Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:20][CH2:19]1.[CH:34]1(N2C(C(O)=O)=NC3C2=NC=NC=3N2CCC(N3C4C=CC=CC=4NC3=O)CC2)C[CH2:35]1.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH:1]1([N:2]2[C:10]([C:11]([NH:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:12])=[N:9][C:8]3[C:3]2=[N:4][CH:5]=[N:6][C:7]=3[N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:20][CH2:19]2)[CH2:35][CH2:34]1
Reactant: O=C(O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1
Reactant: Cn1c(C(=O)NCC2CC2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCC1CC1)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1

Procedure:
9-Cyclopropyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide was prepared in the same manner as 9-methyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide. The 9-cyclopropyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (0.09 g, 0.21 mmol) was treated with cycloproplyamine (0.305 g, 0.429 g mmol, 0.037 mL), HATU (0.163 g, 0.429 mmol), diisopropylethylamine (0.110 g, 0.858 mmol, 0.149 mL) and DMA (8 mL) at room temperature for 18 hours. Purification by preparative reverse phase HPLC (eluting with 0.01% aqueous ammonium acetate and acetonitrile) yielded 0.057 g of 9-cyclopropyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (broad s, 1H), 8.63 (t, 1H), 8.07 (s, 1H), 6.98 (m, 1H), 6.6.716 (m, 3H), 5.11 (broad s, 2H), 4.30 (m, 1H), 3.38 (m, 1H), 3.13 (dd, 1H), 2.93 (t,4H), 2.07 (t, 2H), 1.63 (m, 2H), 0.83 (m, 4H), 0.18 (m, 2H), 0.02 (m, 2H).MS (EI) for C25H28N8O2: 473 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:39][O:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[CH:49]([NH:51][C:52]1[CH:61]=[CH:60][C:59]3[C:54](=[CH:55][CH:56]=[C:57]([NH2:62])[CH:58]=3)[N:53]=1)[CH2:48][CH2:47][CH2:46]2>ClCCl.CN(C)C=O.O>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:62][C:57]1[CH:58]=[C:59]2[C:54](=[CH:55][CH:56]=1)[N:53]=[C:52]([NH:51][CH:49]1[C:50]3[C:45](=[CH:44][CH:43]=[CH:42][C:41]=3[O:40][CH3:39])[CH2:46][CH2:47][CH2:48]1)[CH:61]=[CH:60]2)=[O:5]
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CN(C)C)ccc3n1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
N,N-Dimethylglycine (49 mg, 0.48 mmol), N,N-diisopropyl ethyl amine (217 mg, 1.68 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (220 mg, 0.69 mmol) were dissolved in dichloromethane (6 mL) and dimethylformamide (1.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. rac-N2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine (150 mg, 0.47 mmol) was added and stirred was continued overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined organic phases were dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol 100:0→90:10). The title compound (147 mg, 77%) was obtained as a light brown solid; MS: m/e=405.5 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:22]([NH:24][N:25]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:26](=[O:52])[C@@H:27]([CH2:46][O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>ClCCl.N1CCCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:22]([NH:24][N:25]([CH2:53][CH:54]([CH3:55])[CH3:56])[C:26](=[O:52])[C@@H:27]([CH2:46][O:47][C:48]([CH3:49])([CH3:51])[CH3:50])[NH2:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H](N)COC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A solution of 0.86 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethyloxycarbonyl)-O-tert.butyl-D-seryl]-4-methylvalerohydrazide in a mixture of 8 ml of dichloromethane and 2 ml of piperidine was stirred at room temperature for 3 hours. The solution was evaporated and the residue was treated with diethyl ether. The ethereal solution was filtered and evaporated. Chromatography on silica gel using methanol/dichloromethane (1:19) for the elution followed by evaporation gave 0.39 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(O-tert.butyl-D-seryl)-4-methylvalerohydrazide in the form of a gum.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([O:16][CH3:17])[CH:6]=2.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:3](=[O:27])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([O:16][CH3:17])[CH:6]=2
Reactant: COC(=O)c1cc2nc(Cl)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2nc(Cl)c(=O)[nH]c2cc1OC
Temperature: 25 °C

