Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:8][N:7]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH2:12][C:11]([NH:10][CH:9]2[CH2:8][N:7]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:6]=[C:5]2[CH2:3][OH:2])=[O:21])=[CH:15][CH:16]=1
Reactant: COC(=O)c1nn(CCc2ccccc2)cc1NC(=O)CSc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CSc1ccc(Br)cc1)NC1CN(CCc2ccccc2)N=C1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
150 mg (0.3 mM) of the compound obtained in Example 1 was dissolved in 2 ml of tetrahydrofuran to which 62 mg (0.9 mM) of lithium aluminum hydride was added dropwise at 0, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was terminated, the resultant was acidified with 1N hydrochloric acid solution, extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure, to obtain 96 mg (68.1%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.C(N(CC)CC)C.Br[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32](=[O:33])[O:31]1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O:20][CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32](=[O:33])[O:31]2)=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C(=O)OC1OC(=O)c2ccccc21)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a solution of 8.4 g of 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid in 40 ml of chloroform and 3.4 of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to yield the phthalidyl 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionate; yield 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]2[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: Fc1ccccc1CCBr
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncn(CCc4ccccc4F)c-3n2)c1

Procedure:
The title compounds were prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-2-fluoro-benzene by a procedure similar to examples 1 and 2. The isomers were separated by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-[2-(2-fluoro-phenyl)-ethyl]-9H-purin-6-ylamine: Yield 37%, 1H NMR (DMSO-d6) δ 8.27 (s, 1H), 7.28-7.22 (m, 1H), 7.12-7.00 (m, 4H), 6.87 (dd, J=8.8, 3.2 Hz, 1H), 6.55 (d, J=3.2 Hz, 1H), 4.45 (t, J=6.8, Hz, 2H), 3.72 (s, 3H), 3.62 (s, 3H), 3.08 (t, J=6.8, 2H); LC-MS [M+H]+ 426.1. 8-(2,5-Dimethoxy-phenylsulfanyl)-3-[2-(2-fluoro-phenyl)-ethyl]-3H-purin-6-ylamine: Yield, 18%, 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 8.19 (bs, 2H), 7.33-7.08 (m, 7H), 4.55 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.23 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 426.1.
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1.[NH4+].[Cl-]>CCO.O.[Fe]>[F:18][C:4]([F:3])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1
Reactant: CC(F)(F)CCCCn1ccc([N+](=O)[O-])n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(F)(F)CCCCn1ccc(N)n1
Temperature: 75 °C
Reaction time: 0.67 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-(5,5-difluoro-hexyl)-3-nitro-1H-pyrazole (400 mg, 1.72 mmol), iron powder (290 mg, 5.15 mmol) and NH4Cl (463 mg, 8.58 mmol) in a mixture of EtOH (8.0 mL) and water (4.0 mL) was stirred at 75° C. for 40 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (30 mL) was added followed by 1M NaOH (30 mL). The aq. layer was extracted with CH2Cl2 (2×30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.66 min; [M+H]+=204.25.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[CH3:18][S:19]([CH2:22][C:23](=O)[CH3:24])(=[O:21])=[O:20].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:23]([CH3:24])[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Reactant: CC(=O)CS(C)(=O)=O
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Yield: 27.2 %

Procedure:
(2-Amino-5-bromo-phenyl)-(4-fluoro-phenyl)-methanone (compound of example A.1) (4 g, 14 mmol), methanesulfonylacetone (2.78 g, 20 mmol) and sodium tetrachloroaureate(III) dihydrate (0.27 g, 0.7 mmol) were heated at reflux in 2-propanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), 1 N NaOH (2×) and NaCl (1×). The crude product was purified by chromatography in heptane/ethyl acetate with a gradient from 100:0 to 70:30. One obtained a light brown solid (1.5 g, 28%). MS: m/z=394 (M).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-fluorobenzenesulfonyl chloride as starting materials in 16% yield. LCMS for C30H30ClFN7O3S (M+H)+: m/z=622.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:12]1[C:13](=[O:20])[O:14][C:15]([CH3:19])=[CH:16][C:17]=1[OH:18])[CH3:11]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:20])[CH:12]([C:17](=[O:18])[CH2:16][C:15](=[O:14])[CH3:19])[C:10]([CH3:11])=[N:9]1
Reactant: CC(=NNc1ccccc1F)c1c(O)cc(C)oc1=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)C1C(=O)N(c2ccccc2F)N=C1C
Yield: 100 %

