Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@@H:9]3[CH2:11][C@H:10]3[C:12]([F:15])([F:14])[F:13])[C:5]=2[C:16](OC)=[O:17])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@@H:9]3[CH2:11][C@H:10]3[C:12]([F:14])([F:13])[F:15])[C:5]=2[CH2:16][OH:17])[CH2:2][CH2:3]1
Reactant: COC(=O)c1c([C@@H]2C[C@H]2C(F)(F)F)noc1C1CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1c([C@@H]2C[C@H]2C(F)(F)F)noc1C1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0°C.) solution of methyl 5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclopropyl)isoxazole-4-carboxylate (193 mg, 0.7 mmol) in THF (2.3 mL) was treated with the dropwise addition of lithium aluminum hydride (1.4 mL, 1M solution in THF). Afte(2 hr of stirring, the reaction was cooled to 0°C. and treated with the dropwise addition of 1N HCl (aq.) until a solution persisted. The reaction was then extracted with EtOAc. The organic phase was dried (MgSO4), filtered, concentrated, and chromatographed (SiO2, linear gradient, 0-80%, EtOAc in hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 4.63 (d, J=4.5 Hz, 2H), 2.31 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H), 1.67 (dd, J=5.1, 4.9 Hz, 1H), 1.42 (m, 2H), 1.10 (m, 2H), 1.05 (m, 2H), MS m/z 248.1 (M+1).
Reaction SMILES: O.C(N(CC)CC)C.P(=O)(O)(O)O.C[N+:15]1[CH:16]=[C:17]2[C:22]3OCO[C:21]=3[CH:20]=[CH:19][C:18]2=[C:26]2[CH:35]=[CH:34][C:33]3[CH:32]=[C:31]4OCO[C:30]4=[CH:29][C:28]=3[C:27]=12>CO>[CH:32]1[C:33]2[CH:34]=[CH:35][C:26]3[C:27]([C:28]=2[CH:29]=[CH:30][CH:31]=1)=[N:15][CH:16]=[C:17]1[C:18]=3[CH:19]=[CH:20][CH:21]=[CH:22]1
Reactant: C[n+]1cc2c3c(ccc2c2ccc4cc5c(cc4c21)OCO5)OCO3
Agent: O=P(O)(O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2c(c1)cnc1c3ccccc3ccc21

Procedure:
A 5CN 10u radial pack column (5 mm. ID×100 mm.; from Water Associates) was run at 0.5 ml./min. with a mobile phase containing 84/16 (u/v) methanol: water with 0.005 M. triethylamine and phosphoric acid (pH 4.8). Detection of the benzophenanthridine alkaloid was monitored at 280 nm. using sanguinarine in methanol as a standard. After removal of the 5 ml. samples, the fluid was replaced with 5 ml. of isotonic saline. A 20 μl. sample was injected into the HPLC and analyzed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([C:22]2[O:23][C:24]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)=[CH:25][C:26](=[O:36])[C:27]=2[O:28][Si](C(C)(C)C)(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[OH-].[K+].[CH3:66][O:67][C:68]1[CH:75]=[CH:74][C:71]([CH2:72]Cl)=[CH:70][CH:69]=1>C1COCC1.CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([C:22]2[O:23][C:24]([CH2:37][OH:38])=[CH:25][C:26](=[O:36])[C:27]=2[O:28][CH2:72][C:71]2[CH:74]=[CH:75][C:68]([O:67][CH3:66])=[CH:69][CH:70]=2)=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)=CCc1cccc2c(-c3oc(C(C)(C)O[SiH2]C(C)(C)C)cc(=O)c3O[Si](C)(C)C(C)(C)C)cn(C(=O)OC(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(COc2c(-c3cn(C(=O)OC(C)(C)C)c4c(CC=C(C)C)cccc34)oc(CO)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 204 (191 mg, 0.350 mmol) was dissolved in anhydrous THF (2 mL). TBAF (1 M, 0.7 mL) was added dropwise. The solution was stirred at room temperature overnight. The mixture was extracted with EtOAc. The organic phase was combined and washed with water and brine. The organic layer was dried over Na2SO4 then solvent removed under vacuum. The resulting 3-(3-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-yl)-7-(3-methyl-but-2-enyl)-indole-1-carboxylic acid tert-butyl ester (211) was directly protected as following. KOH (85%, 15 mg, 0.23 mmol) was powdered and dissolved in anhydrous MeOH (3 mL). Then crude 211 was added, followed by p-methoxybenzyl chloride (47 mg, 0.30 mmol). The resulting solution was stirred at room temperature overnight. The mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over Na2SO4 then solvent removed under vacuum. After flash column chromatography, the desired product was obtained as a yellow oil (70 mg, 43%). 