Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[N:12]=[C:11]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2>ClCCl.CC(O)C.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:11]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:10]=[C:9]([N:8]3[CH:1]4[CH2:7][CH2:6][CH:5]3[CH2:4][O:3][CH2:2]4)[N:14]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(NC3CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1ccc(-c2nc(NC3CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Reaction time: 16 h
Yield: 90.5 %

Procedure:
In a 250 mL round bottom flask was placed 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (82 mg, 0.199 mmol) in dichloromethane (7 mL) and 2-propanol (7 mL). A catalytic amount of palladium on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was diluted with dichloromethane, filtered over Celite™ and concentrated to give 69 mg (0.18 mmol, 91%) of a tan solid. HRMS: 382.2236 [M+H]+. For [M+H]+ mass error=−0.1 mDa or −0.35 ppm.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O>CC(O)=O.CC(N(C)C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Reactant: O=Cc1ccccn1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(Nc2nccc(-c3ccc(NCc4ccccn4)s3)n2)c1
Reaction time: 18 h

Procedure:
A solution of [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (prepared according to Method 4) (15 mg, 0.053 mmol) and pyridine-2-carbaldehyde (4.5 uL, 0.048 mmol) were dissolved in a 25% solution of HOAc in DMA (0.5 mL). MP-CNBH3 resin (2.5 eq.) was added after 2 h and the reaction was shaken for 18 h. The reaction was filtered and the resin washed with DMA. The crude mixture was purified by preparative LCMS to afford 11.1 mg, 61.2%). MS: m/z 374 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ2.26 (s, 3H), 4.42 (d, J=6.5 Hz, 2H), 5.96 (d, J=4.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.986 (d, J=5.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.27 (m, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.56 (d, J=4.0 Hz, 1H), 7.73 (br s, 1H), 7.76 (m, 1H), 7.81 (t, J=5.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.53 (br dd, J=4.5 Hz, 1H), 9.24 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[NH2:10][C:11]1[C:19]2[S:18][C:17]([Cl:20])=[N:16][C:15]=2[C:14]([Cl:21])=[CH:13][C:12]=1[F:22]>O.ClCCl>[Cl:20][C:17]1[S:18][C:19]2[C:11]([N:10]=[C:6]=[S:7])=[C:12]([F:22])[CH:13]=[C:14]([Cl:21])[C:15]=2[N:16]=1
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: Fc1cc(Cl)c2nc(Cl)sc2c1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 16.9 g calcium carbonate in 100 ml water was added to a solution of 19.4 g thiophosgene in 100 ml dichloromethane. A solution of 40 g 7-amino-2,4-dichloro-6-fluorobenzothiazole in 500 ml dichloromethane was added, dropwise at 5° C., and the mixture stirred for 8 hours at room temperature. The solid was filtered, the phases were separated, and the organic phase dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (eluent: hexane/ethyl acetate). Yield: 16 g=38% of theory m.p.: 80°-81° C.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[ClH:11].[Cl:12][CH2:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([S:22][CH2:23][CH2:24][CH2:25][Cl:26])[CH:17]=[CH:16][N:15]=1>C(O)(C)C.O>[ClH:12].[ClH:11].[Cl:26][CH2:25][CH2:24][CH2:23][S:22][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:19]=1[O:20][CH3:21]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1c(SCCCCl)ccnc1CCl
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Yield: 67 %

Procedure:
2-Mercapto-1 H-benzimidazole (10 g) and 2-chloromethyl-4-(3-chloropropylthio)-3-methoxypyridine hydrochloride (1 equivalent) are stirred at 80° C. for 5 h in 150 ml of isopropanol and 15 ml of water, the mixture is cooled, and precipitated solid is filtered off and recrystallized from isopropanol/water. The title compound is obtained as a light brown powder; m.p. 117°-119° C. (dec.); yield: 67% of theory.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([NH2:19])[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[N:10]=1)([CH3:5])([CH3:4])[CH3:3].Cl.[NH+]1C=CC=CC=1.O>CCOC(C)=O>[NH2:19][C:8]1[N:9]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[N:10]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: COc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Temperature: 195 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
In a 500 mL round bottom flask was added 5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride (8.42 g, 30 mmol) and pyridinium hydrochloride (13.8 g, 120 mmol). The reaction mixture was heated neat at 195° C. with stirring for 3 h. The mixture was cooled to room temperature, water (300 mL) and EtOAc (300 mL) were added, and then the organic phase was washed with saturated aq NaHCO3 and brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was purified by MPLC (80:20 hexane/EtOAc) to give the product 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (1.3 g, 19%). 1H-NMR (DMSO-d6) δ 7.20 (t, 1H), 7.00 (m, 2H), 6.50 (d, 1H), 5.30 (s, 1H), 5.10 (bs, 2H), 1.30 (s, 9H); MS LC-MS [M+H]+=232.2, RT=0.57 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2.Cl(O)(=O)(=O)=O>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1)C2