Procedure:
Methyl 3-chloro-7-methoxy-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (6.0 g, 15.43 mmol) was added to sulfuric acid (conc, 15 mL) in several batches with stirring at room temperature and then stirred for 10 minutes. The resulting solution was diluted with ice-water (100 mL) and extracted with ethyl acetate (3×200 mL). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-chloro-7-methoxy-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (2.5, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:15][NH:16][CH3:17]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([N:16]([CH3:17])[CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
To a solution of 5-Chloro-2-nitro-benzenesulfonyl chloride (2.0 g, 0.0078 mol) (Lebegue, N.; Gallet, S.; Flouquet, N.; Carato, P.; Pfeiffer, B.; Renard, P.; Leonce, S.; Pierre, A.; Chavatte, P.; Berthelot, P. J. Med. Chem. (2005), 48(23), 7363-7373) in Tetrahydrofuran (10 mL, 0.1 mol) was added 2.0 M of Dimethylamine in Tetrahydrofuran (7.8 mL). The mixture was stirred for 18 hours. The mixture was evaporated and water was added then agitated until a solid precipitated. The solid was filtered and dried. 5-Chloro-N,N-dimethyl-2-nitro-benzenesulfonamide isolated as yellow solid (1.87 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 37 %

Procedure:
Commercially available 4-fluorobenzenesulfonyl chloride (1.00 g, 5.14 mmol) was suspended in water (15 mL), and N-methylpiperazine (0.68 mL, 6.17 mmol) and potassium carbonate (1.56 g, 11.3 mmol) were added, followed by stirring at room temperature for 14 hours under nitrogen atmosphere. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL), and subsequently the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (491 mg, yield 37%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=1)[N:10]=[C:9]2[NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:32]=[CH:31]2.[H][H]>CO.[Pd]>[NH2:24][C:20]1[CH:19]=[C:18]([C:11]2[N:10]=[C:9]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[N:32]=[CH:31]4)[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:44])[CH:7]=3)[N:12]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN(C)C
Temperature: 55 °C

Procedure:
A mixture of tert-butyl 5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g, 0.142 mmol) and 10% Pd/C (0.100 g) in MeOH (20 ml) was hydrogenated at RT using a balloon filled with hydrogen gas. The reaction was heated at 55° C. for 1 h. The reaction mixture filtered through Celite® washing with MeOH. The filtrate was concentrated in vacuo to give tert-butyl 5-(2-(3-aminophenyl)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.065 g, 0.128 mmol, 90%). HPLC retention time 3.42 mins.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Br[C:29]1[CH:72]=[CH:71][C:32]([CH2:33][O:34][CH:35]2[CH:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][O:51][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[O:59][CH3:60])=[CH:43][CH:42]=3)[CH2:39][CH2:38][N:37]([C:61]([O:63][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:62])[CH2:36]2)=[CH:31][C:30]=1[O:73][CH2:74][CH2:75][CH2:76][O:77][CH3:78].[NH:79]1[CH2:83][CH2:82][CH2:81][CH2:80]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:60][O:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[CH2:52][O:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH:40]2[CH2:39][CH2:38][N:37]([C:61]([O:63][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:62])[CH2:36][CH:35]2[O:34][CH2:33][C:32]2[CH:71]=[CH:72][C:29]([N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)=[C:30]([O:73][CH2:74][CH2:75][CH2:76][O:77][CH3:78])[CH:31]=2)=[CH:42][CH:43]=1
Reactant: C1CCNC1
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N1CCCC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The mixture of 0.019 g of 2-(di-t-butylphosphino)biphenyl, 0.005 g of palladium(II) acetate and 0.134 g of sodium tert-butoxide is admixed under argon with the solution of 0.831 g of benzyl 3-[4-bromo-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.100 ml of pyrrolidine in 7.0 ml of toluene. The reaction mixture is stirred at 90° C. over 16 hours, subsequently cooled, poured onto water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.22 (1:1 EtOAc-heptane); Rt=5.40.
Reaction SMILES: C(C1C=CC2CCC3C=C(C[Br:18])C=CC=3SC=2C=1)#N.[C:20]([C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:35]([CH2:36]O)[C:28]=3[S:27][C:26]=2[CH:38]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:35]([CH2:36][Br:18])[C:28]=3[S:27][C:26]=2[CH:38]=1)#[N:21]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(CBr)cc1CC2
Reactant: N#Cc1ccc2c(c1)Sc1c(CO)cccc1CC2
Product: N#Cc1ccc2c(c1)Sc1c(CBr)cccc1CC2
Yield: 95 %