1H NMR (CDCl3): δ 1.61 (9H, s), 1.71 (3H, s), 1.73 (3H, s), 3.71 (3H, s), 3.75 (2H, d, J=6.6 Hz), 4.28 (2H, s), 5.24 (2H, s), 5.25 (1H, m), 6.57 (1H, s), 6.70 (2H, m), 7.08 (2H, m), 7.2-7.3 (2H, m), 7.86 (1H, m), 8.11 (1H, s). 13C NMR (CDCl3): δ 19.1, 22.6, 28.6, 31.3, 33.7, 56.0, 61.9, 73.3, 85.1, 111.4, 114.3, 119.3, 123.1, 124.5, 126.7, 127.3, 129.2, 129.5, 130.9, 133.2, 133.6, 134.5, 137.7, 141.2, 149.4, 149.8, 160.9, 165.1, 175.5. IR (KBr): 3167, 2871, 1554, 1233, 1105 cm−1. HRMS (El): m/z Calcd. for C32H35NO7 [M+] 545.2414, found 545.2429.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:10]([CH3:20])=[C:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:12]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:10]([CH3:20])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl 2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidazole-4-carboxylate (69 mg, 0.17 mmol) was dissolved in dry dichloromethane (2 mL) and treated dropwise with trifluoroacetic acid (2 mL). After stirring at rt for 2 h, the solution was concentrated to give 2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidazole-4-carboxylic acid as a yellow foam, which was used without purification in the preparation of Example 23.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl[C:16]([O:19]C(Cl)=O)(Cl)Cl>O1CCOCC1>[CH3:2][O:3][C:4](=[O:14])[CH:5]([N:6]=[C:16]=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccccc1)N=C=O
Temperature: 55 °C
Yield: 83.7 %

Procedure:
L-Phenylalanine methyl ester hydrochloride (6.00 g., 27.82 mmole) was slurried in anhydrous 1,4-dioxane (125 ml.), treated with trichloromethylchloroformate (5.05 ml., 41.86 mmole) and heated at 55° C. for 17.5 hours. The excess trichloromethylchloroformate and 1,4-dioxane were removed from the reaction mixture by distillation under slightly reduced pressure. The resultant residue was subjected to high vacuum distillation to afford the desired intermediate 2-isocyanato-3-phenylpropionic acid methyl ester (4.78 g., 84% yield). B.P. 83°-85° C. (100 μm Hg.) as a clear colorless liquid. 1H-NMR (200 MHz, CDCl3) δppm =3.12, dd, J=8.5 Hz., 2H (--CH2 --Ph), 3.83, s, 3H (--COOCH3), 4.28, m, 1H (--CH--CH2 --), 7.15-7.4, m, 5H (Ar--H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[CH:33]=[C:34]([O:38][C:39]2[N:44]=[CH:43][C:42]3[N:45]=[C:46]([C:50]4[C:51]([NH2:55])=[N:52][O:53][N:54]=4)[N:47]([CH2:48][CH3:49])[C:41]=3[CH:40]=2)[CH:35]=[CH:36][CH:37]=1>CN(C=O)C.O.CCOC(C)=O>[NH2:55][C:51]1[C:50]([C:46]2[N:47]([CH2:48][CH3:49])[C:41]3[CH:40]=[C:39]([O:38][C:34]4[CH:33]=[C:32]([NH:31][C:1]([C:2]5[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=5)=[O:9])[CH:37]=[CH:36][CH:35]=4)[N:44]=[CH:43][C:42]=3[N:45]=2)=[N:54][O:53][N:52]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4cccnc4)c3)cc21
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a room temperature suspension of 0.036 g of nicotinic acid (0.30 mmols) and 0.061 g of EDCI (0.32 mmols) in dry DMF (2.0 mL) was added 0.043 g of HOBt (0.32 mmols). After stirring for 10 min., 0.10 g of the product of Example 3 (0.3 mmols) was added to the reaction mixture. After stirring for 1 h, the reaction was treated with an additional 0.061 g of EDCI (0.32 mmols). The mixture was allowed to stir for 27 h at rt. The reaction mixture was diluted with 2 mL of water and 10 mL of EtOAc. The layers were separated, and