Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O([C:21](C)(C)C)[K].CI.O>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)O[K]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1H-indazole (3 g, 8.0 mmol) in THF (25 mL) was added KO-tBu (1.28 g, 11.2 mmol) at 0° C. followed by addition of MeI (1.58 g, 11.2 mmol), after the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, then H2O (25 mL) was added to the mixture and product extracted with EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=5:1) to give 5-(tert-butyldimethylsilyloxy)-3-iodo-1-methyl-1H-indazole (2.5 g, 80.3%) as a white solid. (M+H)+=389; 1H NMR (300 MHz, CDCl3), δ 7.22-7.19 (m, 1H), 7.03-7.01 (m, 1H), 6.80 (s, 1H), 4.05 (s, 3H), 1.01 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: [C:1](OC1C=CC(C2C=CC=CC=2)=CC=1)(=[O:4])[C:2]#[CH:3].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C#C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[C:19]1([NH:18][C:1](=[O:4])[C:2]#[CH:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Agent: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C#CC(=O)Nc1ccccc1
Yield: 87 %

Procedure:
The compound 20 was prepared according to the method described for compound 1 employing aniline (1 g, 0.01 mol), propargylic acid (0.76 g, 0.01 mol), DCC (2.2 g, 0.01) and DMAP (8.6 mg, 0.07 mmol) to give brown solid compound 20 (1.35 g, 87%). 1H NMR (300 MHz, CD2Cl2) δ 2.93 (s, 1H), 7.15 (t, J=6.9 Hz, 1H), 7.33 (t, J=7.5 Hz, 2H), 7.52 (t, J=7.4 Hz, 2H), 7.79 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.Br.[CH2:65]([CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1)[CH2:66][CH3:67].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([N:69]2[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]2[CH2:65][CH2:66][CH3:67])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCCC1CCCCN1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCC1CCCCN1c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)OCC)c1
Temperature: 100 °C

Procedure:
To a solution of 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, 1 g (250 mg, 0.49 mmol) in toluene (5 mL) in a sealed tube was added racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (59 mg, 0.15 mmol), Pd(OAc)2 (110 mg, 0.49 mmol), 2-propyl-piperidine hydrogen bromide (152 mg, 0.73 mmol). The system was flushed with nitrogen. To this was added NaOtBu (118 mg, 1.23 mmol) and heated to 100° C. for 3 h. The system was cooled to room temperature and quenched by slow addition of water. The mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with saturated NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-[5-(2-propyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester. Calcd for C29H38F3NO2 (M+H) 490.61, Found 490.4.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[C:17]([C:7]2[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=2)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 550.4 %

Procedure:
4.08 g (30.0 mmol) of 3-trifluoromethylpyrazol, 4.75 mmol (30.0 mmol) of 2-chloro-4-fluorobenzaldehyde and 4.14 g (30.0 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide were stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue afforded 7.18 g of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzaldehyde (yield 87.2%) as a pale yellow powder, after washed with n-hexane.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:10](O)[CH3:11]>>[Br:8][C:6]1[N:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:10]=[CH:11][N:9]=2)[CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CCO
Product: Brc1cn2ccnc2c(Br)n1

Procedure:
A solution of 1.00 equivalents (eq.) of 3,5-dibromo-2-aminopyrazine 1 in ethanol is treated with 2.00 eq. of α-bromoaldehyde 2 at room temperature (RT) and heated for 48 hours (hr). The solvent is removed under reduced pressure and the residue is triturated with diethyl ether and filtered to give the HBr salt 3.
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][N:8]=1)([CH3:5])[CH3:4].O>CO>[CH:3]([NH:6][C:7]1[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)c1cnc(NC(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Nc1ncc(C(=O)O)cn1
Temperature: 66 °C
Yield: 91.6 %

