Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32](Br)[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.O1CCCCC1[O:53][CH2:54][CH2:55][N:56]1[CH:60]=[C:59](B2OC(C)(C)C(C)(C)O2)[CH:58]=[N:57]1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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.O>[Cl:45][C:38]1[C:39]([F:44])=[CH:40][CH:41]=[C:42]([Cl:43])[C:37]=1[C@H:35]([C:27]1[C:28]2[C:29](=[N:30][CH:31]=[C:32]([C:59]3[CH:58]=[N:57][N:56]([CH2:55][CH2:54][OH:53])[CH:60]=3)[CH:33]=2)[NH:25][CH:26]=1)[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(CCO)c3)cc12
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of ((S)-1-{5-bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (190.0 mg, 0.262 mmol), 1-[2-(tetrahydropyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (95.0 mg, 0.294 mol), Pd(PPh3)4 (20 mg, 0.010 mmol), potassium carbonate (181 mg, 1.31 mmol) in a mixed solvent of dioxane and water (v:v=4:1, dioxane:H2O, 10 mL) was heated to 85° C. for 1 h. The organic solvent was removed and the material was transferred to a separatory funnel and extracted with DCM (20 mL×3). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give a residue that was re-dissolved in dioxane (4 mL). 2M aq. HCl (1.0 mL) was added at rt, and the solution was allowed to stir for 1 h. The solvents were removed in vacuo, and the material was dry-loaded onto silica gel for column chromatography, eluting with 3-4% (7N NH3 in MeOH)/DCM to reveal the title compound. MS (ES+): m/z=419.21, 421.19 (100, 85) [MH+]. HPLC: tR=0.92 min (HPLC-ACQUITY, Purity).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:23]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1COc1ccccc1
Yield: 82.5 %

Procedure:
2 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate (cf. Method B), 0.65 g of phenol and 1.1 g of potassium carbonate in 20 ml of acetone are refluxed for 24 hours. The mixture is filtered, the filtrate is evaporated down, the residue is taken up in ether, and the solution is extracted twice with sodium carbonate solution and 3 times with water, dried over MgSO4 and evaporated down. The crude product is recrystallized from n-hexane to give 1.7 g of white crystals of melting point 60° C. (compound No. 1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4].[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:22])[C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.390 g, 1.34 mmol) in DMF (10 mL) was added N-bromosuccinimide (0.263, 1.48 mmol). The reaction mixture was stirred at room temperature for 25 minutes and then quenched with saturated sodium bisulfite. The reaction mixture was diluted with H2O and partitioned between EtOAc/diethyl ether and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.424 g (85%) pure desired product as a lavender foamy solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 70A (0.013 g, 0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.224 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 5% methanol in ethyl acetate to give the title compound (0.009 g, 30% yield). 1H NMR (300 MHz, CDCl3), δ ppm 0.96 (s, 9 H), 1.00 (s, 9 H), 1.27 (m, 1 H), 2.62 (dd, J=13.79, 8.64 Hz, 1 H), 2.85 (m, 5 H), 3.03 (q, J=8.58 Hz, 1 H), 3.39 (m, 1 H), 3.64 (m, 4 H), 3.82 (d, J=9.19 Hz, 1 H), 3.94 (m, 1 H), 4.00 (s, 1 H), 4.11 (m, 2 H), 4.35 (m, 2 H), 5.31 (m, 1 H), 6.13 (m, 2 H), 7.10 (m, 5 H), 7.21 (m, 2 H), 7.33 (m, 7 H), 7.74 (m, 2 H), 7.89 (d, J=8.46 Hz, 2 H), 8.68 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:29]([NH2:31])=[O:30])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@H:15]([NH:17]C(=O)OCC3C=CC=CC=3)[CH3:16])[C:6]=2[N:28]=1>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([C:29]([NH2:31])=[O:30])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@H:15]([NH2:17])[CH3:16])[C:6]=2[N:28]=1
Reactant: C[C@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of benzyl {(1R)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xxiv-a, 13 mg, 0.031 mmol) in ethanol (10 mL) was added palladium on carbon (10 mg, 0.094 mmol). The reaction mixture was stirred under a hydrogen atmosphere overnight. Solids were removed by filtration and the filtrate was concentrated in vacuo to afford 2-amino-9-[(2R)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (35, 7.6 mg, 86%). NH4OAc standard conditions. DAD Retention time=4.90 min. M+H=284. 1H NMR (300 MHz, MeOD-d4): 8.66 (s, 1H), 7.90 (d, J=7.7 Hz, 1H) 7.49 (d, J=8.1 Hz, 1H), 7.23 (ddd, J=7.4, 6.9, 1.2 Hz, 1H), 7.17 (ddd, J1=7.8, 7.7, 1.2 Hz, 1H), 4.33 (d, J=6.1 Hz, 2H), 3.63-3.71 (m, 1H), 1.23 (d, J=6.5 Hz, 3H).
Reaction SMILES: [S-2].[Na+].[Na+].[S].[Br:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16]>C(O)(C)C>[Br:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])[NH2:12]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1Br
Agent: [Na+]
Agent: [S-2]
Agent: [S]
Solvent: CC(C)O
Product: CC(C)c1ccc(N)cc1Br
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
A solution of sodium sulphide (31.2 g, 0.24 mol) and sulphur (7.7 g, 0.24 mol) was stirred at 80° C. for 15 minutes. Isopropanol (160 g) was subsequently added and the mixture was stirred at 75° C. for a further 15 minutes and 2-bromo-1-isopropyl-4-nitrobenzene (XI) (50 g, 0.19 mol) was finally added dropwise over a period of 30 minutes. After stirring for another 5 hours, the reaction was complete. For the work-up, the isopropanol was firstly distilled off and the remaining mixture was extracted with toluene/chlorobenzene. The combined organic phases were distilled under reduced pressure. 3-Bromo-4-isopropylaniline (42 g, 91 GC-% by area, 93% of theory) was obtained as a red oil.
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]C1)=O)(C)(C)C.[O:31]=[S:32]1(=[O:39])CC[CH:34](NC)[CH2:33]1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]([CH:12]3[CH2:34][CH2:33][S:32](=[O:39])(=[O:31])[CH2:13]3)[CH3:10])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: CNC1CCS(=O)(=O)C1
Product: CN(Cc1ccc([C@H]2COc3cccnc3O2)cc1)C1CCS(=O)(=O)C1