the organic layer was washed with water. The organics were dried over MgSO4, filtered, and concentrated. The yellow residue was washed with methanol to yield an off-white solid (73 mg, 57%). MS (ES+) m/e 444 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCOC(C)=O>[CH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:16]=1[C:2]1[N:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3ccccc3c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a solution of 2-bromo-5-hydroxypyridine (1.04 g, 6 mmol) in 25 mL anhydrous THF was added 2-naphthylboronic acid (1.03 g, 6 mmol) and 2 M aq. sodium carbonate (9 mL, 18 mmol). To this reaction mixture was added palladium tetrakistriphenylphosphine (0.7 g, 0.6 mmol) and the mixture was stirred at rt for 15 h under nitrogen. The reaction mixture was diluted with EtOAc, the organic layer was washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2SO4. Removal of solvent gave a white powder which was purified by column chromatography (Silica Gel 230-400 mesh; 3% MeOH in DCM) to give 6-naphthalen-2-yl-pyridin-3-ol (0.225 g, 17%). MS (ES) m/z: 222.96 (M+1), 221.93 (M); Mp. 168-169° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([N:14]1[CH2:17][CH:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[O:25])[CH2:20][CH2:19]3)[CH2:15]1)=[O:13])=[CH:7]2.C([O-])([O-])=O.[K+].[K+]>CCO.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:2]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([N:14]2[CH2:15][CH:16]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([C:26]5[S:27][CH:28]=[CH:29][N:30]=5)=[O:25])[CH2:22][CH2:23]4)[CH2:17]2)=[O:13])=[CH:7]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: O=C(c1ccc2c(Br)cccc2c1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: O=C(c1ccc2c(-c3ccccc3)cccc2c1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Yield: 116 %

Procedure:
A mixture of compound 313 (48 mg, 0.1 mmol), compound 12a (24 mg, 0.2 mmol), K2CO3 (27 mg, 0.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (4 mg, 0.005 mmol) in EtOH (1 mL) and H2O (0.2 mL) was heated in a microwave reactor at 130° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with CH2Cl2, and washed with H2O. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 338 (28 mg). 1H NMR (400 MHz, CD3OD): δ 8.20 (d, J=1.6 Hz, 1H), 7.93 (t, J=9.6 Hz, 2H), 7.88 (d, J=3 Hz, 1H), 7.66-7.43 (m, 9H), 4.52 (bs, 1H), 4.50-4.20 (m, 4H), 4.16 (m, 1H), 3.88 (bs, 1H), 3.83 (bs, 1H), 3.28 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H+) 483.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([CH:30]=[O:31])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1ccc(C#Cc2ccc(Br)cc2)cc1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a dry 2 L three-necked flask under a flow of N2 containing 1-bromo-4-[(4-butylphenyl) ethynyl] benzene (VIIe) (100 g; 0.319 mol) in dry THF (1000 mL) at −78° C. was added n-BuLi (2.5M in hexane, 153.25 mL, 0.383 mol) and the reaction mixture was stirred at this temperature for 2 h. The reaction mixture went dark-green after 5 minutes of the addition of butyl lithium. To this reaction mixture was added DMF (29.56 mL, 0.383 mol) and the resulting mixture was stirred for an additional 1 h at −78° C. The reaction mixture turned black-blue after the addition of DMF. The reaction mixture was then quenched with 1.5M HCl (750 ml) at this temperature and the product was extracted with MTBE (3×500 mL). The combined organic layer were washed with 10% sodium bicarbonate solution (500 ml), water, brine and dried. The solvent was evaporated under reduced pressure to afford the title compound (m=65 g) as a white solid in a 77% yield. Melting point: 76-78° C.