Procedure:
4-[(5,6-Dimethoxy-1-indanon-2-ylidene)methyl]pyridine (50 g) in methanol and dichloromethane (1:1) was hydrogenated in presence of palladium on carbon (5 g) and a catalytic quantity of perchloric acid at 0.5 kg pressure and room temperature. The solvents were evaporated under vacuum and the residue was taken in ethyl acetate (500 ml), washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulphate and evaporated in vacuum to yield the product. Yield: 49 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:9][NH:4][CH2:3][CH2:2][OH:1])[CH2:8][CH2:7][CH2:6]1
Reactant: BrCC1CCC1
Reactant: NCCO
Product: OCCNCC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[CH:9]3[O:18][CH:8]3[C:7]=2[CH:19]=1)#[N:2].[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([N:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]([C:20]#[N:21])=[CH:23]3)[C:7]=2[CH:19]=1)#[N:2]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: COCC1(COC)Oc2ccc(C#N)cc2C2OC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](n2cc(C#N)c3ccccc32)[C@@H]1O
Yield: 64.3 %

Procedure:
A reaction mixture containing 6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran (300 mg), 3-cyanoindole (210 mg) and potassium carbonate (480 mg), in dimethylformamide (3 ml), was stirred at 80° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, 1N-hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 298 mg of the title compound.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=O)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1>>[CH3:26][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:12](=[O:14])[CH:10]([CH2:9][S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:11][C:24]2=[S:25])=[CH:19][CH:18]=1
Reactant: Cc1ccc(N=C=S)cc1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(N2C(=O)C(CSCc3ccccc3)NC2=S)cc1
Yield: 111.7 %

Procedure:
When 10 g of S-benzylcysteine (0.0473 mole), 1.89 g of sodium hydroxide (0.0473 mole) and 7.05 g of p-tolylisothiocyanate (0.0473 mole) was reacted according to the procedure outlined in the preparation of Example 2, 18.1 g of the crude thiourea was obtained and 14.3 g of pure title compound was obtained: RF on silica gel=approximately 0.33 [ethyl acetate-hexane (3:7)].
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][CH2:1][N:9]=[C:11]=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NCCc1ccccc1
Temperature: 25 °C

Procedure:
40 grams of phenethyl amine in 300 ml of dry toluene saturated with dry HCl gas was mixed until a heavy white precipitate formed. An additional 200 ml of dry toluene was added with 50 ml of phosgene (12.5% in benzene). The mixture was refluxed (10 min.) and then 450 ml of phosgene was slowly added over 30 minutes and the mixture refluxed for 4 hours. The reaction mixture was allowed to cool to room temperature slowly and the solvent removed in vacuo leaving a yellow oil. Vacuum distillation of the oil at 82° to 83° C./0.1 mm yield 1.8 g of end product.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:12]([NH:19][C:20]1[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[S:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>O.C1C=CC=CC=1>[CH2:1]([N:19]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:20]1[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[S:23][C:24]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNc2c(-c3ccccc3)sc3ccccc23)cc1
Reactant: O=C(O)c1ccccc1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1
Yield: 62.9 %