Procedure:
Heat at reflux for 1 hour 3-{1-[(2-fluoro-phenyl)-hydrazono]-ethyl}-4-hydroxy-6-methyl-pyran-2-one (0.045 g, 0.163 mmol) in acetic acid (0.3 ml). Add heptane (3 ml) and evaporate the mixture to dryness to give 1-[1-(2-fluoro-phenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione (0.045 g, 0.163 mmol). Use this material for the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Br:11][C:12]1[C:13]([CH3:17])=[N:14][NH:15][CH:16]=1>>[Br:11][C:12]1[C:13]([CH3:17])=[N:14][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:16]=1
Reactant: Cc1n[nH]cc1Br
Reactant: Clc1ccnc2[nH]ccc12
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Temperature: 130 °C
Yield: 87.5 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) and 4-bromo-3-methyl-1H-pyrazole (0.10 g, 0.00066 mol) was heated at 130° C. overnight. The reaction mixture then was subjected to column chromatography (eluting with 5% MeOH/DCM, 0.5% NH4OH, on silica gel) to give 80 mg pale yellow solid which was triturated with MeOH (1.5 mL) to yield the product as a pale yellow solid (44 mg, 44% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=O)[CH2:21][CH2:22][CH2:23][CH3:24])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N1CCOCC1.ClC(OCC)=O.[N+](=C)=[N-]>C1COCC1.C(OCC)C>[C:25]([CH:20]([NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:21][CH2:22][CH2:23][CH3:24])(=[O:27])[CH3:28]
Reactant: CN1CCOCC1
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Agent: C=[N+]=[N-]
Agent: CCOC(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 150 g of anhydrous THF were dissolved 5.4 g of N-benzyloxycarbonyl-L-leucyl-L-norleucine prepared in the same manner as in Example 1-(b) and 3.4 ml of N-methylmorpholine, and 1.6 g of ethyl chloroformate was added thereto under ice-cooling, followed by stirring at 0° C. for 30 minutes. The reaction mixture was added to an excess diazomethane solution in diethyl ether, and the solution was allowed to stand at 0° C. for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 4.0 g of the titled compound as a colorless crystal.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][CH2:12][C:13]1[N:14]=[CH:15][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=1)([CH3:9])[CH3:8].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH3:9][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[CH:17]=1)([CH3:6])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(COCC[Si](C)(C)C)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)cn1COCC[Si](C)(C)C
Temperature: -60 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
nBuLi (2.2 mL of a 1.9M solution in hexanes, 4.2 mmol) was added dropwise to a −78° C. solution of 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (1.20 g, 3.5 mmol) in THF (10 mL). The reaction mixture was stirred at −60° C. for 2 h, cooled to −78° C. and ethyl chloroformate (0.70 mL, 7.3 mmol) was added dropwise. The solution was allowed to warm to RT, quenched by addition of sat'd NaHCO3 and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-50% EtOAc/hex) to afford the title compound (1.21 g, 83%) as a light brown oil and as a mixture of the expected two isomers. Major isomer: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05 (s, 1H), 5.90 (s, 2H), 4.75 (s, 2H), 4.34-4.43 (m, 2H) 3.48-3.58 (m, 2H) 1.40 (t, J=7.15 Hz, 3H), 0.91-0.89 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H), −0.06 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[CH3:18]>CCO.[Pd]>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH:7]=1)[NH2:15]
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cc(-c2cccc(F)c2)cc1F
Reaction time: 48 h
Yield: 43.9 %

Procedure:
A solution of 1-fluoro-5-(3-fluorophenyl)-2-methyl-3-nitro-benzene (4.0 g, 16.0 mmol, 1.0 eq) in EtOH (80 mL) was added to Pd/C (10%, 0.8 g) and the mixture stirred under hydrogen for 48 h. The catalyst was removed by filtration through celite and the compound purified by silica gel chromatography (petroleum ether:EtOAc, 20:1 to 10:1) to give the title compound as a white solid (1.54 g, 44%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[CH3:37][NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][N:40]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([N:38]([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][N:40]=2)[CH3:37])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Reactant: CNc1ccc(C(=O)OC)cn1
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cn2)C1
Yield: 60 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 6-methylaminonicotinate in 60% yield according to a procedure similar to that described in Example 29 (i).
Reaction SMILES: Br[CH:2]1[CH2:4][C:3]1([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(C)([O-])C.[K+].C(OCC)C.O>CS(C)=O>[CH3:11][C:3]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:4]=[CH:2]1
Reactant: CC1(c2ccccc2)CC1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CC1(c2ccccc2)C=C1
Temperature: 72 °C
Yield: 91.5 %

