Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[O:19][C:20]1[C:25]([N:26]=[C:27]=S)=[CH:24][CH:23]=[C:22]([O:29][CH3:30])[N:21]=1)([CH3:16])([CH3:15])[CH3:14]>ClCCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:27]([NH:26][C:25]3[C:20]([O:19][C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[C:13]([CH3:16])([CH3:15])[CH3:14])=[N:21][C:22]([O:29][CH3:30])=[CH:23][CH:24]=3)[NH:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(N=C=S)c(Oc2ccccc2C(C)(C)C)n1
Solvent: ClCCCl
Product: COc1ccc(Nc2nc3ccc(C(C)(C)C)cc3[nH]2)c(Oc2ccccc2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(tert-butyl)-1,2-diaminobenzene (20 mg, 0.12 mmol) in DCE (1 mL) was slowly added 2c (19 mg, 0.06 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture containing 2d and 2d′ was used in the next step without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:34]([C:37]1[CH:44]=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=O)([CH3:36])[CH3:35]>C1COCC1>[CH:34]([C:37]1[CH:44]=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=[CH:2][O:3][CH3:4])([CH3:36])[CH3:35]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1c(C(C)C)cc(Br)cc1C(C)C
Temperature: 0 °C
Yield: 78.8 %

Procedure:
A 150 mL of dry toluene solution of 1-iodo-2,6-diisopropyl-4-bromobenzene (17.6 g, 0.048 mol) was treated with n-BuLi (1.6 M in hexane, 75 mL) at −78° C. in 30 minutes. After stirring for 15 minutes, dry DMF (20 mL) in 50 mL of toluene was added dropwise. The resulting mixture was slowly warmed up to room temperature. After regular work up, the crude product was distilled at 140° C. under vacuum to afford 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g). Methoxymethyl triphenylphosphonium chloride (18.68 g, 54.5 mmol) was suspended in 200 mL of THF at −78° C. Lithium hexamethyldisilazide (1.0 M in THF, 50 mL) was added dropwise. The resulting mixture was warmed up to 0° C. with stirring. After cooling the solution to −78° C., 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g, 42.7 mmol) in 20 mL of THF was added dropwise. The mixture was slowly warmed up to room temperature and continually stirred overnight. After regular work up, the crude product was distilled at 165° C. under vacuum to afford 2,6-diisopropyl-4-bromo-β-methoxystyrene (10 g). This product was dissolved in 20 mL of dioxane and 100 mL of 18% HCl solution and refluxed at 100° C. for 6 h. After regular work up, the crude product was distilled at 160° C. under vacuum to afford 2,6-diisopropyl-4-bromophenylacetaldehyde (7.5 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]1[N:24]=[CH:23][C:22]([OH:25])=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:19]2[N:24]=[CH:23][C:22]([OH:25])=[CH:21][N:20]=2)[CH2:16][CH2:17]1
Reactant: Oc1cnc(Cl)nc1
Reactant: c1ccc2cc(CN3CCNCC3)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cnc(N2CCN(Cc3ccc4ccccc4c3)CC2)nc1

Procedure:
To a mixture of 4.50 g. of 1-(β-napthylmethyl)piperazine(as prepared in Example 7), 2.5 g. of 2-chloro-5-hydroxypyrimidine in 30 ml. of dimethylformamide is added 2.0 g. of sodium bicarbonate and the mixture is refluxed for six hours. The mixture is cooled and filtered and the filtrate concentrated to a small volume in vacuo. The concentrate is diluted with 100 ml. of water and the insoluble material is washed with water and hexane to yield 1-(β-napthylmethyl)-4-(5-hydroxy-2-pyrimidinyl)piperazine.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(#N)C>[CH3:18][S:19]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:21])=[O:20]
Reactant: OC[C@@H]1CCCC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Yield: 50.8 %

Procedure:
The thus obtained compound (2) (5.1 g; 35.4 mmol) is dissolved in triethylamine (10.37 g; 103 mmol) and acetonitrile (127 ml), and methanesulfonyl chloride (8.13 g; 71 mmol) is dropwise added thereto under ice-cooling. The resultant mixture is ice-cooled for 1 hour and allowed to react at room temperature for 3 hours. The reaction mixture is washed with water, dried and concentrated, followed by addition of diethyl ether. Precipitated crystals are collected by filtration to give trans-1,2-bis(methanesulfonyloxymethyl)cyclohexane (3) (5.4 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH:2]([CH3:4])[CH3:3].[CH2:32]([NH2:34])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:32]([NH:34][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16])[CH3:33]
