Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>ClCCl>[N:1]1([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([I:16])=[CH:18][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Ic1ccc(CN2CCCCC2)cc1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a mixture of 0.31 g of piperidine (3.6 mmol) and 0.47 g of N,N-diisopropylethylamine 3.6 mmol) in 10 mL of dichloromethane was added 0.90 g of 4-iodobenzylbromide (3 mmol). The mixture was allowed to stir for 16 h and partitioned between 50 mL of EtOAc and 50 mL of water. The layers were separated and the EtOAc was washed with 25 mL of brine, dried (MgSO4) and concentrated in vacuo to give 0.90 g of 4-(N-piperidinylmethyl)iodobenzene. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=O)[CH:4]=[CH:5][N:6]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:24][C:25]([NH2:27])=[S:26].II.N1C=CC=CC=1>O>[CH3:1][C:2]1[N:3]([C:7]2[S:26][C:25]([NH:24][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][N:18]=3)=[N:27][C:8]=2[C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1CC(=O)c1cccc(C#N)c1
Reactant: NC(=S)Nc1cnccn1
Agent: II
Solvent: O
Solvent: c1ccncc1
Product: Cc1nccn1-c1sc(Nc2cnccn2)nc1-c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
3-(2-Methylimidazol-1-yl-acetyl)-benzonitrile (13.8 g, 0.06 mol) is mixed with pyrazinyl-2-thiourea (9.4 g, 0.06 mol), iodine (15.6 g, 0.06 mol) and pyridine (60 ml). The mixture is stirred, initially at room temperature and then at 60° C. overnight (17.5 hours). The mixture obtained is allowed to cool to room temperature and water (50 ml) added. The solid obtained is filtered off, stirred in water (50 ml) for 30 minutes, and filtered off again. The resulting solid is dried at 40° C. in vacuo over P2O5 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BQ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 97.1%, 497.0259 (M−H)−.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:20][CH3:21])[C:6](=[O:19])[C:7]1[C:12]([CH:13]=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:4]>C(O)C.CCOCC>[CH2:20]([N:5]([CH2:3][CH3:4])[C:6](=[O:19])[C:7]1[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:15]([CH3:17])([CH3:16])[CH3:18])[CH3:21]
Reactant: CCN(CC)C(=O)c1c(C=O)cccc1[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCN(CC)C(=O)c1c(CO)cccc1[Si](C)(C)C
Yield: 74 %

Procedure:
Sodium borohydride (1.0 g, 26.4 mmol) was added to a solution of N,N-diethyl-2-trimethylsilyl-6-formylbenzamide, prepared in Example 97, (5.54 g, 20 mmol) in absolute ethanol (100 mL). After 3 h the mixture was diluted with ether, extracted three times with brine, dried (MgSO4), concentrated, and recrystallized from 1:1 ethyl acetate/hexanes to afford 4.12 g of N,N-diethyl-2-trimethylsilyl-6-hydroxymethylbenzamide as a white solid, a 74% yield. m.p. 81-82.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[CH:29])[CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C>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.[Cu]I.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:29]#[C:28][CH2:27][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[S:18][C:11]=12)[NH2:5]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCN(C)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 60 °C
Yield: 84.1 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200 mg, 0.477 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (Example 17, Step A, 205.8 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium (0) (55.1 mg, 0.0477 mmol), copper(I) iodide (9.074 mg, 0.0477 mmol), N-ethyl-N-isopropylpropan-2-amine (2.49 ml, 14.3 mmol) and THF (25 mL). The reaction mixture was stirred at 60° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.159 g, 84.2%). LRMS (APCI pos): m/e 397 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, 1H), 7.58 (s, 1H), 7.01 (t, 1H), 6.43-6.58 (m, 3H), 3.90 (br s, 2H), 3.61 (s, 2H), 2.48-2.83 (m, 8H), 2.38 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[OH-].[Na+].[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(O)(C)C.O>[C:12]([O:16][C:17]([N:5]1[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1CCCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-oxohomopiperidine.HCl (1.2 g, 8.05 mmol), NaOH (0.68 g, 16.9 mmol) in t-BuOH/H2O (1:1, 10 mL) was added t-butyldicarbonate (1.93 mL, 8.9 mmol) drop-wise. The reaction was stirred at RT overnight, extracted with EtOAc (2×10 mL) and the organic layer separated. The organic layer was dried over Na2SO4 and concentrated under vacuo. Pure 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 84%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H NMR CDCl3 δ: 44 (9H, s), 1.72–1.84 (2H, m), 2.60–2.65 (4H, m), 3.55–3.61 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].O.C[CH2:15][O:16]C(C)=O>>[Cl:8][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]2[O:12][C:15](=[O:16])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Reactant: CCOC(C)=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Reaction time: 2 h
Yield: 98 %