Procedure:
Compound 280 is synthesized from Intermediate C and (1,1-dioxo-tetrahydro-1lambda-6-thiophen-3-yl)-methyl-amine according to General Method N. (LC/MS method 16: ES+ m/z 375.4 [M+H]+, Rt=2.66 min)
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])=[C:4]([OH:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].[CH:21](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[C:1]([C:3]([C:19]#[N:20])=[C:4]([O:18][CH3:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in TI-IF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CN(c1cncc(Br)c1)S(C)(=O)=O
Product: CN(c1cncc(C#Cc2cc(Cl)ccc2OCC(=O)O)c1)S(C)(=O)=O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and N-(5-bromopyridin-3-yl)-N-methylmethanesulfonamide (Intermediate 33), the title compound was obtained as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:32][C:2]([F:33])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: C1CNCCNC1
Product: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure C.
Reaction SMILES: C([N:3](CC)CC)C.[OH:8][C@@H:9]1[CH2:13][N:12]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C@@H:11]([C:26]([OH:28])=O)[CH2:10]1.ClC(OCC)=O>CC(C)=O>[OH:8][CH:9]1[CH2:13][N:12]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:11]([C:26]([NH2:3])=[O:28])[CH2:10]1
Reactant: COc1ccc(C(=O)N2C[C@@H](O)C[C@@H]2C(=O)O)cc1OC
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Product: COc1ccc(C(=O)N2CC(O)CC2C(N)=O)cc1OC
Reaction time: 0.33 h

Procedure:
1.1 equivalents of triethylamine are added to 3 g (0.01 mole) of the trans-4-hydroxy- 1-(3,4-dimethoxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 4 in suspension of 200 ml of acetone at 0° C. The reaction mixture is stirred for 20 minutes and then 1.1 equivalents of ethyl chloroformate are added while maintaining the temperature between 0° C. and 5° C. After stirring for 20 minutes, the mixture is filtered and ammonia is bubbled through the solution. The precipitate formed is separated, the acetone is removed under vacuum and the product obtained is recrystallized in water.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C:9]([CH2:12][S:13]([CH2:16][CH2:17]O)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C:9]([CH2:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)CCO)ccc(Br)c1OC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Yield: 80.6 %

