Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:15])([O:3][CH2:4][CH:5]([O:11][N+:12]([O-:14])=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[O:2].[CH2:16]([O:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[N:41]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:22]2[C:61]([C:65]([O:67][C:68]([CH3:83])([O:70][C:71](OC3C=CC([N+]([O-])=O)=CC=3)=[O:72])[CH3:69])=[O:66])=[CH:62][CH:63]=[CH:64][C:21]=2[N:20]=1)[CH3:17]>ClCCl>[CH2:16]([O:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[N:41]([C:42]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:22]2[C:61]([C:65]([O:67][C:68]([O:70][C:71]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([O:11][N+:12]([O-:14])=[O:13])[CH2:4][O:3][N+:1]([O-:15])=[O:2])=[O:72])([CH3:83])[CH3:69])=[O:66])=[CH:62][CH:63]=[CH:64][C:21]=2[N:20]=1)[CH3:17]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Hydroxyhexane-1,2-diyl dinitrate (intermediate 1, 0.082 g, 0.36 mmol) and N,N-dimethylaminopyridine (0.029 g, 0.11 mmol) were added to a stirred dichloromethane (3.5 mL) solution of 1-methyl-1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (intermediate 9, 0.220 g, 0.24 mmol). The solution was stirred at room temperature for 18 hours. Then it was washed with a 5% solution of sodium dihydrogenphosphate (2×10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, concentrated and purified by flash chromatography (Biotage SP1, 25+M column, TLC method n-hexane/EtOAc 6/4, Rf 0.4), affording the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.04-8.01 (m, 1H), 7.63-7.61 (m, 2H), 7.46-7.18 (m, 12H), 6.98-6.90 (m, 8H), 6.91 (t, 1H), 6.81 (d, 3H), 6.68 (d, 2H), 5.62 (s, 2H), 5.25-5.23 (m, 1H), 4.72 (dd, 1H), 4.28-4.26 (m, 2H), 4.05 (t, 2H), 1.78-1.52 (m, 10H), 1.49-1.42 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7](=[O:24])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[NH:19][CH:20]=[CH:21][CH:22]=1.[CH:28]1([CH2:31]Cl)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7](=[O:24])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[N:19]([CH2:31][CH:28]2[CH2:30][CH2:29]2)[CH:20]=[CH:21][CH:22]=1
Reactant: ClCC1CC1
Reactant: O=C(CC1CCCCN1CCc1ccc[nH]c1=O)NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC1CCCCN1CCc1cccn(CC2CC2)c1=O)NCc1cccc(F)c1

Procedure:
230 mg of N1-(3-fluorobenzyl)-2-[1-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]-2-piperidyl]acetamide obtained in Example 198, 0.08 ml of cyclopropylmethyl chloride, 450 mg of potassium carbonate and 5 ml of DMF were stirred at 60° C. for 1 hour. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. The drying agent was filtered off, and the solvent was evaporated. The residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1, subsequently ethyl acetate), to give 180 mg of a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5]([F:13])[C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:16]1=[O:27].[Cl:28][C:29]1[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([N:24]2[CH2:23][CH2:22][CH:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][C:4]4[C:3]([F:2])=[CH:8][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]=4[F:13])[C:16]3=[O:27])[CH2:26][CH2:25]2)=[N:33][CH:34]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A flask was charged with (S)-3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (0.250 g, 0.590 mmol), 2,5-dichloropyrazine (0.105 g, 0.708 mmol), Hunig's base (0.309 mL, 1.77 mmol), and DMF (5 mL). The reaction mixture was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using silica gel column chromatography eluting with ethyl acetate to provide (S)-1′-(5-chloropyrazin-2-yl)-3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-[1,4′-bipiperidin]-2-one (0.102 g, 0.204 mmol, 34.6% yield) as light yellow solid. Mass spectrum (apci) m/z=500.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[N:6]([CH3:14])[C:5]2(O)[C:15]([NH:17][C:18]([NH2:20])=S)=[O:16].[H-].[Na+].C(Br)C.CN(C)C=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3([C:15](=[O:16])[NH:17][C:18](=[O:30])[NH:20]3)[N:6]([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[CH:10][C:11]=1[Cl:12]
Reactant: CN1C(=O)Nc2cc(Cl)c(Cl)cc2C1(O)C(=O)NC(N)=S
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCBr
Product: CN1C(=O)Nc2cc(Cl)c(Cl)cc2C12NC(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,7-Dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (2.8 g) is dissolved in dimethylformamide (30 ml), and thereto is added sodium hydride (60% oily suspension) (0.32 g), and the mixture is stirred at room temperature for 30 minutes. To the mixture is added ethyl bromide (2 ml), and the mixture is further stirred for 30 minutes, and then the solvent is distilled off under reduced pressure. To the residue [i.e. 6,7-dichloro-3-methyl-4-hydroxy-4-(2-methylisothioureido)-carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline] is added 10% hydrochloric acid (30 ml), and the mixture is stirred at 70° C. for 4 hours. After cooling, the precipitates are taken by filtration, washed with 10% aqueous sodium hydrogen carbonate solution and then recrystallized from dimethylformamide-water to give 6,7-dichloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: O=c1c(Cl)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Cl)CC1

Procedure:
Obtainable by general method 4 from 10.0 g (30.75 mmol) of the compound from Example 2A with 3.6 ml (46.1 mmol) of methanesulfonyl chloride.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][C:7]1[CH:8]=[C:9](O)[C:10]2[CH:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[N:12]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Br:3][C:9]1[CH:8]=[C:7]([CH3:6])[N:12]=[C:11]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=12
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)c2cnn(Cc3ccccc3)c2n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Br)c2cnn(Cc3ccccc3)c2n1

Procedure:
Phosphorus oxybromide (5.31 g, 18.54 mmol) was added to a suspension of 6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.08 g, 12.87 mmol) and toluene (25 mL). The contents were heated to reflux for 1 h, wherein 10 mL DMF were added during this process. The solvent was removed under reduced pressure. The crude residue was suspended in 30 mL water containing ice. The contents were adjusted to pH=10 by addition of sat. NaHCO3. The solid product was filtered and dried under hi-vacuum. The final product was collected as 3.55 g (91%). LCMS E-S (M+H)=302.1/304.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3 H), 5.65 (s, 2 H), 7.16-7.35 (m, 5 H), 7.48 (s, 1 H), 8.12 s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]#[N:17])[C:13]3[N:18]=[CH:19][NH:20][C:12]=3[CH:11]=2)=[CH:6][C:5]=1[C:21]([F:24])([F:23])[F:22])[CH3:2].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30]>>[C:16]([C:14]1[C:13]2[N:18]=[CH:19][N:20]([CH:28]([CH2:27][CH3:26])[C:29]([OH:31])=[O:30])[C:12]=2[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:21]([F:23])([F:24])[F:22])[CH:6]=2)[N:15]=1)#[N:17]
Reactant: COC(=O)CCCBr
Reactant: CCOc1ccc(-c2cc3[nH]cnc3c(C#N)n2)cc1C(F)(F)F
Product: CCOc1ccc(-c2cc3c(ncn3C(CC)C(=O)O)c(C#N)n2)cc1C(F)(F)F

Procedure:
This compound was from 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo-[4,5-c]pyridine-4-carbonitrile (Example 1) with the use of methyl 4-bromobutyrate instead of methyl bromoacetate and using the methods described in examples 2 and 3. 1H NMR (DMSO): δ 8.69 (m, 2H) 8.43-8.38 (m, 2H) 7.42 (d, 1H) 4.44 (t, 2H) 4.27 (q, 2H) 2.29 (t, 2H) 2.11 (m, 2H) 1.38 (t, 3H). MS m/z 419.5 (M+1).
Reaction SMILES: OO.[CH3:3][O:4][C:5]1[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]#[N:15])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[O-:27].[K+].[K+]>CS(C)=O>[CH3:3][O:4][C:5]1[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([NH2:15])=[O:27])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COc1ncccc1-c1cc(C#N)ccc1Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A solution of 30% aqueous hydrogen peroxide (1 mL, 7.6 mmol) was added dropwise to a suspension of 3-(2-methoxypyridin-3-yl)-4-phenoxybenzonitrile (Preparation 20, 0.23 g, 0.76 mmol) and potassium carbonate (0.64 g, 4.6 mmol) in DMSO (3 mL). The reaction mixture was stirred for 2 hours at room temperature, then quenched with aqueous sodium thiosulfate solution (10% w/v, 10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate and the solvent removed in vacuo to afford the title compound as a pale yellow solid (0.2 g).