Procedure:
DCI (36.4 mmol, 5.9 g) was added in one portion to 2-amino-4-chloro-6-nitrophenol 5 (5 g, 26.5 mmol) suspended in AcOEt (150 ml) and the reaction was stirred vigorously for 2 hours. 100 ml of water were added to the reaction and then the organic phase was eliminated by evaporation. HCl 20% was added (20 ml) and the resulting solid material was filtered and washed with HCl 1N, cold water, MeOH and ether obtaining 5.6 g of a beige solid. Yield=98% 1HNMR (DMSO, 200 MHz) δ 7.59 (1H, d, J=2.2 Hz), 7.86 (1H, d, J=2.2 Hz), 12.56 (1H, bs)
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[N:16]3[CH2:23][CH2:24][N:25]=[C:15]3[C:14]=2[CH:13]=1>N1C=CC=CC=1>[C:1]1([S:7]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[N:16]4[CH2:23][CH2:24][N:25]=[C:15]4[C:14]=3[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1Nc2ccc(NS(=O)(=O)c3ccccc3)cc2C2=NCCN12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.1 g of benzenesulphonic acid chloride were added to 4.04 g of 9-amino-5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline in 50 ml of absolute pyridine, whilst cooling with ice. The cooling was removed and the mixture was stirred for 2 hours at room temperature. A large quantity of H2O was then added to the reaction mixture, and the precipitated crystals were filtered off under suction. The crystals were dissolved in aqueous NH3 and the solution was clarified using active charcoal and neutralised using hydrochloric acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[N:3]=1.[NH2:15][C:16]1[C:17](=[O:27])[NH:18][C:19]2[C:24]([N:25]=1)=[C:23]([OH:26])[CH:22]=[CH:21][CH:20]=2>>[NH2:15][C:16]1[C:17](=[O:27])[NH:18][C:19]2[C:24]([N:25]=1)=[C:23]([O:26][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[N:3]=1)[CH:22]=[CH:21][CH:20]=2
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1nc2c(O)cccc2[nH]c1=O
Product: COC[C@H](C)Nc1nc(Cl)cc(Oc2cccc3[nH]c(=O)c(N)nc23)n1

Procedure:
The reaction of (S)-4,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-2-amine from step (a) above (0.62 g, 2.63 mmol) with 3-amino-5-hydroxyquinoxalin-2(1H)-one (0.47 g, 3 mmol, prepared as described in WO 2004/014871) under the conditions of Example 105(a) provided the title compound as an off-white solid. MS (ESI, pos. ion.) m/z: 377 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].O.CO>[NH2:1][C:4]1[C:5]([NH:10][CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC1CC(=O)N(CNc2ncccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCC1CC(=O)N(CNc2ncccc2N)C1
Reaction time: 16 h
Yield: 113.1 %

Procedure:
Palladium on charcoal (10% wt, 0.478 g) is added to a solution of 1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77 (1 eq, 2.5 g, 8.983 mmol) and NH4CO2H (5 eq, 44.9 mmol, 2.832 g) in water and methanol (1/1 (v/v), 35 ml). The resulting slurry is kept under agitation during 16 hours at room temperature, then filtration over celite and evaporation of the crude mixture afford 2.524 g of 1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][OH:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([O:19][CH2:18][C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)(=[O:22])[CH3:21]
Reactant: OCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: CC(=O)Cl
Product: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2[nH]1

