Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH2:33][C:34]#[N:35])([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2([CH2:33][C:34]#[N:35])[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)=[CH:31][CH:30]=1
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCC(Br)C1=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3(CC#N)c2ccc(Cl)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (40.2 mg, 0.15 mmol) and of [3-bromo-1-(4-chloro-phenyl)-2-oxo-cyclohexyl]-acetonitrile (50.0 mg, 0.15 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol/concentrated aqueous NH4OH solution (9:1:0.1 v/v/v) as eluent to yield the title compound (74 mg, 99%) as a yellow gum. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.56 (s, 1H), 7.37 (s, 1H), 7.28 (d, 2H), 7.16 (d, 2H), 6.89 (s, 1H), 3.76 (s, 3H), 3.19 (d, 1H), 3.03 (d, 1H), 2.72 (m, 2H), 2.30 (s, 3H), 2.19 (m, 1H), 1.89 (m, 2H), 1.60 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[O:21][C:22]([C:28]([F:31])([F:30])[F:29])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]([F:31])([F:29])[F:30])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Product: Cc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)c(C(F)(F)F)o1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a colorless foam. MS (ISP): m/z=437.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:8][C:6]1[CH:7]=[CH:2][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)(=[O:20])=[O:19])[C:4]=2[CH:5]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)c1

Procedure:
The title compound was prepared from N-[1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-3-methoxybenzenesulfonamide (454 mg, 1.12 mmol), anhydrous N,N-dimethylformamide (2 mL), and potassium carbonate (311 mg, 2.25 mmol) according to the procedure and in the same manner as described in Example 105, step d, and the product (426 mg, 99%) isolated as a white solid, m.p. 115-117° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].O>CN(C)C=O>[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)c1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(NC(=O)Nc2cccc(C(=O)O)c2)cc1
Reaction time: 20 h
Yield: 85.3 %

Procedure:
A solution of 3-aminobenzoic acid (0.46 g, 3.4 mmol) in dimethylformamide (20 mL) at 0° C. was treated with 4-isopropylphenyl isocyanate (0.59 mL, 3.7 mmol). After stirring for 20 h, the solution was poured into 200 mL water, and the resulting precipitate was collected by filtration, washed with water and tetrahydrofuran, and dried under vacuum to afford the title product (0.85 g, 2.9 mmol, 85%) as a powder (m.p. 295-300° C.). TLC Rf 0.20 (ethyl acetate). 1H NMR (d6-DMSO, 300 MHz): δ 8.82 (1H, s), 8.57 (1H, s), 8.09 (1H, t, J=1.8 Hz), 7.58 (1H, dd, J=8.1, 1.1 Hz), 7.51 (1H, d, J=7.8 Hz), 7.36 (1H, t, J=8.0 Hz), 7.34 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz), 2.82 (1H, heptet, J=6.9 Hz), 1.17 (6H, d, J=6.9 Hz). MS (ES+): 299
Reaction SMILES: [O:1]=[C:2]([CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.[BH4-].[Na+]>CO>[OH:1][CH:2]([CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:5]=1
Reactant: CC(=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 86.5 %

Procedure:
To a stirred solution of tert-butyl 4-(2-oxopropyl)pyridin-2-ylcarbamate (46) (300 mg, 1.20 mmol) in methanol (12 mL) at 0° C., under nitrogen, was added sodium borohydride (45.3 mg, 1.20 mmol). After 10 min the reaction mixture was warmed to RT and stirring continued for 75 min. The mixture was evaporated in vacuo and the residue was taken up into EtOAc and washed with aqueous NaHCO3 solution. The aqueous layer was extracted twice with EtOAc and the combined organic extracts were washed with brine, then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, 10-80% EtOAc in isohexane, gradient elution) to afford the title compound (47) (262 mg, 85%) as a white powder; m/z 253.0 (M+H)+ (ES+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30]Cl)[CH2:25][CH2:24]1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:30][C:29]([N:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)=[O:32])[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cc1
Product: CC(C)c1ccc(N(CC(=O)N2CCOCC2)C(=O)C2CCCc3ccccc32)cc1
Yield: 60 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-morpholino-2-oxoethyl chloride (0.33 g) as starting materials, N-(4-isopropylphenyl)-N-(2-morpholino-2-oxoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43g) was obtained. melting point: 180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:36]5[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2nn3c(-c4cnc(N)nc4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 14.3 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (82 mg, 0.147 mmol, 1 eq), 2-aminopyrimidine-5-boronic acid pinacol ester (48 mg, 0.22 mmol, 1.5 eq), 1,4-dioxane (4 mL), K2CO3 (61 mg, 0.441 mmol, 3 eq), H2O (1.6 ml) and Pd(PPh3)2Cl2 (10 mg, 0.0147 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). Solvents were removed and the residue was purified in an Isolute Flash Si II column (0-3% MeOH in DCM). The product obtained was triturated with EtOAc and filtered. The filtrate was evaporated and the residue was triturated with acetone. The filtrate was evaporated. The residue was purified by column chromatography (EtOAc) to give the desired product (11 mg, 14%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.90 min, [M+H]+ m/z 524.2; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 2H), 7.43 (m, 2H), 7.36 (dd, J=8.3, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.26 (s, 2H), 4.53 (m, 1H), 3.93 (s, 3H), 3.75 (m, 2H), 3.29 (m, 2H), 1.93 (m, 2H), 1.81 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([N:30]([CH3:37])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)C.ClCCl.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>[F:33][C:32]([F:34])([F:35])[C:31]([N:30]([C:26]1[CH:27]=[C:28]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:24][CH:25]=1)[CH3:37])=[O:36]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: CN(C(=O)C(F)(F)F)c1cccc(Br)c1
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: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccc(N(C)C(=O)C(F)(F)F)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), N-(3-bromo-phenyl)-2,2,2-trifluoro-N-methylacetamide (0.282 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.020 g) in ethanol (3 ml) with heating at 90° C. for 2 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane. The product obtained was dissolved in dichloromethane (3 ml), and cooled to 0° C. Trifluoroacetic anhydride (0.09 ml) was added dropwise, the reaction mixture stirred for 1 hour at room temperature, before concentrating under reduced pressure. Methanol (10 ml) and water (10 ml) were added and the resulting mixture was stirred for 30 minutes at room temperature. The product was extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil (0.148 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3O)c(Cl)cc2F)c1=O
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)OC(C)(C)C)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 4106.7 %

