Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)[C:9]2[C:10]([C:15](O)=[O:16])=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:14])[CH:13]=3)[C:15](=[O:16])[N:18]2[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2cn(C)nc2C(=O)O)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C)cc3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-methyl-1H-pyrazole-3-carboxylic acid (Step 13.2). tR: 3.44 min (HPLC 1); tR: 0.77 min (LC-MS 2); ESI-MS: 369 [M+H]+ (LC-MS 2); Rf=0.46 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (s, 3H) 3.37 (s, 3H) 3.95 (s, 3H) 6.15 (s, 1H) 7.22 (d, J=8.6 Hz, 2H) 7.38 (d, J=8.6 Hz, 2H) 7.40 (m, 1H) 7.81 (m, 1H) 7.86 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C)C(=O)C.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)C(=O)C1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Sodium hydride (60% dispersion in oil) (0.40 g, 10.0 mmol) was added portionwise over 10 min to a solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.00 g, 5.0 mmol) in N,N-dimethylacetamide (10 ml). The mixture was stirred for 30 min before addition of bromomethylcyclopropane (1.45 ml, 15.0 mmol) and then stirred for a further 18 h. The mixture was diluted with water (100 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4 and evaporated to give 4-cyclopropylmethyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.27 g, 100%) as a yellow oil. This oil was dissolved in dichloromethane and hydrogen chloride bubbled through the reaction (2×10 min). The solvent was evaporated to give 1-cyclopropylmethylpiperazin-2-one.HCl (0.95 g, 100%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:24])[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:16][C:17]1([CH3:24])[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CC1(C)CCN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1(C)CCn2c(nc(-c3ccncc3)cc2=O)N1
Yield: 33 %

Procedure:
A mixture of 7.68 g (39.8 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 7.9 g (37.9 mmol) of 6,6-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrobromide (prepared according to Bull. Soc. Chim. Belg., 1950, 59, 573-587) and 11 g (79.5 mmol) of potassium carbonate in 80 ml of ethanol were heated at reflux temperature during 18 h. The reaction mixture was cooled and the solvent removed by evaporation. The residue obtained was treated with water and the precipitate recovered by filtration to give 3.21 g (33%) of product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([NH:9][CH3:10])=[O:8])=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7](=[O:8])[NH:9][CH3:10])=[N:4][N:5]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:6]=1
Reactant: CNC(=O)c1n[nH]cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Yield: 41.8 %

Procedure:
4-bromo-N-methyl-1H-pyrazole-3-carboxamide (550 mg), potassium carbonate (579 mg) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1081 mg) in acetonitrile (20 mL) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, brine dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 40 to 70% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-bromo-3-(methylcarbamoyl)pyrazol-1-yl]piperidine-1-carboxylate (436 mg) as a off-white solid. The product gave the following characterizing data: NMR Spectrum: (DMSOd6) 1.42 (s, 9H), 1.79 (dd, 1H), 1.84 (dd, 1H), 1.97-2.05 (m, 2H), 2.71 (d, 3H), 2.91 (bs, 2H), 3.97-4.13 (m, 2H), 4.33-4.43 (m, 1H), 8.05 (q, 1H), 8.15 (s, 1H); Mass spectrum: M+H+ 386-388.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.COO[CH:34](OOC)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.[Na+].[Cl-]>C(Cl)Cl>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH:34]2[O:7][CH:6]([C:5]([NH:4][CH2:3][CH2:2][C:1]([OH:15])=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH2:11][O:12]2)=[CH:36][CH:37]=1
Reactant: COOC(OOC)c1ccc(OC)cc1
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2OCC(C)(C)C(C(=O)NCCC(=O)O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Pantothenic acid (7) (4.6 g, 2.24×10−2 mols) was dissolved in dry DCM (30 mL). Camphor sulfonic acid (0.52 g, 2.24×10−3 mols) and p-anisaldehyde-dimethoxy-acetal (3.82 mL, 2.24×10−2 mols) were added to the reaction mixture. The reaction was stirred overnight at room temperature with a drying tube. The crude reaction product was concentrated and purified silica gel chromatography (6:1 hexane:EtOAC-EtOAc) to yield a white solid (8A1) (3.8 g, 51% yield). mp=135-136° C. 1HNMR (400 MHz, DMSO) 0.93 (s, 3H), 0.99 (s, 3H), 2.38 (t, 2H, J=6.8 Hz), 3.25 (m, 1H), 3.34 (m, 1H), 3.5.9 (d, 1H, J=10.8 Hz), 3.62 (d, H, J=10.8 Hz), 3.74 (s, 3H), 4.07 (s, 1H), 5.50 (s, 1H), 6.91 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz). 13C-NMR (400 Mz, DMSO) 19.7, 22.2, 33.2, 34.4, 34.9, 55.8, 78.0, 83.8, 101.1, 114.0, 128.4, 131.1, 160.3, 168.9, 173.8. IR (NaCl, thin film), 3420, 2959, 1729, 1654, 1617, 1540, 1520, 1251, 1105 cm−1. MS (ESI) [M+Na]+360.1. HRMS (FAB) (m/z): [M+H]+ calcd for C17H23O6N, 338.1598, found 338.1594.
Reaction SMILES: C(C1C=CC(CN)=CC=1)(C)(C)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]=[C:40]=[O:41])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([C:57]([F:60])([F:59])[F:58])[CH:45]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:38][NH:39][C:40](=[O:41])[NH:42][CH2:43][C:44]2[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([C:57]([F:60])([F:58])[F:59])[CH:45]=2)=[CH:36][CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: C=Cc1cc(CN)cc(C(F)(F)F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)c1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(C(F)(F)F)c1NS(C)(=O)=O
Reaction time: 5 h
Yield: 36.88 %