Procedure:
Methyl 3-bromo-6-(2-hydroxyethanesulphonylmethyl)-2-methoxybenzoate (Intermediate 173, 0.68 g) and methanesulphonyl chloride (0.424 g) were added to a solution of triethylamine (0.561 g) in DCM (10 ml) and the resultant mixture was stirred in an ice bath for 1 hour. DCM was added and the solution was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-40% to give methyl 3-bromo-2-methoxy-6-(vinylsulphonylmethyl)benzoate (0.521 g) as a colourless gum which crystallized on standing to a white solid.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:18][C@@H:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: C[C@@H](N)c1ccccc1
Product: CCOC(CN[C@H](C)c1ccccc1)OCC
Yield: 71.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2-bromo-1,1-diethoxyethane (41.3 ml, 270 mmol) was reacted with (R)-(+)-1-phenylethylamine (66.6 g, 550 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1 and 1:1) to obtain the title compound (46.0 g, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:23])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]3[O:22][CH2:21][CH2:20][C:18]3=2)[CH:13]=[CH:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[OH-].[NH4+]>C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:23])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]3[O:22][CH2:21][CH2:20][C:18]3=2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](Cn1ccc2ccc3c(c21)CCO3)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H](CN1CCc2ccc3c(c21)CCO3)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a stirred solution/suspension of (S)-1-[2-(tert-butoxycarbonylamino)propyl]-7,8-dihydrofuro[2,3-g]indole (565 mg, 1.79 mmol) in acetic acid (40 mL) under Ar at 5° C. was added sodium cyanoborohydride (371 mg, 5.90 mmol) and the mixture was allowed to warm to ambient temperature and stir overnight. The resultant solution was poured onto ice-water (100 mL), basified (˜pH 8–9) by the addition of 30% ammonium hydroxide, and the resultant suspension was filtered and the solid washed with ice-cold water. The crude solid was purified by flash column chromatography [SiO2; ethyl acetate-heptane (3:7)] to afford the product (412 mg, 72%) as a white solid: mp 141–142.5° C.; Found: C, 67.87; H, 8.21; N, 8.80%. C18H26N2O3 requires: C, 67.90; H, 8.23; N, 8.79%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[C:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[O:9][C:10](=[O:15])[C:11]=3[NH:12][C:13]=2[CH:14]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[C:26]#[N:27]>CN(C=O)C.C(OCC)(=O)C>[F:31][C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[CH2:22][N:12]1[C:11]2[C:10](=[O:15])[O:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]=2[C:5]2[CH:4]=[C:3]([CH3:20])[C:2]([F:1])=[CH:14][C:13]1=2
Reactant: Cc1cc2c(cc1F)[nH]c1c(=O)oc3ncccc3c12
Reactant: N#Cc1ccc(F)c(CBr)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c3c4cccnc4oc(=O)c3n(Cc3cc(C#N)ccc3F)c2cc1F
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 9-Fluoro-10-methyl-7H-5-oxa-4,7-diaza-benzo[c]fluoren-6-one 1G (167 mg, 0.622 mmol) in DMF (3.0 mL) was added 3-Bromomethyl-4-fluoro-benzonitrile (160.0 mg, 0.747 mmol) and CsCO3 (243 mg, 0.747 mmol) at room temperature and the reaction mixture was allowed to stir overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The concentrated crude was purified using chromatography over SiO2 using 0 to 30% ethyl acetate in hexane to provide 4-Fluoro-3-(9-fluoro-10-methyl-6-oxo-6H-5-oxa-4,7-diaza-benzo[c]fluoren-7-ylmethyl)-benzonitrile 1H (200 mg, 80%). M.S. found for C23H13F2N3O2: 402.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:7]([NH2:9])=[O:8])=[O:25])=[CH:22][CH:21]=1
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: NC(=O)c1c(NC(=O)c2ccc(F)cc2)ncn1CCCc1ccccc1
Yield: 93 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22, using 2.00 g (8.19 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 114 and 4-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.78 g of 4-(4-fluorobenzoylamino)-1-(3-phenylpropyl)-5-imidazolecarboxamide (yield 93%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([Br:20])[C:7]2[O:11][C:10](Br)=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:19]=1)#[N:2].[N+:21]([O-:26])([N+]([O-])=O)=[O:22].C1CCC(C(O)=O)CC=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:20][C:6]1[C:7]2[O:11][C:10]([N+:21]([O-:26])=[O:22])=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:19]=[C:4]([CH2:3][C:1]#[N:2])[CH:5]=1
Reactant: N#CCc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: II
Agent: O=C(O)C1CC=CCC1
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: N#CCc1cc(Br)c2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 16 h

Procedure:
A solution containing 11.1 g. (0.028 mole) of 5-cyanomethyl-2,7-dibromo-3-phenylbenzofuran, 10.7 g. (0.11 mole) of dinitrogen tetroxide, 13.9 g. (0.11 mole) of cyclohexene-4-carboxylic acid and 1 g. of iodine in 500 ml. of chloroform is stirred at room temperature for 16 hours. An additional 13.9 g. of cyclohexene-4-carboxylic acid and 10.7 g. of dinitrogen tetroxide are added, and stirring is continued for 16 hours. The reaction is then treated with 500 ml. of 10 percent sodium thiosulfate. The phases are separated, and the organic phase is washed thrice with 250 ml. portions of saturated sodium bicarbonate, once with 250 ml. of 3 N hydrochloric acid and dried. Evaporation gives 7-bromo-5-cyanomethyl-2-nitro-3-phenylbenzofuran as a yellow solid, recrystallized from ethyl acetate-hexane to give a sample for analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=[CH:11][CH:10]=1.N#N.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:9]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:14]=[CH:13][C:12]([N:15]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=[CH:11][CH:10]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(Br)cc3)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C

Procedure:
A degassed solution of 24.6 g (87 mmol) of 1-bromo-4-iodobenzene and 28.8 g (80 mmol) of biphenyl-4-yl-(9,9-dimethyl-9H-fluoren-2-yl)amine in 1000 ml of dioxane is saturated with N2 for 1 h. Then firstly 0.9 ml (4.3 mmol) of P(tBu)3, then 0.48 g (2.1 mmol) of palladium(II) acetate are added to the solution. 12.6 g (131 mmol) of NaOtBu in the solid state are subsequently added. The reaction mixture is heated under reflux for 18 h. After cooling to room temperature, 1000 ml of water are carefully added. The organic phase is washed with 4×50 ml of water and dried over MgSO4, and the solvent is removed in vacuo. The pure product is obtained by recrystallisation and final sublimation.