Procedure:
First, 0.20 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol was dissolved in 2 ml of N,N-dimethylformamide, to which 0.083 g of potassium carbonate was added, and the mixture was stirred at room temperature for 50 minutes. Then, 0.077 g of t-butyl chloroacetate was added, and the mixture was stirred at 40° C. to 60° C. for 2 hours. After left for cooling, ice water was poured into the reaction mixture, and after addition of ethyl acetate and saturated aqueous sodium chloride solution, the mixture was subjected to phase separation. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to give 10.39 g of t-butyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-121).
Reaction SMILES: [CH3:1][CH:2]1[CH:9]([CH3:10])[N:8]2[C:4](=[C:5]([CH:23]([CH:25]3C(=O)O[C:28](C)([CH3:32])[O:27][C:26]3=[O:34])[CH3:24])[C:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH2:28]([O:27][C:26](=[O:34])[CH2:25][CH:23]([C:5]1[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]2[C:4]=1[CH2:3][CH:2]([CH3:1])[CH:9]2[CH3:10])[CH3:24])[CH3:32]
Reactant: CC1Cc2c(C(C)C3C(=O)OC(C)(C)OC3=O)c(-c3ccccc3)c(-c3ccccc3)n2C1C
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(C)c1c(-c2ccccc2)c(-c2ccccc2)n2c1CC(C)C2C

Procedure:
2.5 mmoles of 59b are dissolved in a mixture of 20 ml absolute pyridine and 2 ml of absolute ethanol and upon addition of some copper powder the batch is reacted as described for 60a. Purification is by column chromatography (silica gel, n-hexane/CH2Cl2 2+1) in isolation.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][C:30]1[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:33]5[N:34]=[CH:35][C:30]([Cl:29])=[N:31][CH:32]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cnc(Cl)cn4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 2,5-dichloropyrazine. Mass spectrum (ESI) 427.9 (M+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.B(O)O>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: OBO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccccc3)n3nccc3n2)cc1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D) and the corresponding boronic acid or ester were used as starting material. The product was obtained a yellow solid (16%). 1H NMR (400 MHz, MeOD) δ ppm 1.57 (s, 6H) 6.55 (d, J=2.27 Hz, 1H) 7.57-7.63 (m, 3H) 7.68 (d, J=8.59 Hz, 2H) 7.99 (d, J=8.84 Hz, 2H) 8.04-8.08 (m, 3H) 8.09 (d, J=2.27 Hz, 1H). ESI-MS: m/z 373.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:12]2=[C:13]([CH2:20][CH2:21][OH:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1(O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([N:8]1[CH2:24][CH2:23][C:12]2=[C:13]([CH2:20][CH2:21][O:22][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1c2n(c3ccccc13)CCN(Cc1ccccc1)CC2
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3c(CCOc4ccccc4)c4ccccc4n3CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
(Chart D, Step 3): A dry round bottom flask is charged with 2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanol (420 mg, 1.31 mmol), phenol (185.2 mg, 1.97 mmol), triphenylphosphine (413 mg, 1.57 mmol), and THF (12 mL, freshly distilled). After cooling the reaction to 0° C., diethylazodicarboxylate (DEAD) (0.248 mL, 1.57 mmol) is added dropwise via syringe. The ice bath is allowed to expire, and the reaction is stirred at ambient temperature for 18 hours. The reaction is quenched with 30% H2O2 (0.20 mL), diluted with ethyl ether and washed twice with 10% aq. NaHSO3. The organics are washed twice with aq. 1N NaOH, once with brine, dried with Na2SO4, filtered and concentrated to 1.08 g of a crude yellow solid. Purification of the crude using silica gel and 10% ethyl acetate in heptane as the eluent gives 392 mg (76%) of 3-benzyl-11-(2-phenoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a pale yellow oil. HRMS (FAB) calculated for C27H28N2O+H1 397.2280, found 397.2271.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[BH4-].[Na+].O.CCOC(C)=O>CO>[CH2:9]([O:8][C:6]([CH:4]1[CH2:5][CH:3]1[CH2:1][OH:2])=[O:7])[CH3:10]
Reactant: CCOC(=O)C1CC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 2-formyl-1-cyclopropanecarboxylate (2 ml, 15.11 mmol) was dissolved in methanol (35 ml) and cooled to 0° C. under N2. Sodium borohydride (1.2 g, 31.7 mmol) was added in portions and resulting solution stirred at 0° C. for 2 h. The solution was then diluted by the dropwise addition of water, followed by the addition of EtOAc (100 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give the title compound. TLC: 20% EtOAc/hexanes, high Rf: 0.35, low Rf: 0.3.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O.Br[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([N+:48]([O-:50])=[O:49])[CH:42]=1>>[CH3:47][C:44]1[CH:45]=[CH:46][C:41]([NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[C:5]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:4][CH:3]=2)=[CH:42][C:43]=1[N+:48]([O-:50])=[O:49]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Sc2ccccc2)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(Nc2ccc(Sc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1[N+](=O)[O-]
Yield: 90 %

