Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[N:6]=1)(=O)=O.[CH3:30][NH:31][CH3:32].CO>>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:7]2[N:6]=[C:5]([N:31]([CH3:32])[CH3:30])[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CNC
Reactant: COc1ccc(CCNc2cc(-c3cccc(OC)c3)nc(S(C)(=O)=O)n2)cc1
Solvent: CO
Product: COc1ccc(CCNc2cc(-c3cccc(OC)c3)nc(N(C)C)n2)cc1

Procedure:
A solution of [2-methanesulfonyl-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [200 mg, 0.42 mmol, Intermediate (34) prepared as in Example 18, step 1] in a 2M solution of dimethylamine in MeOH (2 mL, 4 mmol) is heated to 150° C. for 20 minutes in a Microwave. The mixture is concentrated, and the residue is subjected to chromatography on silica gel eluting with 70% EtOAc in heptane to afford 6-(3-methoxy-phenyl)-N*4*-[2-(4-methoxy-phenyl)-ethyl]-N*2*,N*2*-dimethyl-pyrimidine-2,4-diamine, which is treated with a solution of saturated hydrogen chloride in EtOAc (1 mL). The resulting precipitate is filtered and dried to afford 6-(3-methoxy-phenyl)-N*4*-[2-(4-methoxy-phenyl)-ethyl]-N*2*,N*2*-dimethyl-pyrimidine-2,4-diamine hydrochloride [0.11 g, 70%, Example 19] as a solid. LCMS: RT=2.85 minutes, MS: 379 (M+H). 1H NMR (300 MHz, CD3OD) □7.46 (1H, t, J=8.1 Hz), 7.26-7.1 (5H, m), 6.83 (2H, d, J=8.1 Hz), 6.27 (1H, s), 4.85 (1H, brs), 3.87 (3H, s), 3.74 (3H, s), 3.71 (2H, t, J=7.2 Hz), 3.28 (6H, s), 2.89 (2H, t, J=7.2 Hz). IC50=4652 nM
Reaction SMILES: O=O.[F:3][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=1.[H][H]>CO>[F:3][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([C:21]([NH2:23])=[O:22])[CH2:16][CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: NC(=O)C1=CCCc2cc(Sc3cccc(F)c3)ccc21
Agent: O=O
Solvent: CO
Product: NC(=O)[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 25 °C

Procedure:
In a glove box (O2 content≦2 ppm) a 50 ml autoclave equipped with a mechanical stirrer was charged with 4.00 g (13.36 mmol) of 6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acid amide, 1.07 mg (0.00134 mmol) of [Ru(OAc)2((S)-MeOBIPHEP)] (S/C 10000) and 28 ml of methanol. The asymmetric hydrogenation was run for 18 h at 40° C. under 9 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was evaporated in vacuo. Isolation as described in example 4 afforded after drying (R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide in quantitative yield as an off-white solid with an enantiomeric ratio of 99:1. The conversion was >=99.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C@H:10]([CH3:24])[N:9]=1.[CH2:25]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][C:29]1=[O:38])[C:26]#[CH:27].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[C:26][CH2:25][N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:29]3=[O:38])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C@H:10]([CH3:24])[N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=N[C@H]2C
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=N[C@H]2C

Procedure:
The title compound was prepared by coupling (S)-6-(2-fluorophenyl)-8-iodo-4,1-dimethyl-4H[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 100. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue crystallized very slowly from ethanol/ether to give colorless crystals of (S)-1-{3-[6-(2-fluorophenyl)-4,1-dimethyl4H-[1,2,4]-triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-propynyl}3,4-dihydro-2(1H)-quinolinone with m.p. 155°-160° with foaming. These crystals contained both ethanol and water according analytical and spectral data. [α]D=+87.5° (c=1.0091 in CH2Cl2)
Reaction SMILES: [C:1](=[S:3])=S.[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]1)(=[O:6])[CH3:5]>O1CCCC1>[C:4]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][N:14]=[C:1]=[S:3])[CH2:11][CH2:12]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1CCC(CN)CC1
Reactant: S=C=S
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CN=C=S)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 41.6 parts of N,N'-methanetetraylbis[cyclohexanamine], 101 parts of carbon disulfide and 450 parts of tetrahydrofuran was added dropwise a solution of 31.2 parts of 1-acetyl-4-piperidinmethanamine in 90 parts of tetrahydrofuran. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated. 2,2'-Oxybispropane was added to the residue. The precipitate was filtered off and the filtrate was evaporated, yielding 40 parts (100%) of 1-acetyl-4-(isothiocyanatomethyl)piperidine as a residue (intermediate 10).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[OH:8])(=[O:3])[CH3:2].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.O>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[O:8][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OCCC(O)c1ccc(Br)s1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Yield: 95.8 %