Procedure:
6 ml of a 1N solution of sodium hydroxide are added to a solution of 2-isopropylamino-5-methoxycarbonylpyrimidine (1 g; 5.12 mmol) in 33 ml of methanol. The mixture is refluxed (66° C.) for two hours. A minimum of water is added in order to dissolve the precipitate which forms; the methanol is evaporated under reduced pressure. The remaining solution is acidified at 0° C. with 2N hydrochloric acid. The precipitate obtained is filtered, washed with water and then dried to give 850 mg (92%) of acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[CH:36]([C:38]1[N:39]=[CH:40][NH:41][CH:42]=1)=O.[BH4-].[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)Cl.CO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH:1][CH2:2][C:7]2[C:42]3[N:41]=[CH:40][NH:39][C:38]=3[CH:36]=[CH:5][CH:6]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=Cc1c[nH]cn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(-c2csc3c(/C=C/CNCc4cccc5[nH]cnc45)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
In a round bottom flask was combined N-(4-{4-amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.050 g, 0.104 mmol), 4-formylimidazole (0.0083 g, 0.086 mmol), and toluene (1.5 mL). The flask was flushed with nitrogen gas, followed by the addition of titanium (IV) isopropoxide (0.061 g, 0.215 mmol). The mixture was heated under a nitrogen atmosphere to 50° C. for 16 hours. The reaction mixture was cooled to room temperature and treated with methanol (1 mL) and sodium borohydride (0.010 g, 0.263 mmol). The resulting mixture was stirred for 12 hours at room temperature, followed by the addition of a 10% aqueous solution of sodium hydroxide (5 mL) and methylene chloride (5 mL). The mixture was filtered through an Empore™ cartridge, the solvents removed, and the product purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 5% acetonitrile-0.1M ammonium acetate isocratic for 5 minutes, then 5-100% acetonitrile-0.1M ammonium acetate over 30 min, 21 ml/min). The acetonitrile was removed and the aqueous solution was lyophilized to give the title compound as an off-white solid: 0.012 g (24%): LCMS (Conditions b): MH+=467.3, RT=2.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.15 (dd, J=7.8 Hz, 7.0 Hz, 1H), 7.08 (dd, J=7.8 Hz, 1.6 Hz, 1H), 6.88 (s (br), 1H), 6.67 (d, J=16.0 Hz, 1H), 6.30 (td, J=16.4 Hz, 5.5 Hz, 1H), 5.61 (s (br), 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.67 (s, 2H), 3.39 (d, J=5.5 Hz, 2H), 2.78 (s, 15H, acetate)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=2[O:23][CH3:24])(=[O:14])=[O:13])=[C:2]([NH:1][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:7]=1
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(Br)cc1N
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1cc(Br)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC

Procedure:
A solution of 12.38 g of N-[2-(2-amino-4-bromo-phenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide, 3.68 mL of ethyl bromoacetate, and 7.88 mL of N,N-diisopropylethylamine in 100 mL of N,N-dimethylformamide was stirred at 55° C. for 16 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 7.38 g of ethyl [5-bromo-2-[2-(5-cyano-2-methoxybenzenesulfonylamino) ethyl]phenylamino]acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Sn](C)(C)C)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)(=O)=O>[Pd]>[CH2:1]([O:8][C:9]1[NH:10][CH2:11][C:12]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: C[Sn](C)(C)c1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CC=C(C2=CC=C(OCc3ccccc3)NC2)CC1