Procedure:
As described previously for the 3-cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin, the title compound was prepared from 3-cyano-6-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin in 95% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:24])[C:8]=2[C:12]2[C:13]([OH:23])=[CH:14][CH:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18](Br)=[CH:17]3)[CH:3]=1.[Cl-].O.NN.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C1COCC1>[C:29]1([C:18]2[CH:19]=[CH:20][C:21]3[C:16](=[CH:15][CH:14]=[C:13]([OH:23])[C:12]=3[C:8]3[C:7]([OH:24])=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:4][CH:3]=3)=[CH:3]4)[CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ccc2cc(Br)ccc2c1-c1c(O)ccc2cc(Br)ccc12
Reactant: OB(O)c1ccccc1
Agent: NN
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1-c1c(O)ccc2cc(-c3ccccc3)ccc12

Procedure:
12.0 g (25.7 mmol) of (±)-6,6′-dibromo[1,1′]binaphthalinyl-2,2′-diol, 11.5 g (41 mmol) of sodium metaborate octahydrate and 800 mg of bistriphenylphosphinepalladium(II) chloride are initially introduced in 100 ml of water and 20 ml of THF, 0.13 ml of hydrazine hydrate is added, and a solution of 7.0 g (57 mmol) of benzeneboronic acid in 80 ml of THF is added dropwise. The batch is subsequently heated under reflux overnight, added to water and extracted three times with MTB ether. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate (19:1) and evaporated, and the product is recrystallized once each from toluene/cyclohexane (1:1) and isopropanol, giving (±)-6,6′-diphenyl[1,1′]binaphthalinyl-2,2′-diol as colorless crystals.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][C@@H:11]([CH2:19][CH:20]=[O:21])[O:10][C@H:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]4[O:28][CH2:29][CH2:30][O:31][C:23]=34)[C:8]=2[CH:32]=1.[OH:33]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:12][C@@H:11]([CH2:19][C:20]([OH:33])=[O:21])[O:10][C@H:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]4[O:28][CH2:29][CH2:30][O:31][C:23]=34)[C:8]=2[CH:32]=1
Reactant: CC(C)(C)CN1C[C@@H](CC=O)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Product: CC(C)(C)CN1C[C@@H](CC(=O)O)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Reaction time: 0.75 h
Yield: 72.6 %

Procedure:
Aqueous hydrogen peroxide (30% by weight; 69 mL, 605 mmol) was added to a solution of [trans-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-acetaldehyde (250 mg, 582 mmol), aqueous sodium phosphate monobasic (63 mg in 1 mL water) and acetonitrile (1.25 mL). Sodium chlorite (1M in water; 640 mL, 640 mmol) was then added dropwise. After 45 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite, concentrated, taken up in water and extracted with ethyl acetate (3×). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (2% methanol/chloroform) to give 170 mg (66%) of the title compound as a white foam.
Reaction SMILES: [CH:1]([C@:4]1([C:16]([N:18]2[CH2:23][CH:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([C@:4]1([C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:22][CH2:23]2)=[O:17])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](NC2CCOCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCC(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](NC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.1 %

Procedure:
To a solution of N-((1R,3S)-3-isopropyl-3-[4-[3-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonylcyclopentyl)tetrahydro-2H-pyran-4-amine (12.0 mg, 0.026 mmol) in methanol (1.0 mL) under N2 was added palladium (5.5 mg) (10% dry weight on wet activated carbon). The reaction mixture was stirred at room temperature under H2 (1 atm) overnight (22 h) and filtered through celite. The celite was washed with methylene chloride and the filtrate was concentrated to give the desired product (11.9 mg, 99%). MS calculated for C26H38F3N2O2: (M+H) 467.3; found 467.2.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: Nc1nc(Cl)nc2ccccc12
Reactant: NN
Solvent: CCO
Product: NNc1nc(N)c2ccccc2n1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
A mixture of 2-chloroquinazolin-4-amine (Example 38) (100 mg, 0.56 mmol) and hydrazine (0.09 mL, 2.79 mmol) in ethanol (5 mL) was heated in a sealed tube at 80° C. overnight. After the reaction mixture was cooled down, the resulting precipitate was collected by filtration, rinsed with ethanol and dried in the air to give the title compound (84 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 4.2 (bs, 2H), 4.6 (bs, 2H), 7.0 (t, J=7.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.61 (s, 1H), 7.87 (d, J=7.6 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.C1C=CC2N(O)N=NC=2C=1.[CH3:20][N:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([O-])=[O:26]>CN(C)C=O>[CH3:20][N:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][CH2:2][OH:1])=[O:26]
Reactant: OCCC1CCCCN1
Reactant: CN(C)CCCC(=O)[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)CCCC(=O)N1CCCCC1CCO