Reactant: CCN
Reactant: CC(C)Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (47.0 mg) was prepared by following General Procedure F starting from 1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), ethylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 479 and 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (1H, m), 8.09 (1H, m), 7.91 (1H, m), 7.73 (1H, m), 7.54 (1H, m), 7.37-7.35 (1H, m), 4.04-4.00 (2H, m), 3.32 (2H, m), 2.28 (1H, m), 1.16-1.13 (3H, t), 0.95-0.91 (6H, m), 2 —NH proton signals were not observed.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[C:23]=[O:24]>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:23]([NH:22][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[CH3:33])=[O:24])[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: COc1ccc(N=C=O)c(C)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: ClCCl
Product: COc1ccc(NC(=O)NC2N=C(c3ccccc3)c3cc(Cl)ccc3N(C)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-7-chloro-5-phenyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 1) (0.299 g, 1 mmol) in dichloromethane (15 ml) was added 1-isocyanato-4-methoxy-2-methyl-benzene (0.163 g, 1 mmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.197 g, 42%). 1H-NMR (CDCl3): δ 7.57-7.48 (m, 3H), 7.47-7.44 (m, 1H), 7.39-7.38 (m, 3H), 7.36-7.29 (m, 2H), 6.77-6.73 (m, 2H), 6.71 (d, J=2.8 Hz, 1H), 6.61 (s, 1H), 5.51 (d, J=8.4 Hz, 1H), 3.78 (s, 3H), 3.39 (s, 3H) and 2.29 (s, 3H). MS (ESI) (M+H)+=463.
Reaction SMILES: [CH3:1][SiH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Rh]>[CH3:1][Si:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C=CCCCCCC
Reactant: CCCCCCCCCC[SiH2]C
Agent: [Rh]
Product: CCCCCCCCCC[Si](C)(CCCCCCCC)CCCCCCCC
Reaction time: 0.5 h

Procedure:
There was added 40 grams of methyldecylsilane for a period of 25 minutes to a mixture of 95.5 parts of 1-octene and 8 parts per million of rhodium catalyst as prepared in Example 2. A slow stream of air bubbled into the solution prior to the addition of the methyldecylsilane. The octene solution containing the rhodium catalyst was also preheated to a temperature of 80° C. After an additional 30 minutes of heating, an additional amount of rhodium catalyst was added to the mixture for a final total of 17 parts per million. After 1/2 hour, a quantitative yield of methyldecyldioctylsilane was obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([CH:4]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C#N
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 2-carbamoyl-4,4-difluoro-piperidine-1-carboxylate, 13g, (1.72 g, 6.51 mmol) in CH2Cl2 (50 mL) was added was N,N-triethylamine (2.03 mL, 14.61 mmol) followed by the dropwise addition of (2,2,2-trifluoroacetyl)-2,2,2-trifluoroacetate (1.02 mL, 7.32 mmol). After 15 minutes, the mixture was diluted with aqueous saturated NaHCO3 solution and the layers were separated. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was passed through a plug of silica gel and eluted with 10-30% EtOAc/hexanes to afford the desired product, 13h.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:59][O:60][C:61](=[O:65])[C@H:62]([CH3:64])[NH2:63]>CN(C=O)C>[CH3:59][O:60][C:61](=[O:65])[C@@H:62]([NH:63][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])=[CH:7][C:8]=2[N:9]=1)[CH3:64]
Reactant: COC(=O)[C@H](C)N
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, addition funnel and nitrogen in/outlet was charged with 10 g (25.3 mmol) of bendamustine hydrochloride, 10.6 g (27.8 mmol) of HATU and 100 mL of DMF. The batch was cooled to 1.9° C. where 8.8 mL (6.54 g, 50.6 mmol) of DIPEA was added over 2 minutes. The reaction exothermed to 9° C. and became orange. A solution of 3.57 g (25.6 mmol) of L-alanine methyl ester hydrochloride and 6.2 mL (4.57 g, 35.4 mmol) of DIPEA in 20 mL of DMF was added drop-wise over 10 minutes at 4.9-5.7° C. The reaction was slowly warmed to RT over one hour and stirred for three hours at which time an in process assay indicated the reaction was complete. The batch was quenched onto 400 mL of 1:1 ethyl acetate/DI water. The layers were separated, the organic was washed with 10% sodium hydrogen phosphate (1×200 mL), 8% sodium bicarbonate 91×200 mL) and brine (1×200 mL), before drying over sodium sulfate, filtering and evaporating to dryness in vacuo. The residue was purified by chromatography using 100 g of silica gel 60, 230-400 mesh, eluting with 1% MeOH/MDC (3 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (500 mL) collecting ˜100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 7.1 g (16.0 mmol, 63.3%) of the desired product as a white solid with an HPLC purity of 97.4A %. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=6.92 Hz), 1H), 7.40 (d, J=8.84 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.86 (dd, J=2.32, 8.88 Hz), 4.25 (q, 1H), 3.72 (s, 8H), 3.71 (s, 3H), 3.62 (s, 3H), 2.87 (t, J=7.48 Hz, 2H), 2.25 (t, J=7.52 Hz, 2H), 1.99 (m, 2H), 1.26 (d, J=7.32 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([OH:23])[N:22]=[C:16]4[C:15]=3[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:34]([CH3:36])[CH3:35].O>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([O:23][CH:34]([CH3:36])[CH3:35])[N:22]=[C:16]4[C:15]=3[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(O)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(OC(C)C)nc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the solution of compound 177 in DMF (10 mL) is added anhydrous potassium carbonate (2 eq.) and 2-iodopropane (2 eq.). The resulting mixture is stirred at 60° C. overnight. On cooling the reaction mixture is poured into water (50 mL) and the mixture extracted with dichloromethane, dried over sodium sulfate. The organic solution is concentrated and purified with PTLC to give product 176 as sticky oil. LCMS (M+1) 396.3.
Reaction SMILES: I[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Si:13]([C:17]#[CH:18])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C(OCC)(=O)C.[Cu](I)I>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([C:18]#[C:17][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([NH2:12])=[N:4][CH:5]=1
Reactant: Nc1ncc(C(F)(F)F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a stirred solution of 3-Iodo-5-trifluoromethylpyridin-2-amine (61.38 g, 213 mmol) in anhydrous THF (200 mL) under a nitrogen atmosphere was added Pd(PPh)3Cl2 (1.5 g, 2.1 mmol), and copper iodide (0.406 g, 2.1 mmol) and the reaction mixture degassed under nitrogen. The reaction mixture was cooled in an ice bath and TMS acetylene (36 mL, 256 mmol) was added dropwise over 30 minutes. Upon complete addition the reaction was allowed to warm to room temperature and monitored until the reaction was complete. The mixture was diluted with ethyl acetate (200 mL) and filtered through silica washed through with 4×150 mL ethyl acetate. The filtrates were concentrated and the solid was triturated from heptane (250 mL) to give 56 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1)[N:6]=[C:7]2O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:7]1[C:8]2[C:3](=[C:2]([Cl:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)[CH:4]=[C:5]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:6]=1
Reactant: COc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Chloro-6,7-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol and POCl3 to give (1,5-Dichloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 353 (MH+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1(=O)[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>>[C:12]([CH2:11][CH:10]=[C:9]1[C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[O:2][C:1]2[C:8]1=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=2)([OH:14])=[O:13]
Reactant: O=C1CCC(=O)O1
Reactant: Oc1cccc(O)c1
Product: O=C(O)CC=C1c2ccc(O)cc2Oc2cc(O)ccc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Resorcinol (33.0 g, 0.300 mol) and succinic anhydride (30.0 g, 0.300 mol) were placed in a round bottomed flask and purged with nitrogen. Methanesulfonic acid (150 mL) was added and the solution was stirred at 65° C. for 2 hours under an atmosphere of nitrogen. The reaction mixture was added dropwise to rapidly stirred, ice-cooled water (1 L) with simultaneous addition of 50% aqueous sodium hydroxide to maintain pH 2.5 +/0.5. The product which appeared as a granular precipitate was collected by filtration and rinsed with water (3×100 mL) then acetone (3×100 mL). The product was air-dried then vacuum-dried (vacuum oven) at 110° C. for 18 hours to afford a dark red powder (37.7 g, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:9]1([C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1ccc(-c2ccccc2)c[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