Procedure:
40.2 g (0.33 mol) of benzoic acid are added to 100 milliliters of absolute benzene and, by cooling and stirring, 3.78 g (0.1 mol) of NaBH4 are added in portions sufficiently slowly for the temperature not to exceed 20° C. After the addition of 6.3 g (20 mmol) of 3-benzylamino-2-phenyl-benzo(b)thiophene the mixture is refluxed for 60 minutes. The still hot reaction mixture has added to it by stirring half a liter of water and is neutralised by ammonia. By evaporating the organic phase dried over K2CO3 and recrystallising the residue in ethanol, 5.1 g (41% of theory) of 3-dibenzylamino-2-phenyl-benzo(b)thiophene are obtained, colourless crystals, mp 98°-100° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@@H:25]([C:26]([OH:28])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8].[C:35](=O)(O)[O-].[Na+]>CO>[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@H:25]([C:26]([O:28][CH3:35])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8]
Reactant: O=C([O-])O
Reactant: COC(=O)Nc1ccccc1[C@H]1[C@@H](C(=O)O)c2cc(OC)c(OC)cc2C(=O)N1C
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Nc1ccccc1[C@H]1[C@H](C(=O)OC)c2cc(OC)c(OC)cc2C(=O)N1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Thionyl chloride (10 mL) was added slowly to a suspension of cis 10 (0.75 g, 1.8 mmol) and trans 10 (1.35 g, 3.3 mmol) in methanol (100 mL) at 0° C. The resulting mixture was stirred for 6 h at 0° C. After completion of the reaction (TLC), the reaction mixture was poured slowly into a mixture of ice (200 g) and a saturated solution of sodium bicarbonate (100 mL). The resulting mixture was extracted with chloroform (3×150 mL), and the combined extracts were dried with sodium sulfate, filtered though a thin pad of silica gel, and evaporated to dryness to obtain 11 as amorphous glassy solid (2.1 g, 96%). IR (film) 1733, 1637 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1 H), 7.52 (d, J=7.7 Hz, 1 H), 7.25 (t, J=7.0 Hz, 1 H), 7.03 (t, J=7.5 Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.73 (s, 1 H), 6.54 (s, 1 H), 5.45 (s, 1 H), 3.95 (s, 3 H), 3.89 (s, 1 H), 3.82 (s, 3 H), 3.72 (s, 3 H), 3.63 (s, 1 H), 3.03 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.06, 164.17, 155.49, 152.15, 149.18, 134.39, 132.53, 129.10, 126.67, 126.53, 125.93, 125.14, 121.60, 111.86, 110.17, 59.32, 56.29, 56.20, 53.27, 53.06, 48.66, 34.57; ESIMS m/z (rel intensity) 429 (MH+, 100), 451 (56); ESIHRMS m/z MH+ calcd. for C22H24N2O7, 429,1662; found, 429.1665.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[CH3:22][C:23]12[CH2:33][CH:27]3[CH2:28][C:29]([CH3:32])([CH2:31][C:25]([C:34]([O:36][CH:37](Cl)[CH3:38])=[O:35])([CH2:26]3)[CH2:24]1)[CH2:30]2>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:38][CH2:37][O:36][C:34]([C:25]12[CH2:31][C:29]3([CH3:32])[CH2:28][CH:27]([CH2:33][C:23]([CH3:22])([CH2:30]3)[CH2:24]1)[CH2:26]2)=[O:35])=[O:19]
Reactant: CC(Cl)OC(=O)C12CC3CC(C)(CC(C)(C3)C1)C2
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: CC12CC3CC(C)(C1)CC(C(=O)OCCOC(=O)[C@H]1[C@@H]4C[C@H](F)[C@@](N)(C(=O)O)[C@@H]41)(C3)C2
Yield: 9.6 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 500 mg) and 1-chloroethyl 3,5-dimethyladamantane-1-carboxylate (A-5-1, 1.13 g) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-5, 70 mg) as a colorless solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[C:10]([N:38]([CH3:40])[CH3:39])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][N:38]([CH3:39])[C:10]1[C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:12][C:13]2[NH:14][C:15](=[O:30])[CH2:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH:19]=3)=[N:7][C:8]=2[CH:9]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1-c1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1-c1ccccc1F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {2-dimethylamino-2′-fluoro-5-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example M70) (810 mg, 1.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (61 mg).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])[C:24]([F:43])=[CH:23][N:22]=1>>[F:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1F
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.041 g, 42%). MP: 95-136° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, 1H, J=8.6 Hz), 8.15 (s, 1H), 7.92-7.89 (m, 1H), 7.39 (s, 1H), 7.38-7.32 (m, 1H), 7.20-7.17 (m, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.54-6.49 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.22-3.16 (m, 4H), 3.11 (s, 2H), 2.90 (d, 3H, J=5.1 Hz), 2.88-2.82 (m, 4H), 2.72-2.66 (m, 4H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS: 579.30 (MH)+.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].ClCCl.[N:21]1C2C(=CC=CC=2)C=C[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:22]#[N:21])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2ncccc2c1
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)Cc1cc(C#N)ccc1-2

Procedure:
A mixture of 2-acetyl-7-bromofluorene (13.2 g.) and cuprous cyanide (8.2 g.) in quinoline (40 ml.) was heated to reflux for 40 minutes, cooled to 100° and poured into a mixture of ice-cold dilute aqueous ammonia and dichloromethane. The organic layer was separated, filtered to remove a yellow solid, washed with N-hydrochloric acid, dried over sodium sulphate and evaporated. The residual solid was recrystallised from ethanol containing a small amount of dimethylformamide to give 2-acetyl-7-cyanofluorene m.p. 182°-188°.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])([CH3:5])[CH3:4])#[N:2].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:23])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (10 g, 52.8 mmol) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (80 μL) and oxalyl chloride (6.28 mL, 72.0 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give 3-(cyano-1-methylethyl)benzoyl chloride as a pale-brown oil. To a solution of 3-aminophenol (5.24 g, 48.0 mmol) in tetrahydrofuran (40 mL) was added an aqueous suspension (60 mL) of sodium hydrogen carbonate (6.05 g, 72.0 mmol), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise a solution of 3-(cyano-1-methylethyl)benzoyl chloride in tetrahydrofuran (60 mL) synthesized above under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate (200 mL) and washed with saturated brine (200 mL). The extract was dried over anhydrous magnesium sulfate and decolored with activated carbon. The insoluble material was filtered off through a pad packed with silica gel and celite in two layers. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (13.03 g, 96%) as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: c1cc2c(c(N3CCNCC3)c1)COC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4COC5)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.257 g, 1.107 mmol, 1.1 eq) and 1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine (0.204 g, 0.998 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.433 g, 2.043 mmol, 1.84 eq). The slurry was allowed to stir overnight at room temperature (18 h). The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.064 g, 12%). CHN Found: C, 64.37; H, 6.54; N, 12.13. This calculates out for C24H28N4O3×0.74HCl.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:22][O:23][CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[F:26][C:27]1[N:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:33]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:34])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)[CH2:22][O:23][CH3:24])(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(F)nc1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(F)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 38 %

Procedure:
4-tert-Butyl-N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide was prepared from N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide and 6-fluoro-pyridine-3-carbaldehyde using the procedure described in examples 35 and 36.