Procedure:
To a solution of 1.56 g (0.00739 mol) of 2-bromo-1-methyl-1-phenylcyclopropane in 5 ml of dimethylsulfoxide was added 1.429 g (0.0127 mol) of potassium tert-butoxide. After the reaction was heated to 72° C. for 4 hours, diethyl ether and water were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 0.88 g of 70% pure 3-methyl-3-phenylcyclopropene as an oil. The major byproduct (roughly 20%) was 1-methyl-1-phenylcyclopropane.
Reaction SMILES: [H-].[Na+].O[C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[C:5]1=[O:14])[CH2:11]2.IC.C1C[O:20][CH2:19]C1>>[CH3:19][O:20][C:10]12[CH2:12][CH:6]3[CH2:7][CH:8]([CH2:13][CH:4]([C:5]3=[O:14])[CH2:11]1)[CH2:9]2
Reactant: C1CCOC1
Reactant: O=C1C2CC3CC(C2)CC1(O)C3
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a suspension of NaH (60% dispersed in nujol, 0.96 g, 24 mmol) in THF (40 mL) cooled to ice bath temperature was added hydroxyadamantanone (3.32 g, 20 mmol) dissolved in THF (40 mL) via a syringe over a period of 15 minutes. After stirring the reaction mixture for 30 min., iodomethane (1.38 mL, 22 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 h until TLC revealed completion of the reaction. Excess NaH was quenched by adding saturated aq. NH4Cl solution to the ice cooled reaction mixture. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain crude reaction mass which was purified by column chromatography to yield 5-methoxyadamantan-2-one (3.0 g) in 83% yield. m/z (M+1), 181; 1H NMR (CDCl3) 300 MHz δ 3.26 (s, 3H), 2.67-2.61 (m, 2H), 2.39-2.33 (m, 1H), 2.20-1.93 (m, 10H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH2:9])=[O:8])=[O:4].[CH:10](=O)[CH3:11]>CO>[CH3:10][CH:11]1[NH:1][CH2:2][C:3](=[O:4])[N:5]1[CH2:6][C:7]([NH2:9])=[O:8]
Reactant: NCC(=O)NCC(N)=O
Reactant: CC=O
Solvent: CO
Product: CC1NCC(=O)N1CC(N)=O

Procedure:
A solution of glycylglycinamide (0.5 g) and acetaldehyde (0.4 ml) in methanol (5 ml) was stirred at room temperature for 8 hours. Evaporation of the solvent gave a residue which was chromatographed on a silica gel column (eluant dichloromethane/methanol 75:25). The selected fractions were collected, evaporated to give the title compound (Rf=0.3, dichloromethane/methanol 7:3, silica gel plates). Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=142 (M+ -CH3), 99.
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)CO)(C)(C)C.C([O:34][CH2:35][C@@H:36]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])[C:37]1[C:38]([C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([C:48]([F:51])([F:50])[F:49])[CH:41]=[CH:40]2)(=O)C(C)(C)C>>[C:60]([O:59][C@@H:36]([C:37]1[C:38]([C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([C:48]([F:49])([F:51])[F:50])[CH:41]=[CH:40]2)[CH2:35][OH:34])([CH3:63])([CH3:61])[CH3:62]
Reactant: Cc1cc2nc(C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(Cl)cc2n1
Product: Cc1cc2nc(C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
Following the procedure used to prepare compound 1K of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethyl pivalate (7H) was used instead of compound 1J. LCMS-ESI+ (m/z): 438.2, 440.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>O1CCCC1>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH:16][S:33]([C:31]3[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=3)(=[O:35])=[O:34])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:18][CH3:19]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(CN)cc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)[C@@H]1CCc2ccc(CNS(=O)(=O)c3cn(C)cn3)cc2C1
Temperature: 15 °C

Procedure:
Using procedure 9, (R)-7-(dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenemethanamine 9 and triethylamine in dry tetrahydrofuran was cooled to 15° C., and 1-methylimidazole-4-sulfonyl chloride was added. After extraction, purification by flash chromatography (tetrahydrofuran/ethyl acetate) gave the title compound as an oil. [α]D =+46° (25° C., CH3OH, c=0.7458).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].O.NN>[Ni]>[NH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)[N:14]=[CH:13][N:12]=[C:11]2[NH:10][C:4]1[C:5]([F:9])=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCCN1CCOCC1
Agent: [Ni]
Agent: NN
Solvent: O
Product: Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCCN1CCOCC1
Yield: 75 %

Procedure:
4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitroquinazoline was reacted with hydrazine hydrate and Raney®Nickel, as described hereinabove, to produce 6-amino-4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]quinazoline in 75% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[C:24]1([C:30]#[C:31][CH:32]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:32]([C:31]#[C:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=CC#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: C(#Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (38.0 mg, 0.119 mmol) in dimethylformamide (2 mL) was added phenylpropargylaldehyde (ca. 90%, 22.6 μL, 0.360 mmol) and oxone (73.2 mg, 0.119 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (20.0 mg, 49% yield) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[BH4-].[Na+]>CO>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCCC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Yield: 99.7 %

Procedure:
A solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone (152 mg; 0.256 mmol) and sodium borohydride (22 mg; 0.582 mmol) in methanol (1.5 mL) was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate, washed twice with water and then brine. The organic layer was dried sodium sulfate and concentrated under reduced pressure. The residue was purified over 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 20-50% ethyl acetate in heptane) to give 152 mg (99.7% yield) of the title compound as a colorless gum. MS (ES+): Calc: 595.5, Found: 596.1 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.66 (s, 2H), 7.57 (d, J=8.30 Hz, 1H), 7.55 (d, J=8.30 Hz, 1H), 7.36 (s, 1H), 4.88 (d, J=15.77 Hz, 1H), 4.79 (d, J=15.77 Hz, 1H), 4.76 (d, J=15.77 Hz, 1H), 4.70 (d, J=16.18 Hz, 1H), 4.66 (d, J=7.05 Hz, 1H), 4.21 (s, 3H), 2.20 (bs, 1H), 1.94 (d, J=12.45 Hz, 1H), 1.78 (m, 1H), 1.69-1.51 (m, 4H), 1.2-0.88 (m, 4H).