Procedure:
2-(2-Hydroxyethyl)piperidine, HOBt and WSCI are added to N,N-dimethylformamide solution of 4-(dimethylamino)butyrate while being cooled with ice and the mixture is reacted at room temperature to obtain 1-[4-(dimethylamino)butanoyl]-2-(2-hydroxyethyl)piperidine.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:17])[C@H:6]([CH3:16])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].Cl>CO>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:15])[C:8]=1[NH:7][C@H:6]([C:5]([OH:17])=[O:4])[CH3:16]
Reactant: COC(=O)[C@H](C)Nc1c(C)cccc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C)c1N[C@@H](C)C(=O)O
Yield: 68.8 %

Procedure:
1,000 ml (2 mol) of 2 molar methanolic potassium hydroxide solution were added to a solution of 207 g (1 mol) of N-(2,6-dimethylphenyl)-alanine methyl ester in 1,000 ml of methanol and the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was acidified with 190 ml of concentrated hydrochloric acid, the potassium chloride which had precipitated was filtered off and the filtrate was evaporated in vacuo. The oily residue crystallized on grinding and warming with 350 ml of ethyl acetate and 100 ml of petroleum ether. 133 g (68% of theory) of N-(2,6-dimethylphenyl)-alanine with a melting point of 178°-180° C. were obtained.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([S@@:22]([NH2:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH:1]([S:4][C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1/[CH:7]=[N:24]/[S@:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=1)=[O:23])([CH3:3])[CH3:2]
Reactant: Cc1ccc([S@@](N)=O)cc1
Reactant: CC(C)Sc1ccc([N+](=O)[O-])cc1C=O
Solvent: ClCCl
Product: Cc1ccc([S@](=O)/N=C/c2cc([N+](=O)[O-])ccc2SC(C)C)cc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To 2-(isopropylthio)-5-nitrobenzaldehyde (234 mg, 1.0 mmol) and (S)-(+)-p-toluenesulfinamide (161 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added Ti(OEt)4 (25% tech, 0.54 mL). The mixture was heated at 75° C. for 3.0 h. TLC indicated a clean reaction. Solvent was removed and the residue was redissolved in EtOAc, under stirring sat. Na2SO4 solution was added and the slurry was stirred at rt for 30 min before it was filtered through a pad of Celite®. The filtrate was extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of solvent, 98A (320 mg, 88% yield) was obtained as a solid used for next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (d, J=6.59 Hz, 6H) 2.34 (s, 3H) 3.51-3.61 (m, 1H) 7.27 (d, J=7.91 Hz, 2H) 7.45 (d, J=8.79 Hz, 1H) 7.59 (d, J=8.35 Hz, 2H) 8.14 (dd, J=8.79, 2.64 Hz, 1H) 8.69 (d, J=2.64 Hz, 1H) 9.17 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[OH:12]
Reactant: CC1CCc2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1O

Procedure:
We found that both the yield and the enantioselectivity of the arylation of 2-methyl-α-tetralone could be brought to good levels by running the arylation using 10-20 mol % Pd(0)/12-24 mol % BINAP in toluene at 100° C.8,9 It was found that an excess of aryl bromide was necessary to ensure complete conversion of the ketone; 2-methyl-1-naphthol, biaryls, and compounds resulting from aldol condensation were formed as side-products. In some reactions, the α-phenylated ketone was also observed as a side product. Subsequent experiments demonstrated that the latter side product was a result of aryl transfer from the phosphine ligand.10 Using the conditions described above, the arylations of 2-methyl-α-tetralone proceeded with enantioselectivities up to 88% (Table 1).11 We have also briefly examined the reactions of 2-methyl-1-indanone, 1. Using 5 mol % Pd(OAc)2/12 mol % BINAP the reaction with