Reaction SMILES: [CH:1](=[C:8]1[C:24](=[O:25])[C:23]2([CH3:26])[CH:10]([CH:11]3[CH:20]([CH2:21][CH2:22]2)[C:19]2[CH:18]=[CH:17][C:16]([OH:27])=[CH:15][C:14]=2[CH2:13][CH2:12]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.C1COCC1>[CH:1](=[C:8]1[CH:24]([OH:25])[C:23]2([CH3:26])[CH:10]([CH:11]3[CH:20]([CH2:21][CH2:22]2)[C:19]2[CH:18]=[CH:17][C:16]([OH:27])=[CH:15][C:14]=2[CH2:13][CH2:12]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16-Benzylidene-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-one (179 mg, 0.50 mmol, CAB01122) was dissolved in ethanol (10 ml) and THF (10 ml). The resulting light yellow solution was cooled to 0° C. (ice bath) and sodium borohydride (100 mg, 2.64 mmol) was added. The reaction mixture was stirred overnight at room temperature, the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (40 ml). The organic solution was washed with water (2×25 ml) and brine (25 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and precipitated by addition of hexane. The white solid was filtered off and dried under high vacuum. Yield 175 mg (97%). 1H-NMR (d6-DMSO, 270 MHz), δ: 0.61 (s, 3H), 1.20-1.50 (m, 5H), 1.82-0.98 (m, 2H), 2.20-2.35 (m, 3H), 2.58-2.82 (m, 3H), 3.95-4.05 (m, 1H, H-17), 5.15 (d, J=6.2 Hz, 1H), 6.43 (s, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.52 (dd, J=8.2, 2.3 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.15-7.20 (m, 1H), 7.31-7.41 (m, 4H). LRMS (FAB+): 343.2 (80), 360.2 (100, [M]+). LRMS (FAB−): 359.3 (100, (M−H]−). HRMS (FAB+) 360.209709 C25H28O2 requires 360.208930
Reaction SMILES: ClC1C=CC([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=C(C(OC)C2C=CC=CC=2F)C=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:16]([O:15][C:13]([C:12]1[CH:11]=[N:10][N:9]([CH3:18])[CH:8]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(OC)c1ccccc1F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 20.1 g of 3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole in 250 ml methylene chloride is added 54 ml of a 1.4 molar boron trichloride solution in methylene chloride, and the mixture is stirred during 16 hours. Ice/water is then added; the organic layer separated, washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The aqueous layers are reextracted with methylene chloride. After removal of the solvent, the 3-[4-chloro-2-fluoro-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole is obtained as the solid residue, which is directly used in the next step.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:16]>O>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([Cl:16])[N:7]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)nc(Br)c1
Temperature: -50 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of 56 g 6-amino-2-bromo-4-methylpyridine in 500 ml of concentrated hydrochloric acid was cooled to -50° C. and saturated with gaseous HCl via a gas inlet. Under continuous cooling a solution of 25 g sodium nitrite in 60 ml water was added slowly. The reaction mixture was stirred for a further 2 hours at -50° C. The mixture was allowed to warm up to ambient temperature and set alkaline with a 50% aqueous solution of sodium hydroxide. The aqueous phase was extracted three times each with 200 ml dichloromethane. The combined extracts were dried with calcium chloride, and the solvent removed in vacuo to afford 22.5 g (40%) of 2-bromo-6-chloro-4-methylpyridine as a pale brown solid of melting point 76° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:34][CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: COc1ccc(CCN)cc1
Solvent: COCCOC
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2[N+](=O)[O-])cc1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 2-(4-methoxyphenyl)ethylamine in DME. ES-MS m/e (%): 356 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[CH3:14][N:13]([CH3:15])[C:11](=[O:12])[C:10]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[NH:8][C:6]1[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)[N:7]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccccc4C(=O)N(C)C)n3)cc2)CC1
Yield: 12 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N,N-dimethylbenzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 12% yield (pale yellow oil that solidifies on standing) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 8.28 (s, 1H), 8.15 (d, 1H, J=8.2 Hz), 7.44 (d, 2H, J=8.5 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.21 (t, 1H, J=7.5 Hz), 7.02 (t, 1H, J=7.4 Hz), 6.81 (s, 1H), 3.50 (s, 2H), 3.09 (s, 3H), 2.96 (s, 3H), 2.49 (bs, 8H), 2.30 (s, 3H); MS (ESI): 514.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].CCOCC.Br.[CH3:23][CH:24]1[C:29](=[O:30])[CH2:28][CH2:27][NH:26][CH2:25]1>O>[CH2:1]([O:8][C:9]([N:26]1[CH2:27][CH2:28][C:29](=[O:30])[CH:24]([CH3:23])[CH2:25]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1CNCCC1=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1CN(C(=O)OCc2ccccc2)CCC1=O

