Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([CH3:43])[C:35](=[O:44])[CH:34]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][CH2:52][N:53]([CH2:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)[CH2:54][CH2:55][CH2:56]O)[CH:46]=1.C(OC(=O)C)C.[ClH:71]>C(OCC)(=O)C.O1CCCC1>[ClH:71].[ClH:71].[ClH:71].[CH3:43][N:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([O:32][CH2:56][CH2:55][CH2:54][N:53]([CH2:52][CH2:51][C:47]2[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=2)[CH2:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)=[CH:34][C:35]1=[O:44]
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Reactant: Cn1c(=O)cc(O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)cc(OCCCN(CCc2cccnc2)Cc2ccncc2)c2ccccc21
Reaction time: 8 h

Procedure:
Triphenyl phosphine (102 mg) and diethyl azodicarboxylate (68 mg) were added to a tetrahydrofuran (THF) solution (5 ml) of 4-hydroxy-1-methyl-1H-quinolin-2-one (63 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propane-1-ol (81.4 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.29 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and dried to give the title compound (126.8 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[CH3:58][N:59](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.O>[C:58]([C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13])#[N:59]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
Under an argon atmosphere, to a mixture of 5-(3-bromo-5-nitrophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (312 mg), zinc powder (19 mg), biphenyl-2-yl (di-tert-butyl)phosphine (40 mg), zinc (II) cyanide (66 mg), and N,N-dimethylacetamide (6.13 mL) was added palladium trifluoroacetate (II) (20 mg), followed by heating at 100° C. for 4 hours. After leaving to be cooled, to the reactant was added water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-cyano-5-nitrophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (250 mg) as a red solid.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([Cl:17])[C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[N:11][CH:12]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[Cl:17][C:9]1[C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[N:11][CH:12]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])[N:6]=2)[CH:8]=1
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ncc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Yield: 123.6 %

Procedure:
5-(3-bromo-1,2,4-thiadiazol-5-yl)-3-chloro-2-[(1-methylethyl)oxy]pyridine (D109) (1.3 g, 3.89 mmol), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.239 g, 7.77 mmol), tripotassium phosphate (2.474 g, 11.66 mmol) and Pd(Ph3P)4 (0.449 g, 0.389 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (5.00 mL) were heated by Biotage Initiator to 120° C. for 30 min. The reaction solution was concentrated and the slurry was diluted with ethyl acetate, washed with water, dried and purified by ISCO column chromatography to afford 3-chloro-5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]pyridine (D110) (2 g). MS (ES): C21H22ClN3O2S requires 415.1. found 416.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[C:3]=1[OH:11].C(C1C=C(C=C(C)C=1O)[C:17]([NH:19][OH:20])=[NH:18])C>>[OH:11][C:3]1[C:4]([CH2:8][CH2:9][CH3:10])=[CH:5][C:6]([C:17]([NH:19][OH:20])=[NH:18])=[CH:7][C:2]=1[CH3:1]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCCc1cccc(C)c1O
Product: CCCc1cc(C(=N)NO)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-methyl-6-propyl-phenol in analogy to literature procedures (e.g. B. Roth et al. J. Med. Chem. 31 (1988) 122-129; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.54 min; [M+1]+=209.43; 1H NMR (D6-DMSO): δ 0.90 (t, J=7.3 Hz, 3H), 1.48-1.59 (m, 3H), 2.19 (s, 3H), 2.56 (t, J=7.3 Hz, 2H), 7.37 (s, 1H), 7.40 (s, 1H), 9.34 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:14][C@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
10 wt % Pd on carbon (120 mg, 0.11 mmol) was added to a solution of tert-butyl [(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate (0.34 g, 1.1 mmol) in MeOH (15.0 mL). The mixture was stirred at room temperature under a hydrogen atmosphere (1 atm.) for 15 h. The reaction was filtered through a pad of diatomaceous earth (eluted with MeOH), and then concentrated under reduced pressure. The resulting crude product was used directly in the next step without further purification (0.21 g, 88%). LCMS calc. for C11H23N2O2 (M+H)+: m/z=215.2. found: 215.2. 1H NMR (CDCl3, 400 MHz) δ 4.33 (1H, m), 3.46 (1H, m), 3.25 (1H, m), 2.94 (1H, dd, J=3.6 and 12.8 Hz), 2.18-2.02 (3H, m), 1.60 (1H, m), 1.43 (9H, s), 0.85 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][C:8]=1[Cl:17].C[O:19][B:20](OC)[O:21]C.Cl>C1COCC1>[Cl:17][C:8]1[CH:9]=[C:10]([O:13][CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:12][C:7]=1[B:20]([OH:21])[OH:19]
Reactant: CC(C)Oc1ccc(Br)c(Cl)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 1-bromo-2-chloro-4-isopropoxybenzene (19.4 mmol, 4.85 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-Chloro-4-isopropoxyphenyl)boronic acid (1.82 g, 44%) as a white precipitate, which was filtered and dried. 1H NMR (CD3OD, 300 MHz): 7.19 (1H, d, J 8.4 Hz), 6.87 (1H, d, J 2.2 Hz), 6.82 (1H, dd, J 8.4 and 2.2 Hz), 4.58 (1H, m), 1.28 (6H, d, J 5.9 Hz.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:39](=[O:41])[CH3:40])=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CC(Cc2ccc(NC(C)=O)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Temperature: 22 °C
Yield: 62.9 %