Procedure:
4-tert-Butyl-benzylamine (1.5 eq, 15.20 μl, 0.09 mmol), BOC2O (1.5 eq, 0.09 mmol, 20.70 μl), and DMAP (0.2 eq, 0.01 mmol, 1.34 mg) were added to methylene chloride. The reaction mixture was stirred for 5 hr. After confirming the synthesis of the 1-tert-butyl-4-isocyanatomethylbenzene with TLC, N-(4-Aminomethyl-2-trifluoromethyl-6-vinylphenyl)methanesulfonamide (1 eq, 0.06 mmol, 20.5 mg) and TEA (2 eq, 0.12 mmol, 16.72 μl) were added into the reaction mixture. The reaction mixture was stirred for 12 hr and purified with similar procedure to step 7 of example 8 to gave title compound (10.7 mg 36.88%).
Reaction SMILES: NC1CC[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)CC1.C(N(CC)CC)C.ClC(OC[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1)=O>O1CCCC1>[CH3:29][CH2:28][CH2:27][CH2:32][CH2:31][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:9][CH2:8][NH2:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
To a 0° C. solution of 4-amino-1-benzylpiperidine 11 (41.2 g, 216.5 mmol) and triethylamine (51.3 mL, 369 mmol) in 600 mL of tetrahydrofuran was added benzyl chloroformate (31 mL, 217 mmol) dropwise over a period of 30 to 45 min. at such a rate that the reaction temperature was kept between 5° C. and 10° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stir for 12 hours. The solvent and volatiles were removed under reduced pressure. Water (500 mL) and ethyl acetate (1.2 L) were then added and the reaction was partitioned between the two phases. The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×, 150 mL) and then dried (brine, MgSO4). Evaporation of the solvent yielded a tan liquid which was purified via column chromatography (SiO2, EtOAc/Hexane-30/70 to EtOAc-100) to provide 27.8 g of the amine 12 as a white solid (mass spec. M+=324, MP=79.1-79.6° C.).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>O1CCCC1.C(OCC)(=O)C>[C:21]([CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[CH:14][C:15]=1[O:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])#[N:22]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: N#CCc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccccc1CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (6.2 ml, 39.4 mmol) was added dropwise to an ice-cooled solution of 3-hydroxyphenyl acetonitrile (preparation 126) (4.2 g, 31.5 mmol), triphenylphosphine (10.34 g, 39.4 mmol) and tert-butyl 2-hydroxyethylcarbamate (5.4 ml, 34.9 mmol) in tetrahydrofuran (70 ml), and once addition was complete, the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400 ml), washed with 1N NaOH solution, water, brine, then dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (30:70) as eluant to give the desired product as a yellow/green oil, that crystallised on standing, (5.88 g, 68%).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:27][CH3:28])[C:10]1=[O:29])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:27]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:29])[CH3:28]
Reactant: [H][H]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCOCC3)cc21
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCOCC3)cc21
Yield: 94.8 %