Procedure:
The title compound was prepared from [5-(benzyloxy)-1H-indol-2-yl]methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a gray solid. Mass spectrum (ESI, [M+H]+) m/z 296. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.45 (d, 2H, J=7.33 Hz), 7.38 (t, 2H, J=7.49 Hz), 7.30 (d, 1H, J=7.20 Hz), 7.24 (d, 1H, J=8.71 Hz), 7.08 (s, 1H), 6.81 (dd, 1H, J=8.70 and 1.45 Hz), 6.34 (s, 1H), 5.13 (s, 2H), 5.06 (s, 2H), 2.04 ppm (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C@H:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:16]1([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:36]#[N:37])[C:25]([CH3:35])=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27]=3F)[N:23]=2)[CH2:18][CH2:17]1>CS(C)=O>[CH:16]1([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:36]#[N:37])[C:25]([CH3:35])=[C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:27]=3[N:6]3[CH2:7][CH2:8][C@H:4]([NH:3][CH2:1][CH3:2])[CH2:5]3)[N:23]=2)[CH2:18][CH2:17]1
Reactant: CCN[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN[C@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C4CC4)oc23)C1
Temperature: 95 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
(3S)-3-(Ethylamino)pyrrolidine (85 μl, 0.684 mmol) and triethylamine (95 μl, 0.684 mmol) were added to a dimethyl sulfoxide (2 ml) solution of 2-cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (100 mg, 0.342 mmol), followed by stirring in an oil bath at 95° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with isopropyl ether to obtain the entitled compound (31.0 mg, 23%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:21]=[CH:20][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([CH2:18][OH:19])([CH3:17])[CH2:13][CH2:12]3)=[C:8]([CH3:22])[CH:7]=2)[CH2:2]1.[C:23]1([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C-]#N.[Na+]>CO>[OH:19][CH2:18][C:14]1([CH3:17])[CH2:15][CH2:16][N:11]([CH2:10][C:9]2[CH:20]=[CH:21][C:6]([O:5][CH:3]3[CH2:4][N:1]([C:34]([C:32]4[O:33][C:29]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)=[N:30][N:31]=4)=[O:35])[CH2:2]3)=[CH:7][C:8]=2[CH3:22])[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: Cc1cc(OC2CNC2)ccc1CN1CCC(C)(CO)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CCC(C)(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 69C (1.65 g, 5.42 mmol) in methanol (25 mL) was added commercially available ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (1.30 g, 5.96 mmol) followed by sodium cyanide (53 mg, 1.10 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed by evaporation and the residue was dissolved in DCM. The solution was washed with NaHCO3, filtered through a phase separator and then evaporated to near dryness. Ether was added and the formed solid was filtered off and washed with ether. The product was dried in vacuo to afford 1.85 g (72%) of 69 as a crystalline solid, m. p. 167° C. 1H NMR (500 MHz, CDCl3): δ 0.96 (s, 3H), 1.31 (m, 2H), 1.52 (m, 2H) 2.28 (m, 2H), 2.34 (s, 3H), 2.51 (m, 2H), 3.38 (s, 2H), 3.40 (s, 2H), 4.31 (dd, 1H), 4.62 (dd, 1H), 4.73 (dd, 1H), 5.05 (m, 1H), 5.13 (m, 1H), 6.54 (dd, 1H), 6.60 (d, 1H), 7.18 (d, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 8.17 (d, 2H), MS (APCI+) m/z 477 [M+H]+, LC purity: 99%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[Si:20]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10.0 g (49.7 mmol) of tert-butyl 4-hydroxypiperidine-1-carboxylate and 4.06 g (59.7 mmol) of imidazole were initially charged in 100 ml of anhydrous DMF, and 15.02 g (54.7 mmol) of tert-butyl(diphenyl)silyl chloride were added at 0° C. After the reaction mixture had been stirred at RT for 48 h, it was poured into 1.6 liters of water and then extracted three times with approx. 500 ml each time of diethyl ether. The combined organic extracts were washed successively with saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The remaining residue was roughly purified by means of suction filtration (approx. 300 g of silica gel, eluent: cyclohexane→2:1 cyclohexane/ethyl acetate). 22.21 g (91% of theory, approx. 90% purity) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Cl)c3)c2)CC1
Yield: 32.1 %

Procedure:
N-(3-Chlorobenzyl)-5-fluoro-2-nitrobenzenamine (624 mg, 2.2 mmol), t-butyl piperazine-1-carboxylate (414 mg, 2.2 mmol), N,N-diisopropylethylamine (287 mg, 2.2 mmol) were stirred at 80° C. in dry acetonitrile (10 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (316 mg, 32% yield). 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.05 (d, 1H), 7.32-7.21 (m, 4H), 6.18 (d, 1H), 5.72 (s, 1H), 4.46 (d, 2H), 3.49 (m, 4H), 3.27 (m, 4H), 1.45 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4: 446.17; Observed: 469.4 (M++Na).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].C(O)(=O)C.[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:31][CH:32]=2)[CH:11]=1>C1COCC1>[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][N:18]=2)[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH:34]3[CH2:39][CH2:38][N:37]([C:2]([NH2:3])=[O:1])[CH2:36][CH2:35]3)=[CH:31][CH:32]=2)[CH:11]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNCC3)nc2)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCN(C(N)=O)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium cyanate (9.47 mg, 0.117 mmol), acetic acid (0.017 mL, 0.292 mmol), 4-methyl-N6′-(piperidin-4-yl)-N6-(4-(trifluoromethyl)pyridin-2-yl)-2,3′-bipyridine-6,6′-diamine (25 mg, 0.058 mmol), and THF (1 mL) were combined. The mixture was stirred at room temperature for 16 hours. The crude solution was purified via reverse phase high pressure liquid chromatography to afford 4-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-ylamino)piperidine-1-carboxamide. MS ESI calcd. for C23H25F3N7O [M+H]+ 472. found 472. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.53-8.49 (m, 3H), 8.28 (s, 1H), 8.24 (d, J=6.5 Hz, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.22-7.16 (m, 2H), 4.42 (m, 1H), 3.80 (m, 1H), 3.72-3.65 (m, 2H), 3.45 (dd, J=11.0, 4.0 Hz, 1H), 2.36 (s, 3H), 2.22 (m, 1H), 2.00 (m, 1H), 1.82 (s, 3H). rhSyk IC50=4 nM.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC[O:11][C:12]([CH:14]1[C:18](=O)[CH2:17][CH2:16][CH2:15]1)=O>COCCO>[CH3:8][C:7]1[C:2]2=[N:1][C:15]3[CH2:16][CH2:17][CH2:18][C:14]=3[C:12](=[O:11])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Cc1cccnc1N
Solvent: COCCO
Product: Cc1cccn2c(=O)c3c(nc12)CCC3
Yield: 70.8 %

Procedure:
A mixture of 10.8 g of 2-amino-3-picoline, 31.2 g of ethyl cyclopentanone-2-carboxylate, and 250 ml of ethylene glycol monomethyl ether is stirred and heated under reflux for 40 hours. The solution is concentrated as far as possible on a rotary evaporator. The residual oil crystallizes and is filtered with suction to give 14.15 g of air-dried solid. This is recrystallized from 425 ml of cyclohexane to give 11.3 g of product, after drying at 78°. The melting point is 100°-102°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17].P(Cl)(Cl)([Cl:20])=O.CCN(C(C)C)C(C)C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:20])[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccc(Br)c2nc(Cl)n1C1CCC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of 8-bromo-3-cyclobutylquinazoline-2,4(1H,3H)-dione (2.33 g, 7.89 mmol), phosphorous oxychloride (Acros Organics, Geel, Belgium; 3.68 ml, 39.5 mmol), and DIPEA (5.50 ml, 31.6 mmol) was heated over a 130° C. oil bath for 5 h. The reaction mixture was then cooled to RT and poured onto ice, and the resulting mixture was diluted with water (250 mL) to provide a brown suspension. 10N aqueous NaOH was added to the vigorously stirred suspension (maintaining the reaction mixture at 0° C.) until a pH of 10 was achieved. The precipitated solid was collected by vacuum filtration, washed with water (3×20 mL), and dried in vacuo to provide 8-bromo-2-chloro-3-cyclobutylquinazolin-4(3H)-one (1.888 g, 6.02 mmol, 76% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (1H, dd, J=8.0, 1.4 Hz), 7.99 (1H, dd, J=7.8, 1.4 Hz), 7.32 (1H, t, J=7.8 Hz), 5.22 (1H, quin, J=8.8 Hz), 2.89-3.05 (2H, m), 2.43-2.56 (2H, m), 1.98 (1H, q, J=10.7 Hz), 1.74-1.90 (1H, m). m/z (ESI, +ve) 313.0/314.9/316.9 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:26])[C@@H:10]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]([SH:14])([CH3:13])[CH3:12])C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:12][C:11]1([CH3:13])[S:14][C@H:7]2[CH2:6][CH2:5][CH2:4][N:8]2[C:9](=[O:26])[C@H:10]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(CCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)S)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)S[C@H]2CCCN2C(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.9 %

Procedure:
To a round bottom flask was added (R)-benzyl 1-(4,4-diethoxybutylamino)-3-mercapto-3-methyl-1-oxobutan-2-ylcarbamate (6.90 g, 16.2 mmol), DCM (50 mL) and TFA (1.87 mL, 24.3 mmol). The reaction was stirred at rt for 5 hr. The reaction was diluted with DCM (200 mL) and the organics was washed with saturated aqueous NaHCO3 (200 mL), water (200 mL) and saturated aqueous NaCl (200 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give benzyl (3R,8aS)-2,2-dimethyl-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]thiazin-3-ylcarbamate (1.89 g, 5.65 mmol, 34.9% yield) as a clear oil. Anal. Calcd. for C12H22N2O3S m/z 334.3. found: 335.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.29-7.44 (m, 5H), 5.92 (d, J=7.15 Hz, 1H), 5.14 (s, 3H), 4.57 (d, J=7.70 Hz, 1H), 3.89-3.68 (m, 1H), 3.60-3.40 (m, 1H), 2.55-2.34 (m, 1H), 2.18-2.00 (m, 1H), 1.99-1.83 (m, 2H), 1.51 (s, 3H), 1.13 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 167.31, 157.00, 136.19, 128.54, 128.20, 128.08, 67.23, 60.46, 55.12, 48.93, 46.26, 33.10, 29.56, 27.70, 23.39.