Procedure:
In an analogous manner to that described above, by a palladium catalyzed coupling of 2-benzyloxy-5-trimethylstannyl-pyridine with tert-butyl 4-trifluoromethylsulphonyloxy-3,6-dihydro-2H-pyridine-1-carboxylate [Example 126(c)] there was obtained tert-butyl 6-benzyloxy-3',6'-dihydro-2H-[3,4']bipyridine-1'-carboxylate as a colourless solid MS: 367 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][O:16]C(=O)C1C=CC=CC=1.N>CN(C=O)C.CO>[OH:16][CH2:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12]
Reactant: O=C(OCCBr)c1ccccc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ncnc2c1ncn2CCO
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of 60% NaH in mineral oil (1.70 g, 42.57 mmol) in anhydrous DMF (120 mL) was added adenine (5.23 g, 38.70 mmol) under argon, and the mixture was heated at 60° C. for 1 h. 2-Bromoethylbenzoate (9.2 mL, 58.06 mmol) was added dropwise at 60° C., and the reaction was stirred at this temperature for 16 h. The mixture was then filtered to remove insoluble materiel, the filtrate was evaporated under reduced pressure and co-evaporated three times with toluene. The residue was triturated with EtOAc then filtered to give a white solid, which was immediately resuspended in a saturated ammonia solution in MeOH (400 mL). The reaction mixture was stirred for 14 h at room temperature, and then methanol was removed under reduced pressure. Recrystallization from EtOH afforded compound 2 (5.87 g, 85%): mp 236° C. (Lit. 238-239° C.); 1H NMR (DMSO-d6): 8.13 (s, 1H, H-2), 8.10 (s, 1H, H-8), 7.23 (bs, 2H, NH2), 5.05 (bs, 1H, OH), 4.19 (t, J=5.2 Hz, 2H, CH2O), 3.71 (t, J=5.2 Hz, 2H, CH2N). 13C NMR (DMSO-d6) δ: 155.79, 152.23, 149.44, 141.46, 118.55, 59.17, 45.61. MS (GT, FAB+): 136 (B+1H)+, 180 (M+1H)+, 202 (M+Na)+.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[N:66]=[CH:65][C:64]([O:67][CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:63][CH:62]=1.CC1(C)C(C)(C)OB([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)O1>>[CH3:71][N:70]([CH3:72])[CH2:69][CH2:68][O:67][C:64]1[CH:63]=[CH:62][C:61]([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)=[N:66][CH:65]=1
Reactant: CN(C)CCOc1ccc(Cl)nc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CN(C)CCOc1ccc(-c2ccc(O)cc2)nc1

Procedure:
Compound 90B was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 90A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.29 (d, J=2.76 Hz, 1H), 7.83 (d, J=8.59 Hz, 2H), 7.74 (d, J=8.59 Hz, 2H), 7.41 (dd, J=8.59, 2.76 Hz, 2H), 6.82 (d, J=8.29 Hz, 2H), 4.14 (t, J=5.68 Hz, 2H), 2.64 (t, J=5.68 Hz, 2H), 2.22 (s, 6H). ESI (+)/MS: 258 (M+H)+.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:5]([O:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reaction time: 8 h

Procedure:
A solution of tert-butylchlorodiphenylsilane (5.56 mL, 21.36 mmol) in DCM (20 mL) was added dropwise to a stirred solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS no. 142253-56-3) (4.0 g, 21 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (9.1 mL, 53 mmol) in DCM (45 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 3 hours 4-dimethylaminopyridine (100 mg) was added and the reaction was left overnight. The reaction mixture was concentrated and diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the crude product (9.87 g) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][OH:11]>[Pd]>[CH3:9][C:4]1[N:1]=[CH:10][O:11][C:5]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: CO
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pd]
Product: Cc1ncoc1-c1cccc(N)c1
Reaction time: 20 h

Procedure:
A solution of the nitrobenzene adduct (50 g) produced in the previous step C in MeOH (600 mL) was prepared in parr-shaker bottle; Pd/C (5 g) was transferred carefully and hydrogenated at 3.5 kg pressure for 20 h. The reaction mixture was filtered over celite bed and the filtrate was concentrated. The residue was purified by silica gel column chromatograph using 40% EtOAc in pet.ether to get yellow color solid. Yield 18 g (42%). 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.08 (t, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.71 (d, J=7.9 Hz, 1H), 6.52 (d, J=8.2 Hz, 1H), 5.24 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1cccnn1
Product: O=C(NC(=S)NCCSCc1cccnn1)c1ccccc1