Procedure:
A mixture of 23.2 parts of 1-amino-4-phenylmercaptoanthraquinone, 9 parts of sodium carbonate and 150 parts of nitrobenzene is heated to the boil, whilst stirring, and dehydrated in the course of one hour, whilst a stream of nitrogen is passed through. 30 parts of 4-bromo-2-nitrotoluene and 1 part of copper-I chloride are then added to the mixture, which has been cooled to 150°. After stirring for 15 hours at 150° and, at the same time, passing a moderate stream of nitrogen through the mixture, the reaction mixture is allowed to cool. The reaction product is precipitated by gradually adding 200 parts of methanol and is filtered off, washed with methanol and hot water and finally boiled thoroughly with 5% strength hydrochloric acid. This gives 29.5 parts (90% of theory) of 1-(4'-methyl-3'-nitrophenylamino)-4-phenylmercaptoanthraquinone with a melting point of 199°-201°. The colorant dyes polyester violet in bulk.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=O)[NH2:2].Cl.[OH-].[Na+]>B.C1COCC1>[NH2:2][CH2:1][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCCN1Cc1ccc(Cl)cc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC1CCCN1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
2-carbamoyl-1-(4-chlorobenzyl)pyrrolidine was dissolved in 1M BH3-THF (9.4 mL) and heated to 70° C. After 16 h and 25 h, additional 0.5 equiv. of 1M BH3-THF were added. After 40 h, 1 N aqueous HCl solution (14 mL) was added and the reaction was heated to reflux for 3 h, 3 N aqueous HCl solution (6 mL) was added and the reaction was heated for an additional 3 h. The reaction mixture was cooled to 25° C., basicified with 4 N aqueous NaOH solution and extracted with CH2Cl2 (4×15 mL). Chromatography (SiO:, 8:1:1 −PrOH—H O—NH4OH) afforded 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (1.21 g, 86%).
Reaction SMILES: O1CC1[CH2:3][C:4]12[O:10][CH:5]1[CH:6]=CC=[CH:9]2.[CH2:12]([CH2:14][NH2:15])[OH:13]>O>[OH:13][CH2:12][CH2:14][NH:15][CH2:6][CH:5]([OH:10])[CH:4]([CH3:3])[CH3:9]
Reactant: C1=CC2OC2(CC2CO2)C=C1
Reactant: NCCO
Solvent: O
Product: CC(C)C(O)CNCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound could be made in the same manner as Example 1 using the appropriate epoxide: 1 eq. of (2,3-Epoxypropyl)benzene oxide and 4 eq. ethanol amine The above compound could be made in the following manner: stirred at room temperature overnight. The solution could be poured into water and the water is extracted with dichloromethane. The combined dichloromethane layers could be washed with brine and concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12](N(OC)C)=[O:13])=[CH:10][CH:9]=1.C([Li])(C)(C)C>C(OCC)(=O)C>[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12]([C:2]2[CH:3]=[N:4][NH:5][CH:6]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: Brc1cn[nH]c1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1)c1cn[nH]c1

Procedure:
The title compound was prepared from 4-bromopyrazole and 4-bromo-N-methoxy-N-methylbenzamide following the general method of Method 1 using two equivalents of t-butyllithium as the base. The crude product was re-crystallized from ethyl acetate and petroleum ether affording 0.28 g (44% yield) of the title compound as colorless crystals: mp 213-215° C.; 1H NMR (300 MHz, CD3OD) δ 7.95 (br s, 2 H), 7.58 (m, 2 H), 7.51 (m, 2 H); 13C NMR (100.5 MHz, CD3OD) δ 190.3, 139.6, 138.8, 133.4, 132.1, 128.6, 123.1; MS (TSP) m/z 251, 253 (M+1).