Procedure:
In an oven-dried round bottomed flask was added L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (100 mg, 0.23 mmol), and tetrahydrofuran (5 mL). The solution was stirred at 22° C., and treated with pyridine (0.037 mL, 0.45 mmol, 2.0 eq) followed by acetyl chloride (0.024 mL, 0.34 mmol, 1.5 eq). The reaction mixture was allowed to stir for one hour. The solvent was removed in vacuo and the residue partitioned between EtOAc (50 mL) and sat. NaHCO3 (50 mL). The organic layer was washed with sat. aq. NaCl, dried (MgSO4) and concentrated to an oil. The oil was purified by flash chromatography to provide 70 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-acetyl)aminophenyl)ethylamide as a foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[C:26]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:25]=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cnn(Cc2ccccc2)c1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3cnn(Cc4ccccc4)c3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-benzyl-1H-pyrazol-4-ylamine. The title compound was obtained as a yellow oil (Yield=40%). MS ISP (m/e): 355.2 (100) [(M+H)+].
Reaction SMILES: [Cl:1][CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[NH4+:14]>CO>[NH2:14][C:7]([CH3:9])=[C:2]([Cl:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C(Cl)=C(C)N
Yield: 63.9 %

Procedure:
50 g (0.33 mol) of methyl 2-chloroacetoacetate are reacted with 64 g (0.83 mol) of ammonium acetate in 100 ml of methanol and worked up in analogy to Example 2. Yield: 63.9% [GC]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=O)[C:12]([C:21](OCC)=[O:22])=[CH:11]1.P(Cl)(Cl)(Cl)=O.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][NH2:39].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2=[N:39][N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])[C:21](=[O:22])[C:12]2=[CH:11]1
Reactant: CCOC(=O)c1cn(Cc2ccc(I)cc2F)c2ccccc2c1=O
Reactant: NNc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1c2cn(Cc3ccc(I)cc3F)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Ethyl 1-[(2-fluoro-4-iodophenyl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.4 g, 3.1 mmol) was dissovled in phosphorus oxychloride (6.0 mL, 64 mmol, 21 equiv) and stirred for 2.5 hours at ambient temperature. The mixture was diluted with toluene (10 mL) and concentrated in vacuo. The residue was dissolved in dioxane (17 mL), treated with 2-fluorophenylhydrazine (0.87 g, 6.8 mmol, 2.2 equiv) and potassium carbonate (1.3 g, 9.4 mmol, 3 equiv) and stirred at ambient temperature for 5 minutes. The mixture was placed into a preheated oil bath at 80° C. for 1 hour, cooled to ambient temperature and diluted with chloroform (150 mL). The organic mixture was washed once with water (50 mL) and brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a chloroform:methanol (95:5) solution (30 mL). The solid was filtered and dried in vacuo, providing the titled compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C@H:7]1[CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:5].[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31].CC(O)C>CC(C)=O.C(O)C.O>[C:34]([CH:32]([CH:30]([C:29]([OH:38])=[O:37])[OH:31])[OH:33])([OH:36])=[O:35].[NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C@H:7]1[CH2:13][O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:5]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Solvent: CCO
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 0.5 h

Procedure:
55 mg of the compound obtained in Example 11 was dissolved in 0.56 mL of acetone to which a solution of 26 mg of L-tartaric acid in 0.35 mL of ethanol/water (9/1(v/v)) was then slowly added, followed by stirring for 30 min. 0.56 mL of 2-propanol was added thereto, followed by stirring for 10 min and filtration to afford 77 mg of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccncc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3ccncc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), Pyridin-4-ylamine (0.24 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give Pyridin-4-yl-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine as brown solid in 66% yield.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:13]1[O:15][CH2:14]1.[NH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>C(O)C>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH2:26][CH:17]1[NH:16][CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: NC1CCc2ccccc2C1
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Solvent: CCO
Product: OC(CNC1CCc2ccccc2C1)COc1ccc2ccccc2c1
Yield: 53.2 %