A mixture of 5-bromopyridin-2(1H)-one (500 mg), phenylboronic acid (385 mg), tetrakis(triphenylphosphine)palladium(0) (498 mg), 2M aqueous sodium carbonate solution (2.87 mL) and toluene (7.0 mL) was stirred at 100° C. for 1 hr under microwave irradiation. The reaction mixture was cooled to room temperature, and filtered through celite. To the filtrate was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([C:7]1([C:14]([F:17])([F:16])[F:15])[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[CH2:5][CH3:6].[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[O:29][CH3:30])=[CH:21][C:20]=1F.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[O:29][CH3:30])=[CH:21][C:20]=1[O:13][CH:10]1[CH2:11][CH2:12][C:7]([CH:4]([NH2:3])[CH2:5][CH3:6])([C:14]([F:15])([F:16])[F:17])[CH2:8][CH2:9]1
Reactant: COc1nccc2cc(F)c(Cl)cc12
Reactant: CCC(N)C1(C(F)(F)F)CCC(O)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3ccnc(OC)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
160 mg (4.00 mmol) of NaH were suspended using 3 ml of DMA and a solution of 300 mg (1.33 mmol) of 4-(1-Amino-propyl)-4-trifluoromethyl-cyclohexanol (74) in 3 ml of DMA added. The mixture was stirred for 1 h at ambient temperature. Afterwards, a solution of 282 mg (1.33 mmol) of 7-chloro-6-fluoro-1-methoxy-isoquinoline in 4 ml of DMA was added and the mixture was stirred for 3 h at ambient temperature. The mixture was then poured into 100 ml of a saturated aqueous solution of NaHCO3 and extracted three times using 50 ml of ethyl acetate each. The organic layer was washed twice using 50 ml of water, dried using MgSO4 and evaporated. Chromatography on silica gel using ethyl acetate/n-heptane, followed by chromatography on silica gel using t-butylmethyl ether/n-heptane 1:1+1% acetic acid yielded 162 mg of the desired product as the acetate. Rt=0.77 min (Method P).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O.CCOC(C)=O>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)[CH3:30])[N:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: CC(N)c1ccc(N2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1)c1ccc(N2CCCCC2)cc1
Yield: 36.6 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (93 mg, 0.38 mmol) and 1-(4-(piperidin-1-yl)phenyl)ethanamine (410 mg, 2.01 mmol, 5.2 equiv) in DMSO (1 mL) was heated at 110° C. for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 100%) provided (4S)-4-isopropyl-3-(2-((1-(4-(piperidin-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (57 mg) in 36% yield. A mixture of (4S)-4-isopropyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one was resolved on a column (AD-H 4.6×100 mm) using 5 to 55% MeOH with 0.2% Et2NH in CO2 to give (S)-4-isopropyl-3-(2-((R)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][NH:8][C:7](=O)[C:6]=2[CH:15]=1.CCN(CC)CC.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:7]1[C:6]2[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
As illustrated in the scheme above, 7-chloro-3,4-dihydro-1-methyl-1H-1,4-benzodiazepine-2,5-dione (5.00 g, 22.3 mmol) was suspended in POCl3 (100 mL) and heated at 100° C. for 30 min. The reaction was cooled and concentrated in vacuo. Traces of POCl3 were removed by adding toluene and concentrating the mixture in vacuo (2×). The residue was dissolved in CH2Cl2, the solution was cooled to 0° C., and Et3N (6.8 mL, 48.8 mmol) was added dropwise. The mixture was stirred for 1 h and allowed to slowly warm to room temperature, and was then concentrated in vacuo once again. The residue was purified by silica gel column chromatography (5:1 CH2Cl2:EtOAc+0.5% Et3N) to provide the title compound as an orange solid (4.68 g, 86%). 1H-NMR (CDCl3): δ 7.79 (d, J=2.5 Hz, 1H), 7.55 (dd, J=2.4 Hz, J=8.9 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.67 (br s, 1H), 3.72 (br s, 1H), 3.39 (s, 3H). MS (ESI) (M+H)+=243.