Procedure:
To a mechanically stirred mixture of benzylchloroformate (33.1 mL, 232 mmol, 105 mol %), sodium bicarbonate (37.2 g, 442 mmol, 200 mol %), ether (250 mL), and water (250 mL) is added 3-methyl-4-piperidone hydrobromide salt (42.9 g, 221 mmol) in portions over 10 min. The resultant mixture is stirred for 2 h and the organic phase separated. The aqueous phase is extracted with ether (2×150 mL) and the combined organics dried (MgSO4), filtered, and concentrated to an oily residue. This residue crystallized on standing at 23° C. and was recrystallized from hexanes/ethyl acetate to give N-benzyloxycarbonyl-3-methyl-4-piperidone as a solid: 51.2 g; 93%; mp 33°-35° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[C:31]4[C:26](=[C:27]([N:32]5[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]5)[CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:38]([N:35]1[CH2:36][CH2:37][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:26]=2[CH:25]=[CH:24][N:23]3[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][CH:13]3[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][CH2:7][OH:6])[S:41]([CH3:44])(=[O:43])=[O:42])[CH2:15][CH2:14]3)[N:22]=2)[CH2:33][CH2:34]1)(=[O:40])[CH3:39]
Reactant: CC(=O)N1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)CC3)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(N(CCO)S(C)(=O)=O)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
1-{1-[2-(4-{[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-methanesulfonylamino}-cyclo-hexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-4-acetyl-piperazine (0.119 g, 0.178 mmol) in THF (2.5 mL) was cooled in an ice bath under N2, and TBAF (0.18 mL, 1.01 eq) slowly added. The reaction mixture was allowed to warm to RT slowly, and stirred at RT for 15 h. The product was taken up in water and EtOAc, extracted with EtOAc, and the organic fractions washed with water, dried over Na2SO4, concentrated, and chromatographed (0% to 5% MeOH/DCM) to provide N-(4-{4-[4-(4-acetyl-piperazin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-N-(2-hydroxy-ethyl)-methanesulfonamide (Compound 320, 61.4 mg, 62%).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 66.2 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (121.0 mg, 0.41 mmol), benzotriazol-1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (218.1 mg, 0.49 mmol), triethylamine (172 μL, 1.23 mmol), and 2-aminothiazole (45.3 mg, 0.45 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25° C. under nitrogen for 24 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution (1×100 mL), water (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 to 3/1 hexanes/ethyl acetate gradient elution) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide (102.2 mg, 66%) as a white solid: mp 194-195° C.; EI-HRMS m/e calcd for C23H24N2OS (M+) 376.1609, found 376.1612.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:7]1(=[O:25])=[O:24].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.Cl>>[F:16][C:13]1[CH:14]=[CH:15][C:9]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:7](=[O:25])(=[O:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:29][CH:26]3[CH2:28][CH2:27]3)[CH2:11][C:10]=2[CH:12]=1
Reactant: O=S1(=O)N(CCCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Reactant: NC1CC1
Agent: Cl
Product: O=S1(=O)N(CCCCNC2CC2)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 85 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]butyl}cyclopropanamine (0.094 g, 85%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17])=[C:10]([NH:19][CH2:20][C:21]#[CH:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][O:15][CH2:16][CH3:17])[N:19]([CH2:20][C:21]#[CH:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C#CCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A solution of N-[2-chloro-4-(prop-2-ynylamino)quinolin-3-yl]-2-ethoxyacetamide (26.7 g, 84.0 mmol) and triethylamine (17.5 mL, 126 mmol) in ethanol (250 mL) was heated at 60° C. for 1.7 days. Additional triethylamine (17.5 mL) was added and the solution was heated at 60° C. for two more days. The volatiles were removed under reduced pressure and the resulting white solid was triturated with water, isolated by filtration, and dried to provide 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (24.2 g, 96%).