Procedure:
A solution of 3-(5-bromothiophen-2-yl)-3-hydroxypropyl acetate (1.92 g, 6.9 mmol, 1.0 equiv.), TBDMSCl (1.24 g, 8.3 mmol, 1.2 eq) and 1H-imidazol (1.4 g, 20.7 mmol, 3.0 eq) in CH2Cl2 (50 mL) was stirred for 4 h at 60° C. Water was added and the reaction was extracted with EtOAc (3×200 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EA=100:1 as eluant) to produce 3-(5-bromothiophen-2-yl)-3-(tert-butyldimethylsilyloxy)propyl acetate (2.6 g, 97.6%) as yellow oil. LC-MS (m/z): 393.1 [M+H]+;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:41][C@:42]1([C:47]([NH:49][S:50]([CH:53]2[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:44][C@H:43]1[CH:45]=[CH2:46].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:53]1([S:50]([NH:49][C:47]([C@@:42]2([NH:41][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:44][C@H:43]2[CH:45]=[CH2:46])=[O:48])(=[O:52])=[O:51])[CH2:55][CH2:54]1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.4 g, 25.3 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide p-toluenesulfonate salt (11.2 g, 27.8 mmol), and N,N-diisopropylethylamine (17.6 ml, 101 mmol) in CH2Cl2 (200 ml) was added HATU (11.5 g, 30.4 mmol). The mixture was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel and was thrice washed with aq. 1N HCl; then brine. The organic phase was dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was subjected to silica gel chromatography to afford tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate as a light-orange solid foam (14.8 g, 94%).
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].O[Li].O.O>C(O)C>[C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:19][OH:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: ON=C(c1ccccc1)c1cc2ccncc2[nH]1
Yield: 43.1 %

