxime in 200 ml of diethyl ether, and the mixture is stirred at room temperature for 3 h.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH3:35])=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:39]3[CH2:38][CH2:37][N:36]([C@@H:34]([C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)[CH3:35])[CH2:41][CH2:40]3)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Oc2cccc3[nH]c(=O)c(N)nc23)n1
Reactant: C[C@H](c1ccc(F)cc1)N1CCNCC1
Product: COC[C@H](C)Nc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(N2CCN([C@H](C)c3ccc(F)cc3)CC2)n1

Procedure:
The reaction of (S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (75 mg, 0.2 mmol, Example 122(b)) with (R)-1-(1-(4-fluorophenyl)ethyl)piperazine (42 mg, 0.2 mmol, prepared as described in US 2005/0176726A1) under the condition of Example 104(c) provided the title compound. MS (ESI, pos. ion) m/z: 549 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH:22][C:32](=[O:34])[CH3:33])=[N:19][O:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.05 g, 0.143 mmol), pyridine (0.022 g, 0.282 mmol), acetyl chloride (0.013 g, 0.169 mmol) and a catalytic amount of DMAP in DMF (5 ml) is stirred at 80° C. for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 202-205° C.
Reaction SMILES: CI.[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH2:13])=S)[CH:7]=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18][NH2:19]>CO.C(O)C>[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH:19][CH2:18][C:17]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])=[NH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(OC)c1CN
Reactant: NC(=S)Nc1cccc(Br)n1
Solvent: CCO
Solvent: CI
Solvent: CO
Product: COc1cccc(OC)c1CNC(=N)Nc1cccc(Br)n1
Yield: 73.5 %

Procedure:
0.37 mL (5.89 mmol) methyl iodide diluted in 2 mL methanol was added dropwise to 1.032 g (4.46 mmol) N-(6-bromopyridin-2-yl)thiourea suspended in 30 mL methanol, and the mixture was heated for 2 hr under reflux. The reaction mixture was in solution. The methylated intermediate product, consisting of methyl N-(6-bromopyridin-2-yl)imidothiocarbamate hydroiodide (ESI-MS [M+H+]=247.85 calculated for C7H8BrN3S=246), was freed of solvent under vacuum. The intermediate product was then suspended in 30 mL ethanol, and 1.122 g (6.442 mmol) 2,6-dimethoxybenzylamine was added, whereupon the solid completely dissolved. The mixture was then heated for 2.25 hr under reflux. The colorless solid which precipitated was suctioned off and washed with ethanol. 1.197 g N-(6-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine was obtained as crude product. Repeated crystallization from acetonitrile/water resulted in the isolation of 1.311 g (3.589 mmol, 81%) N-(6-bromopyridin-2-yl)-N-(2,6-dimethoxybenzyl)guanidine, which was also used for the subsequent reaction and derivatizations.