Procedure:
Five percent Pd/BaSO4 (50 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-morpholino-1H-quinazoline-2,4-dione (Example G, 0.23 g, 0.58 mmol) in 70 mL of THF and 5 mL methanol. The mixture was shaken under 50 PSI of hydrogen for 16 hours, filtered, and concentrated to afford 0.17 g of the title compound as a solid, mp 162-163° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([O:19]C)=[O:18])[CH:8]=1)=[O:4].[Li+].[OH-]>O.CO>[C:3]([CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)COc1cc(C(=O)OC)nc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1cc(C(=O)O)nc2ccccc12
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A sample of methyl 4-methoxycarbonylmethyloxy-2-quinolinecarboxylate(0.20 g, 0.00073 mole) prepared as in Example II, was hydrolyzed by the addition of lM LiOH (2.2 ml, 0.0022 mole) in H2O/MeOH. After stirring for 18 hours, the MeOH was evaporated, the product dissolved in H2O, and acidified to pH 2.6 with lN HCl thereby precipitating a white solid. A yield of 0.15 g (83%) of 4-carboxymethyloxy-2-quinolinecarboxylic acid was obtained after filtering and drying in a vacuum dessicator. Melting point was 240° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[OH:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: NN
Reactant: COc1c(O)cccc1C(=O)CCC(=O)O
Solvent: O
Product: COc1c(O)cccc1C1=NNC(=O)CC1

Procedure:
3-(3-hydroxy-2-methoxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(3-hydroxy-2-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH2:26][C:27]([C:30](O)=[O:31])=[N:28][N:29]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[C:13]([C:12]1[C:11]([F:18])=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:30]([C:27]3[CH:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[NH:29][N:28]=3)=[O:31])[N:5]=2)=[CH:16][C:15]=1[F:17])#[N:14]
Reactant: N#Cc1c(F)cc(-c2ccn(CCN)n2)cc1F
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(F)cc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)n2)cc1F
Yield: 18.5 %

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.3 g, 0.773 mmol), 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.161 g, 0.851 mmol), DIPEA (0.202 ml, 1.160 mmol), HOBt (0.157 g, 1.160 mmol) and EDCI (0.222 g, 1.160 mmol) using the method of Example 34(d) affording 0.06 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.70 (t, 2H), 4.39 (t, 2H), 7.01 (d, 1H), 7.79 (m, 2H), 7.88 (d, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH2:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.[BH3-]C#N.[Na+]>CO>[NH:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:31][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([CH2:22][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[CH:24][CH:25]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2nc3ccccc3[nH]2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Using General Procedure A: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (140 mg, 0.34 mmol) and 2-aminobenzimidazole (45 mg, 0.0.34 mmol) in MeOH (4 mL) was added NaBH3CN (64 mg, 1.1 mmol) and the mixture was stirred at room temperature for 20 hours. Purification of the crude yellow foam by column chromatography on silica gel (200: 1:1—EtOAc:MeOH:NH4OH) followed by radial chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded AMD9693 (26 mg, 15%) as a white solid. 1H NMR (CDCl3) δ 1.57-1.74 (m, 1H), 1.87-2.05 (m, 2H), 2.10-2.20 (m, 1H), 2.63-2.75 (m, 1H), 2.75-2.90 (m, 1H), 3.54 (s, 2H), 3.86 (d, 1H, J=16.8 Hz), 4.03-4.16 (m, 2H), 4.24-4.35 (m, 2H), 5.44 (br s, 1H), 6.88-6.91 (m, 4H), 7.10-7.19 (m, 7H), 7.42 (d, 1H, J=7.5 Hz), 7.54 (br s, 2H), 8.65 (d, 1H, J=4.2 Hz); 13C NMR (CDCl3) δ 21.16, 24.26, 29.10, 46.66, 48.40, 53.29, 60.62, 111.39 (br), 118.11 (br), 120.13, 121.81, 122.37, 127.22, 128.57, 133.86, 134.79, 137.41, 138.17, 143.78, 146.67, 155.56, 156.41, 157.20. ES-MS m/z 514.4 (M+H). Anal. Cald. for C32H31N7.0.8CH2Cl2.0.4C4H8O2: C, 66.98; H, 5.85; N, 15.90. Found: C, 67.14; H, 5.66; N, 15.87.
Reaction SMILES: Cl.[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:3].Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: CCN(CC1CCNCC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Reactant: Brc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC1CCN(c2ccccn2)CC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Temperature: 165 °C
Yield: 15.3 %