Procedure:
To a mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (161 mg, 0.72 mmol) and hydroxylamine hydrochloride (100 mg, 1.45 mmol) in ethanol (3.6 mL) were added LiOH.H2O (120 mg, 2.16 mmol) and water (1.0 mL). The reaction mixture was heated under reflux until TLC analysis indicated consumption of the ketone. The mixture was concentrated to dryness. The residue was treated with water, and the residual solid was collected by filtration to give predominately one isomer of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone oxime (75.8 mg, 0.31 mmol, 44%) as a yellow solid. The aqueous filtrate was extracted with methylene chloride (3×). The combined extracts were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated to give ca. 1:1 mixture of isomers of the oxime (72 mg, 0.30 mmol, 42%) as a yellow solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([NH:16][C@:17]2([C:22]([OH:24])=O)[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:15])[C:11]2=[N:25][NH:26][CH:27]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1.C1CCN2C(=NCCC2)CC1>ClCCCl>[CH:40]1([S:43]([NH:46][C:22]([C@@:17]2([NH:16][C:14]([CH:12]3[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C:10]4=[CH:27][NH:26][N:25]=[C:11]34)=[O:15])[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:24])(=[O:45])=[O:44])[CH2:42][CH2:41]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of acid 8b (47.0 mg, 0.125 mmol) and CDI (22.3 mg, 0.150 mmol) in dry DCE (1.0 mL) was stirred at rt for 8 h. The cyclopropyl sulfonamide 9b (18.2 mg, 0.150 mmol) and DBU (22.8 mg, 0.150 mmol) were sequentially added and the mixture stirred at rt for 48 h. The solvent was evaporated and the residue diluted with EtOAc (2 mL). The mixture was washed sequentially with 0.5 M HCl (2×), deionized H2O and brine. The EtOAc solution was dried over MgSO4, filtered through a Celite plug capped with a layer of MgSO4 and concentrated. The crude product was purified via a SiO2 column (CH2Cl2, 25% EtOAc/hexanes then 50% EtOAc/hexanes) to give compound 104 as an ivory solid; 3:2 mixture of diastereomers, 27 mg, 45% (3:2 mixture of diastereomers), MS m/z 478.1 (APCI−, M−1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][N:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C2CCNC2)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
460 mg of 3-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine and 214 mg of triethylamine were dissoved in 15 ml of dichloromethane and cooled in an ice bath. During agitation, 229 mg of ethyl chloroformate was added in drops. After dropping, agitation was continued for 1 hour at a room temperature. Thereafter, the agitated solution was poured into ice water and then extracted with dichloromethane. After organic layers were cleaned by water and dried over magnesium sulfate, it was concentrated under a reduced pressure. The residue was purified by means of the silica gel column chromatography to obtain 92 mg of Compound No. 4 in Table 1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:34])[C@@:18]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:34])[C@@:18]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN=[N+]=[N-])csc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
A solution of Example 186A (17 mg, 0.03 mmol) in 2 mL of ethanol was degassed, treated with palladium on carbon (˜1 mg, 10%), put under an atmosphere of hydrogen, stirred for 4 h at room temp, filtered through a plug of celite, and concentrated to afford a yellow solid. The crude material was chromatographed on silica gel with a gradient of methanol in dichloromethane (0-10%) to afford the title compound (8.2 mg, 51% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.44 (m, 1H) 0.70 (s, 9H) 0.79 (m, 1H) 1.39 (s, 3H) 1.74 (m, J=3.31 Hz, 1H) 2.15 (td, J=12.41, 4.23 Hz, 1H) 4.12 (s, 2H) 7.22 (s, 1H) 7.33 (m, 1H) 7.48 (m, 2H) 8.04 (d, J=7.35 Hz, 1H) 8.17 (br. s, 2H) 16.99 (s, 1H); MS (APCI+) m/z 474 (M+H)+.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:10][C:11](=[O:40])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=3Br)[CH:22]=2)=[CH:16][C:15]=1[CH3:39]>>[CH3:39][C:15]1[CH:16]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:29]=3[O:7][C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[CH3:8])[CH:22]=2)[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][C:11]([OH:40])=[O:10]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Cc1ccccc1O
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3C)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 38 by using o-cresol and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 229 mg (21%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[N+:18]([O-])=O)=[CH:5][CH:4]=1)#[N:2]>ClCCl.C(O)C.[Pd]>[NH2:18][C:11]1[C:12]([CH3:17])=[N:13][C:14]([CH3:16])=[CH:15][C:10]=1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Cc1cc(Nc2ccc(C#N)cc2)c([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(Nc2ccc(C#N)cc2)c(N)c(C)n1
Yield: 94.8 %