Procedure:
By the procedure of Example 18, 3-[(2-aminoethyl)-thiomethyl]pyridazine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-pyridazinylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-pyridazinylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[O:25][C:24](=[O:26])[NH:23][N:22]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>CN(C=O)C>[CH3:1][N:23]1[N:22]=[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:25][C:24]1=[O:26]
Reactant: CC(C)(C)[O-]
Reactant: O=c1[nH]nc(-c2ccccc2SCc2ccccc2)o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(-c2ccccc2SCc2ccccc2)oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a suspension of 2.9 g of potassium t-butoxide in 60 ml of DMF under a N2 atmosphere was added portionwise 7 g of the product of Example 1 while maintaining the reaction temperature at 25°-30° C. with an ice-water bath. After stirring at 25° C. for 1 hour, 7 g of methyl iodide was added dropwise to cause an exotherm to 37° C. The suspension was heated at 40°-60° C. for 5 hours, then cooled to 25° and poured onto excess ice-water to yield a precipitate. The suspension was filtered, and the isolated solid was dissolved in tetrahydrofuran and dried over MgSO4. The isolated solid was passed through a silica gel column with methylene chloride and, after evaporation of the first eluant, 5 g of the subject compound was obtained; m.p. 137°-140° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CCN(S(C)(=O)=O)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
1.3 mL of methanesulfonyl chloride was slowly added to a solution of 2 g of 1-Boc-piperazine and 1.3 mL of pyridine in 6 mL of dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h while being monitored by TLC. Upon completion, the mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatograph (20-100% ethyl acetate/hexane) to afford tert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate. 930 mg of tert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate was treated with 4N HCl in dioxane for 2 h. The reaction mixture was evaporated to give the HCl salt of 1-(methylsulfonyl)piperazine. Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide, 69 mg of 1-(methylsulfonyl)piperazine and DIEPA (1 eq) in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)nicotinamide. MS (Q1) 486.3 (M)+.
Reaction SMILES: [C:1]1(=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3](=[O:12])[NH:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+]>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:2]1[C:3](=[O:12])[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:1]1=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2C(=O)N1CCCCBr
Yield: 60 %

Procedure:
A solution of 200 mg of 1,3,4,5-tetrahydro-2-benzazepine-1,3-dione dissolved in 20 ml of dimethylformamide was ice-cooled, and then 0.209 ml (1.5 equivalents) of 1,4-dibromobutane, 54.8 mg (1.2 equivalents) of 60% sodium hydride were added, followed by stirring under ice-cooling for 1.5 hours. The reaction treatment and purification were conducted in the same manner as in Example 13, to obtain 213 mg of the desired compound (yield 60%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[F:10].C(N(CC)CC)C.[C]=O.C[CH2:21][O:22][C:23](C)=[O:24]>CO>[CH3:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([C:23]([O:22][CH3:21])=[O:24])=[CH:7][C:6]=1[Cl:8]
Reactant: CCOC(C)=O
Reactant: Cc1cc(F)c(Br)cc1Cl
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(Cl)c(C)cc1F
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (10 g, 44.7 mmol) in 200 mL of methanol were added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting reaction mixture was placed in a bomb, pressurised to 80 psi of carbon monoxide and heated at 80° C. for 18 hours. The reaction mixture was concentrated in vacuo to yield a semi-solid which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a white crystalline solid (8.47 g, 93%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([NH2:21])=[O:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.O>Cl.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2c[nH]c3ccc(/C=C/C(N)=O)cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CN1CCC(c2c[nH]c3ccc(CCC(N)=O)cc23)CC1
Reaction time: 24 h
Yield: 28.7 %

Procedure:
A solution of the product of stage (ii) (650 mg) in ethanolic hydrogen chloride was hydrogenated over pre-reduced 10% palladium on carbon (0.20 g of a 50% w/w paste with water) at 25° and atmospheric pressure for 24 h. The catalyst was removed by filtration and the solvent evaporated in vacuo to give a foam. The residue was purified by flash column chromatography eluting with dichloromethane:ethanol:0.88 ammonia (50:8:1). Evaporation of the solvent in vacuo from the appropriate fractions gave the title compound as a foam (188 mg).