Procedure:
A mixture of ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064 mmol), 2-bromopyridine (0.62 μL, 0.64 mmol), and triethylamine (26 μL, 0.19 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 30 minutes at 165° C. The crude mixture was purified by HPLC to provide compound A126 as a white solid (5 mg, 15%). Exact mass calculated for C25H28FN7O2S 509.2, found 510.5 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19]O)[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:7]=1.S(Cl)([Cl:23])=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:19][Cl:23])[CH:3]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Oc2cc(Br)cc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of (3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methanol (5.5 g, 15.8 mmol) in dry THF (30 mL) cooled to 0° C. was added thionyl chloride (3.22 mL, 44.3 mmol) dropwise. The reaction was warmed to RT and stirred for 2 h. The reaction mixture was then cooled and water was added. The mixture was extracted with ethyl acetate three times. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and evaporated to dryness to give the title compound (4.7 g). 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 7.05 (d, J=8.5 Hz, 1H), 4.54 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:12][CH:11]([C:13]([OH:15])=O)[C:8]2([CH2:10][CH2:9]2)[C:7]1=[O:16].[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.O>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[N:31]1[C:13]([CH:11]1[C:8]2([CH2:9][CH2:10]2)[C:7](=[O:16])[N:6]([CH2:5][C:4]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:3]=2[O:2][CH3:1])[CH2:12]1)=[O:15])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2CC(C(=O)O)C3(CC3)C2=O)c(OC)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C3(CC3)C2=O)c(OC)c1
Reaction time: 4 h

Procedure:
To a solution of 5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid (1.59 g) in chloroform (16 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (1.11 g), WSC.HCl (1.20 g) and N,N-dimethyl-4-aminopyridine (318 mg) at room temperature, and the mixture was stirred for 4 hours. To this reaction mixture was added water, and the organic layer was separated from the solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to separate a low-polarity component as the titled compound (1.39 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([SH:11])[C:6]1[O:10][CH:9]=[CH:8][CH:7]=1>>[CH3:2][C:1]([S:11][CH2:5][C:6]1[O:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: CC(=O)Cl
Reactant: SCc1ccco1
Product: CC(=O)SCc1ccco1

Procedure:
Furfurylthiol acetate was prepared by reacting acetic chloride or anhydride with furfurylmercaptan according to the method described in Houben-Weyl, 4th ed., vol. 9, 753 (1955). The product has a b.p. of 90°-92°C./12 mm. Hg.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24].C(N(CC)CC)C>ClCCl>[CH3:20][O:21][C:22](=[O:33])[C@@H:23]([NH:24][C:17]([NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])=[O:18])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C=Nc1ccccc1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)Nc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A solution of 2-benzenesulfonylphenyl isocyanate (600 mg, 2.31 mmol, prepared as described in Preparation 20) in dichloromethane (4 ml) was slowly added to a solution of L-tyrosine methyl ester hydrochloride (589 mg, 2.54 mmol) and triethylamine (0.64 ml, 4.62 mmol) in dichloromethane (4 ml) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (50 ml) and washed with hydrochloric acid 1N (2×20 ml), saturated aqueous NaHCO3 (2×20 ml) and brine (1×20 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to yield the title compound (930 mg, 89%) as a viscous oil.
Reaction SMILES: C1(NC2C=CC(NC3C=CC=CC=3)=CC=2)C=CC=CC=1.[CH3:21][C:22]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])[CH2:23][CH2:24][OH:25].[C:34](OCC)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([O:25][CH2:24][CH2:23][C:22]([CH3:21])([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26])(=[O:37])[CH:35]=[CH2:36]
Reactant: CC(C)(CCO)Sc1ccccc1
Reactant: C=CC(=O)OCC
Agent: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Product: C=CC(=O)OCCC(C)(C)Sc1ccccc1
Temperature: 112.5 °C

Procedure:
Into a 3-neck round-bottomed flask was placed (in order): N,N′-diphenyl-1,4-phenylenediamine (0.53 g, 2.04×10−3 moles), 3-Methyl-3-(phenylthio)butan-1-ol (50.0 g, 0.255 moles) and ethyl acrylate (276 mL, 2.55 moles). The apparatus was then assembled for reactive distillation through a Claisen head and purge-filled with nitrogen gas. The reaction flask was heated to 110-115° C. and after ca. 5 mL of ethyl acrylate had distilled over, titanium(IV) isoproproxide (TPT, 2.26 mL, 7.65×10−3 moles) was added to the reaction mixture via syringe in one portion. The rate of distillation immediately increased significantly and the distillate vapour temperature decreased from 99° C. to 90° C. These distillation conditions were maintained for a period of 150 minutes before the apparatus was evacuated by means of a 10 mbar PTFE-diaphragm pump and the remaining ethyl acrylate was stripped from the reaction mixture. The apparatus was then pumped down using a two-stage oil pump and the crude product distilled over at a vapour temperature of 109.5-112° C. (0.18 Torr, appearance: golden liquid, yield: 50.8 g).