Procedure:
A mixture of 1-(2-naphthyloxy)-2,3-epoxypropane (1.95 g), 2-aminotetralin (2.65 g) and ethanol (35 ml) is heated to the reflux temperature for 5 hours. The solvent is then evaporated off and the thus obtained solid residue is crystallized from ethyl acetate (5 ml), recovered by filtration, washed with ethyl acetate and then with ethyl ether, and dried yielding 1.8 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-naphthyloxy)propanamine, as the free base; m.p. 102°-115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Sn](C)(C)C>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: C[Sn](C)(C)c1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3c(F)cccc3Cl)cc3c1N2CCS3
Yield: 57.4 %

Procedure:
The tert-butyl(6bR,10aS)-5-(2-chloro-6-fluorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (276 mg, 57%) was prepared via coupling tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (1.0 g, 1.043 mmol) with 2-chloro-6-fluorophenyltrimethyl stannane (3.0 g, 3.129 mmol) as illustrated by the general procedure described in Example 447 Step G. 1H NMR (CDCl3, 300 MHz) δ1.44 (s, 9H), 1.83-1.99 (m, 2H), 2.80-3.32 (m, 5H), 3.33-3.50 (m, 2H), 3.55-3.71 (m, 3H), 6.82 (d, 1H, J=8.1 Hz), 7.01 (t, 1H, J=8.1 Hz), 7.12-7.35 (m, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:18][C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:18][C:19]=1[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Reactant: CNS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]cc(C=O)c3c2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 88 using 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde and 3′-fluoro-N-methyl-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. MS (ESI): mass calcd. for C21H16FN3O3S, 409.09; m/z found, 410.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].ClCCl>CO>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: C=CC(=O)OC
Solvent: CO
Solvent: ClCCl
Product: CCCCN(CCCC)CCC(=O)OC
Temperature: 50 °C
Yield: 94.5 %

Procedure:
A! A solution of dibutylamine (1 l, 5.88 moles) in methanol (2.35 l), kept under stirring at 50° C., was slowly added dropwise with methyl acrilate (1.051 l, 11.76 moles). The mixture was then brought to room temperature and kept under stirring for 1 hour, thereafter 1.174 l of dichloromethane were added and the product extracted with 4.7 l of 3N HCl. The organic phase was washed with water (3×2.35 l). The aqueous phase was brought to pH-9 with 5N sodium hydrate and extracted with dichloromethane (2×2.35 l). The organic phase was washed with 2.35 l of distilled water, then anhydrified over sodium sulfate and evaporated under vacuum thus obtaining 1197 g of methyl N,N-dibutyl-3-amino-propionate (yield: 94.5%) as a pale yellow oil which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([N:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1CCCNC1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N[C@H]1CCCN(c2ccc3ncc(-c4cccc(Cl)c4)n3n2)C1
Temperature: 180 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (200 mg, 0.78 mmol) and (S)-Piperidin-3-amine (290 mg, 2.12 mmol) in NMP (1.0 mL) was added NaHCO3 (118 mg, 1.52 mmol), the mixture was stirred at 180° C. for 60 mins under microwave irridation. The mixture was purified by flash chromatograph to give (S)-1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-amine (32 mg, 0.098 mmol, 13%) as a pale yellow solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([NH:36]C(=O)OC(C)(C)C)[CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([NH2:36])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)NC1CCCCNC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCCCC(N)C5)n4)n[nH]c3cn2)cn1
Yield: 58.6 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl azepan-3-ylcarbamate were reacted. The product was deprotected to give 226 as a white solid (58.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.4 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.18 (d, J=12 Hz, 1H), 4.13-4.06 (m, 1H), 3.90 (s, 3H), 3.54 (m, 1H), 3.36 (d, J=8.8 Hz, 1H), 3.32 (s, 1H), 2.05-1.95 (m, 1H), 1.84-1.69 (m, 3H), 1.53-1.41 (m, 1H), 1.40-1.27 (m, 1H); 2 protons not seen. LC/MS: m/z 389.2 [M+1]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[C:10]2=O)=O)=[CH:3][CH:2]=1.O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:9]3[CH2:16][C:12]4[S:13][CH:14]=[CH:15][C:11]=4[C:10]=3[NH:20][N:19]=2)=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C(c1ccncc1)C1Cc2sccc2C1=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: c1cc(-c2n[nH]c3c2Cc2sccc2-3)ccn1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
5-(Pyridine-4-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.95 g, 8 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.4 mL) and ethanol (20 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-Pyridin-4-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.16 g, 4.2 mmol) as white solid in 53% yield.