Procedure:
A solution of 4-(4-cyanophenyl)amino-2,6-dimethyl-3-nitropyridine (5.00 g, 18.6 mmol) in a mixture of dichloromethane (20 ml) and ethanol (100 ml) was hydrogenated at 20° C. over 10% palladium on charcoal (500 mg) at 138 kPa (20 p.s.i.) for 3 hours. The catalyst was filtered off and the solvents were removed under reduced pressure to give the title compound as a brown solid (4.20 g, 94%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.Cl[CH2:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:17]=2[N:16]=1>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:17]2[N:16]=[C:15]([CH2:14][N:7]3[CH:8]=[N:9][C:10]4[C:6]3=[N:5][CH:4]=[N:3][C:11]=4[NH2:12])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=2[CH:26]=1
Reactant: Nc1ncnc2[nH]cnc12
Reactant: Fc1ccc2nc(CCl)n(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride, NaH (60% in mineral oil, 23 mg, 0.69 mmol) was added to a suspension of 9H-purin-6-ylamine (93 mg, 0.69 mmol) in DMF (1 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 15 min then 2-chloromethyl-6-fluoro-1-phenyl-1H-benzoimidazole (148 mg, 0.57 mmol) in DMF (1 mL) added. After 30 min stirring at RT, the temperature was increased to 70° C. and stirring continued for 3 h. The volatiles were removed under reduced pressure and the resulting residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2N NH3/MeOH in DCM) to afford still impure 9-(6-fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)-9H-purin-6-ylamine. Impure 9-(6-fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)-9H-purin-6-ylamine was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98%, 0.1% HCO2H in acetonitrile/water) to afford pure 376 as a white solid (45 mg, 22%). LCMS (Method K): RT 3.18 min [M+H]+ 360.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.06 (1H, s), 8.04 (1H, s), 7.68-7.55 (6H, m), 7.21 (2H, br s), 7.15-7.08 (1H, m), 6.97 (1H, dd, J=8.98, 2.55 Hz), 5.58 (2H, s)
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F-].[Cs+].[CH3:8][O:9][C:10](=[S:32])[NH:11][CH2:12][C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)=[C:20]([F:31])[CH:19]=2)[CH:17]=1>C(O)C.C(OCC)(=O)C>[CH3:8][O:9][C:10](=[S:32])[NH:11][CH2:12][C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][C:27](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:26][CH2:25]3)=[C:20]([F:31])[CH:19]=2)[CH:17]=1
Reactant: COC(=S)NCc1cn(-c2ccc(N3CCC(=O)CC3)c(F)c2)nn1
Reactant: N#CCC#N
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=S)NCc1cn(-c2ccc(N3CCC(=C(C#N)C#N)CC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of malononitrile (22 mg, 0.33 mmol) and CsF (42 mg, 0.28 mmol) in ethanol (5 ml) was added {1-[3-Fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-1H-[1,2,3]triazol-4-ylmethyl}-thiocarbamic acid O-methyl ester (100 mg, 0.28 mmol), obtained in Example 82. The reaction mixture was allowed to stir at room temperature for 2 h and then diluted with ethyl acetate (100 ml). The organic portion was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles and purification of the resulting residue by silica gel column chromatography (ethyl acetate/pet. ether, 1:1), the title compound was obtained as white solid (45 mg, 40%). Mp. 198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Yield: 38 %

Procedure:
A solution of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (238 mg, 0.43 mM) in 20 mL THF and 25 mL concentrated aqueous ammonium hydroxide was sonicated for 20 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 86.9 mg (38%) of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.7 (m, 1H), 7.55 (d, 1H, J=8 Hz), 7.45 (m, 2H), 7.3 (m, 2H), 7.15 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.2 (d, 1H, J=8 Hz), 5.75 (s, 2H). IR (CHCl3, cm−1) 3500, 3400, 3200 (br), 1649, 1597, 1585, 1446, 1431, 1331, and 1269. MS (ES) m/e 349, 351, 353.
Reaction SMILES: Cl[C:2]1[C:3]([CH:15]([CH3:17])[CH3:16])=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:18][CH2:19][CH3:20].[Na+].O>C(O)C>[CH2:19]([O:18][C:2]1[C:3]([CH:15]([CH3:17])[CH3:16])=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:20]
Reactant: CC[O-]
Reactant: CC(C)c1c(Cl)nn2c(N)nnc2c1C(C)C
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c(C(C)C)c1C(C)C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
6-Chloro-7,8-diisopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.015, 0.1 g) was dissolved in ethanol (15 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (110 mg) and stirred at RT for 1 h, then at 55° C. for 1 h. Subsequently, the mixture was left to stand overnight, then stirred again at 55° C. for 7.5 h and then the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 100 mg of the title compound were obtained. LC-MS rt: 0.90 min [M+H]+: 264.2 (met. b)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](Cl)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.O.O.O.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2cc(Cl)c(F)cc2c1=O
Solvent: O
Product: O=C(O)c1cn(Cc2ccccc2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 79.1 %

Procedure:
A mixture of 1-benzyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.1 g and piperazine hexahydrate 10 g was heated in a sealed tube at 125°-135° C. (inner temperature) for 22 hours. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in warm acetic acid and the insoluble matters was filtered off. The filtrate was neutralized with an aqueous solution of NaOH, and the precipitated crystals were collected by filtration, washed with water and dried. Recrystallizing the crystals from dimethylformamide, 1.0 g (79%) of 1-benzyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid was obtained. Colorless powders.