Reaction SMILES: C(O[C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:14]=[CH:15][C:10]=2[S:9][C:8]1=[O:24])=[O:5])C.[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:4]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=4)[CH:14]=[CH:15][C:10]=3[S:9][C:8]2=[O:24])=[O:5])[CH2:30][CH2:29]1
Reactant: OCCN1CCNCC1
Reactant: CCOC(=O)Cn1c(=O)sc2ccc(C3=NNC(=O)NC3C)cc21
Product: CC1NC(=O)NN=C1c1ccc2sc(=O)n(CC(=O)N3CCN(CCO)CC3)c2c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
A mixture of the object compound of Example 21 (1.0 g) and 1-(2-hydroxyethyl)piperazine (1.2 g) was stirred for 4 hours at 120° C. After cooling, the reaction mixture was chromatographed on silica gel (45 g) by eluting with a mixture of chloroform and methanol (9:1) to give 0.9 g of 3-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-(5-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)benzothiazolin-2-one.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].F[C:10]1[CH:38]=[CH:37][C:13]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=2)=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:38]=[CH:37][C:13]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=2)=[O:15])=[CH:12][CH:11]=1)[CH3:7]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(F)cc3)ccc2C)cc1OC
Reactant: CNCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(N(C)CCCN(C)C)cc3)ccc2C)cc1OC
Temperature: 130 °C
Yield: 34.1 %

Procedure:
N-(3-Dimethylaminopropyl)-N-methylamine (0.325 g) was added to a stirred mixture of N-[5-(4-fluorobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.38 g), potassium carbonate (0.39 g) and DMSO (5 ml). The mixture was stirred and heated to 130° C. for 10 days. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated to give an oil which was purified by column chromatography on silica gel using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether and the resultant solid was dried under vacuum at 60° C. There was thus obtained the title compound (0.16 g), m.p. 164-165° C.; NMR Spectrum: (DMSOd6) 1.6 (m, 2H), 2.16 (s, 3H), 2.2 (s, 6H), 2.3 (t, 2H), 2.94 (s, 3H), 3.4 (t, 2H), 3.83 (s, 6H), 6.72 (d, 2H), 7.06 (d, 1H), 7.18 (d, 1H), 7.55 (m, 2H), 7.63 (m, 1H), 7.79 (d, 2H), 7.84 (d, 2H), 9.71 (br s, 1H), 9.8 (br s, 1H); Mass Spectrum: M+H+ 505; Elemental Analysis: Found C, 65.9; H, 7.0; N, 10.4; C29H36N4O4 1.3H2O requires C, 66.0; H, 7.4; N, 10.6%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[C:13]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:12]=1)C>C1COCC1>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][OH:9])=[CH:12][C:13]=1[S:29]([NH2:30])(=[O:32])=[O:31])(=[O:20])=[O:19]
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(CO)ccc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.1 %

Procedure:
Lithium aluminum hydride (1M in THF, 6.6 mL, 6.6 mmol) was added slowly to a stirred solution of 4-(2,3-dichloro-benzenesulfonylamino)-3-sulfamoyl-benzoic acid ethyl ester (600 mg, 1.32 mmol) in dry THF (15 mL) at −10° C. The reaction mixture was allowed to warm to RT and stirring was continued for 4 h. The reaction mixture was then cooled to 0° C. and quenched by addition of water, followed by 1N HCl. The product was extracted with ethyl acetate, the combined organic phases were washed with water and brine, and dried over sodium sulfate. Volatiles were removed under reduced pressure and the crude product was purified by preparative HPLC to afford the title compound (60 mg, 11%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CC(C)c1ccccc1Br
Product: CC(C)c1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 98.3 %

Procedure:
