Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccnc(Cl)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (68 mg, 84%), MS (ISN) m/z=323.5 [(M+H)+], mp 286° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[Br:10][C:11]1[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=1[F:18].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:11]1[CH:16]=[C:15]([C:9]#[C:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[CH:14]=[CH:13][C:12]=1[F:18]
Reactant: Fc1ccc(I)cc1Br
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (77 mg, 0.11 mmol), copper (I) iodide (42 mg, 0.22 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (300 mg, 2.2 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (0.78 g, 2.6 mmol) in triethylamine (3.3 mL, 33 mmol). Stir at room temperature for 24 h then concentrate. Purify by silica gel chromatography, eluting with 75:25 dichloromethane:hexanes to 100:0 dichloromethane:hexanes to 95:5 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 95:5 to 90:10 hexanes:ethyl acetate, to give the title compound as a white solid (560 mg, 82%).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:9]=1)([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:1]([S:4][C:5]1[S:6][C:7]([Cl:18])=[C:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[N:9]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Sc1nc(OS(C)(=O)=O)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
3.5 g of 2-isopropylthio-4-methylsulfonyloxy-1,3-thiazole (No. 171) was dissolved in 50 ml of methylene chloride. 2 g of sulfuryl chloride was added dropwise to the solution keeping the temperature below 0° C., followed by stirring at room temperature for 2 hours. Then, 20% aqueous solution of sodium carbonate was added to the reaction mixture to cease the reaction, and the methylene chloride layer was separated and washed with water, followed by drying over anhydrous sodium sulfate. The oil obtained by concentration was purified by silica-gel column chromatography to 2 g of the objective compound as a pale yellow oil (yield: 50.4%).
Reaction SMILES: I[C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[N:20]=[CH:21][C:22]([C:2]3[CH:11]=[N:10][C:5]4[NH:6][CH2:7][CH2:8][NH:9][C:4]=4[CH:3]=3)=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Ic1cnc2c(c1)NCCN2
Product: CN1CCN(c2ccc(-c3cnc4c(c3)NCCN4)cn2)CC1
Yield: 20 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (704 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow solid (20% yield). M.p. 225° C. (dec), LCMS: m/z=311.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 2.49-2.56 (m, 4H), 3.36-3.42 (m, 2H), 3.53-3.63 (m, 6H), 4.90 (bs, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.77 (d, J=1.5 Hz, 1H), 7.58 (dd, J=8.8 Hz, 2.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Clc1ccc(-c2csc(Br)n2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Yield: 25 %

Procedure:
A solution of 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole (6.89 g, 22.3 mmol), tert-butyl piperazine-1-carboxylate (8.31 g, 44.6 mmol) and potassium carbonate (3.08 g, 22.3 mmol) in dimethylformamide (70 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.31 g (25.0%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N:29][S:30][N:31]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[C:3]3[C:4]([CH:5]=2)=[N:29][S:30][N:31]=3)=[O:28])[CH2:34][CH2:33]1
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nsnc3cc12
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1cc2nsnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
See step f) of example H2 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-7-oxa-2-thia-1,3,5-triaza-cyclopenta[b]naphthalen-8-one as starting material and cyclopropanemethylamine. After 18 hours reaction and chromatography column purification, a slightly brown solid is obtained (85%). LC/MS: 556/558 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc(Cl)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.30-7.35 (3H, m) 7.41-7.43 (1H, m), 7.47 (1H, s), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.72 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H11ClN4O, 311; Found, 311.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH2:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH:27][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN)c3ccccc23)CC1
Reactant: Cc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CNC(=O)c3ccccc3C)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (32) (60 mg, 0.153 mmol) in DCE (5 mL), was added pyridine (62 ul, 0.765 mmol), 2-methyl-benzoyl chloride (22 ul, 0.168 mmol) and dimethyl-pyridin-4-yl-amine (4 mg, 0.031 mmol). After stirring at 70° C. overnight, the resultant solution was concentrated in vacuo to give the crude product. Purification using reverse phase HPLC provided the title compound (G-1). LCMS showed m/z: 510 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:36]1([CH2:42][CH2:43][S:44][CH:45]([C:49](O)=[O:50])[C:46](O)=[O:47])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[OH:50][C:49]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[C:12]([CH3:20])[CH:13]=2)[O:19][C:46](=[O:47])[C:45]=1[S:44][CH2:43][CH2:42][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: COc1ccccc1COc1ccc(C(C)=O)cc1C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1C

Procedure:
The title compound was prepared by Method A using 4'-[(2-methoxyphenyl)methoxy]-3'-methylacetophenone (1.36 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3 H), 2.77 (t, 2 H), 2.97 (t, 2 H), 3.84 (s, 3 H), 5.17 (s, 2 H), 6.67 (s, 1 H), 6.98 (t, 1 H), 7.70 (d, 1 H), 7.27 (m, 6 H), 7.41 (t, 1 H), 7.43 (d, 1 H), 7.65 (m, 2 H), 11.81 (bs, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.CC(C)N=C=NC(C)C.O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:12][C:7]2[CH:6]=[C:5]([C:4]([OH:3])=[O:13])[CH:10]=[CH:9][C:8]=2[N:11]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 3,4-diamino-benzoic acid ethyl ester (5.0 g, 27.8 mmol) and 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h. DIC (4.40 mL, 28.2 mmol) was added and the mixture stirred overnight. After 30 min stirring at 80° C. water was added and the mixture was concentrated i.vac. The residue was taken up in ethanol and 1 M aq. NaOH. The mixture stirred overnight at reflux. Ethanol was evaporated and the aq. phase diluted with water. The precipitate was filtered and washed with water. The filtrate was acidified with formic acid and cooled. The mixture was filtered and washed with water.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[CH:19][C:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:9][C:8]=1[O:21][CH3:22].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1.CCCCCC>[Si:12]([O:11][C:10]1[CH:19]=[CH:20][C:7]([B:23]([OH:28])[OH:24])=[C:8]([O:21][CH3:22])[CH:9]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B(O)O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, n-butyl lithium (a hexane solution) was added at −75° C. to a THF solution of (4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane, followed by stirring at −75° C. for 1 hour. Triisopropyl borate was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was treated with hydrochloric acid to obtain (4-{[tert-butyl(dimethyl)silyl]oxy}-2-methoxyphenyl)boronic acid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:23][C:22]([NH:15][N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)=[O:21]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A mixture of methyl [1-[4-phenoxyphenyl]hydrazino]acetate (Intermediate 76, 11 g, 0.004 mol), sodium cyanate (0.9 g, 0136 mol) and trifluoracetic acid (1 ml, 0.0124 mol) in dry toluene (15 ml) was stirred under nitrogen at room temperature for 1 hour. The mixture was poured into 8% sodium bicarbonate solution (75 ml) and extracted with ethyl acetate (2×75 ml). The organic extract was dried (MgSO4) and evaporated to give a pale yellow semi-solid. This was triturated with ether to give the title compound (Intermediate 77) as a white solid (0.6 g, 48%) m.p. 110°-113° C.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[CH2:1]([C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Diethyl prop-1-ylmalonate (70.23 g) was added dropwise to a stirred suspension of sodium hydride (8.35 g) in dimethylformamide (400 ml) under an atmosphere of nitrogen at 10° to 15° C. Following the addition, the mixture was allowed to stir at room temperature until effervescence ceased. The resulting clear solution was cooled again and ethyl bromoacetate (58.06 g) was added. The mixture was heated at 70° C. for 2 hours then allowed to cool, diluted with water, and extracted with ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated to give almost pure diethyl 2-prop-1-yl-2-ethoxycarbonylsuccinate (97.35 g, 97%) as a pale yellow liquid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH2:30]Br)=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br.[CH3:33][O-:34].[Na+]>C(O)(=O)C.CO>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH2:30][O:34][CH3:33])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CBr)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Reactant: C[O-]
Agent: Br
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1ncc(COC)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1

Procedure:
2-n-Butyl-5-hydroxymethyl-4-{N-[(2-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine hydrochloride, the product of Example 2B, is converted to 2-butyl-5-bromomethyl-4-{N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine by treatment with hydrogen bromide in acetic acid according to the method of A. Schellenberger and K. Winter in Z. Physiol. Chem., 322, 164 (1960). The bromomethyl intermediate is then converted to the title compound by treatment with sodium methoxide in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[NH:14][C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1.C([O-])([O-])=O.[K+].[K+].CS([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])(=O)=O.CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])[C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1
Reactant: CCc1nc2c([nH]1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Reactant: C=CCC(CC=C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCC(CC=C)n1c(CC)nc2c1C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.9 %

Procedure:
Prepared by the method described in example 8 using the appropriate starting materials except for part “B” to give the desired product. Part “B” was replaced with the following procedure. A solution of 3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (65 mg, 0.20 mmol) in anhydrous DMF (1.2 mL) was treated with finely ground K2CO3 (83 mg, 0.60 mmol). After stirring 5 min at rt, 4-methanesulfonyl-1,6-heptadiene (203 μL, 1.11 mmol) was added via syringe and the reaction mixture was heated at 90° C. for 4 h. The mixture was cooled to rt and transferred to a separatory funnel containing ether (50 mL). The organic layer was washed with water (4×15 mL), brine (15 mL), dried over MgSO4, filtered, and concentrated. Purification of the residue by prep plate (1000 μM silica gel plate, 25% ethyl acetate in hexanes) followed by further purification by reverse phase HPLC afforded the title compound (15 mg, 18% yield) as a colorless oil; HRMS (ESI) m/e 419.1435 [(M+H)+, calcd for C21H25N4OCl2 419.1405].
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.Cl[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]2)[CH:26]=[N:25][CH:24]=1>C1COCC1>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30]2)[CH:26]=[N:25][CH:24]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cncc(Cl)n2)C1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCCC(NC(=O)OC(C)(C)C)C2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a solution of tri-n-butyltin hydride (1.686 mL, 6.39 mmol) in THF (10 mL) at 0° C. was added LDA (1.8 M solution in heptane/THF/ethylbenzene, 3.55 mL, 6.39 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min and tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-3-ylcarbamate (1.00 g, 3.20 mmol) was added. The reaction mixture was kept at 0° C. for 2 h, then quenched with 10% KF solution. The mixture was extracted with DCM and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-25% EtOAc in Hexanes) to give tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (400 mg, 22.1% yield). MS (ESI, pos. ion) m/z: 569 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=4)[CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCNCC2
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Temperature: 90 °C

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (0.10 g, 0.40 mmol), 2-chloro-3-methyl-5-nitropyridine (0.0718 g, 0.416 mmol) and potassium carbonate (0.11 g, 0.79 mmol) in N,N-dimethylformamide (2.0 mL) was heated at 90° C. overnight. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was used directly in next step without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29](SC)[N:30]=[CH:31][C:26]=4[CH:25]=3)[C:21]([CH3:38])=[CH:20][C:19]=2[F:39])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:51][NH2:52]>C1COCC1>[C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29]([NH:52][CH3:51])[N:30]=[CH:31][C:26]=4[CH:25]=3)[C:21]([CH3:38])=[CH:20][C:19]=2[F:39])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c(F)cc3C)c(=O)n(C)c2n1
Yield: 71 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (148 mg, 0.263 mmol), MCPBA (81 mg, 0.328 mmol) and 2.0N methylamine in THF (1.3 mL) were combined to afford 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (103 mg, 71% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.59 (s, 9H), 2.08 (s, 3H), 2.92 (s, 3H), 3.55-3.62 (m, 3H), 7.25-7.30 (m, 1H), 7.69 (s, 1H), 7.70-7.80 (m, 1H), 7.93 (s, 1H), 7.95-8.05 (m, 1H), 8.51 (s, 1H), 8.20-8.25 (m, 1H), 9.04 (s, 1H); MS (ESI) m/z: 547.2 (M+H+).
Reaction SMILES: FC1C=CC=CC=1CCN[C:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12].[CH2:19]([C:26]1([N:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(N=C=NC(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C>[CH2:19]([C:26]1([N:33]([CH3:34])[CH3:35])[CH2:31][CH2:30][CH:29]([NH:32][C:11](=[O:12])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCCC(=O)NCCc1ccccc1F
Reactant: CN(C)C1(Cc2ccccc2)CCC(N)CC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C1(Cc2ccccc2)CCC(NC(=O)CCCC(=O)O)CC1

Procedure:
As described for Example 341, 0.95 mg 4-[2-(2-fluorophenyl)ethylcarbamoyl]butyric acid and 0.87 1-benzyl-N,N-dimethylcyclohexane-1,4-diamine were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.50 g 1-hydroxybenzotriazole and the crude product (1.65 g yellow solid) similarly isolated. 720 mg of the non-polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide was obtained by column chromatography on silica gel (3.0×20 cm) with 450 ml diethyl ether, followed by 450 ml diethyl ether/methanol (V:V=4:1) and 450 ml diethyl ether/methanol (V:V=1:1), was dissolved in 25 ml 2-butanone, 25 ml ethyl acetate and converted into the corresponding hydrochloride by adding 28 μl water and 198 μl chlorotrimethylsilane (657 mg of vitreous solid).