With 8.2 g of 1-bromo-2-isopropyl benzene and 3.0 g of 5-chloroisatin as starting materials, 4.9 g of the title compound (pale yellow amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)C3C=CC=CC=3)[N:8]=2)[CH:6]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](N[C:59](COC(=O)C)=[O:60])[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][C@H:29]([CH2:59][OH:60])[CH2:30][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:8]=2)[CH:6]=1
Reactant: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: Nc1cnn(-c2nc(N[C@H](CO)Cc3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP), by substituting acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate ZM) for acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][CH2:11]O.S(Cl)([Cl:15])=O.Cl.[OH-].[Na+]>O.CCOCC.C1C=CC=CC=1>[Cl:15][CH2:11][CH2:10][CH2:9][N:3]1[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1CCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[C@@H]1CCC[C@H](C)N1CCCCl

Procedure:
A stirred solution of 171 g. of cis-2,6-dimethyl-1-piperidinepropanol in 400 ml. of benzene is cooled to 0°-5° and 143 g. of thionyl chloride is added dropwise over a period of 30 minutes. The mixture is then heated at reflux for 2 hours, cooled and diluted with 1 l. of ether. The resulting precipitate of cis-1-(3-chloropropyl)-2,6-dimethylpiperidine hydrochloride is collected by filtration; m.p. 173°-174° C. after crystallization from 2-propanol-ether. The free base is prepared as needed by dissolving the hydrochloride in a minimum amount of water, cooling and adding a slight excess of 50% aqueous sodium hydroxide. The liberated base is immediately extracted with several portions of benzene. The extracts are combined, dried and evaporated to give the free base, cis-1-(3-chloropropyl)-2,6-dimethylpiperidine.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[NH:8][CH:7]=[N:6][C:5](=O)[CH:4]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[CH:4]=[C:3]([CH:2]([F:10])[F:1])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)F)[nH]cn1
Solvent: CCN(CC)CC
Product: FC(F)c1cc(Cl)ncn1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
6-(Difluoromethyl)-4(1H)-pyrimidinone (0.50 g, 3.42 mmol) was treated with triethylamine (0.477 mL, 3.42 mmol) and phosphorus oxychloride (1.595 mL, 17.11 mmol) and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, evaporated under reduced pressure and the residue was poured into 2M aqueous hydrochloric acid solution (5 mL). This solution was extracted with DCM (×2). The DCM layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (117 mg);
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12]([O:17][CH3:18])=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[C:12]=2[O:17][CH3:18])=[N:22][CH:23]=1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)ccc2c1CCC(NCC(F)F)CC2
Yield: 32 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide to yield 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (33.59 mg, 32% yield) as a beige powder. 1H-NMR (CDCl3) δ 9.40 (s, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 6.82 (d, J=8.2 Hz, 1H) 5.83 (m, 1H), 3.73 (s, 3H), 3.23 (m, 1H), 3.02 (m, 2H), 2.83 (m, 2H), 2.73 (s, 3H), 2.67 (m, 1H), 2.49 (m, 1H), 2.09 (m, 2H), 1.30 (m, 2H). LC/MS (ESI+)=581 (M+H). MP=118° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][NH2:15])[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-:3])=[O:2].[C:22](OCC)(OCC)(OCC)[CH3:23]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:22]([CH3:23])=[N:15][N:14]=[C:9]1[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-:3])=[O:2]
Reactant: NNc1cc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3)c3cc([N+](=O)[O-])ccc3n12

Procedure:
In the manner given in Example 2, 6-nitro-4-phenyl-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-nitro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline.