Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[Cl:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:22])[CH2:14]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][CH2:26]2)=[O:22])[CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC1CCNCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)CC1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
Methane sulphonyl choride (0.013 ml) was added to a solution of Intermediate 18 (0.054 g) and N,N-diisopropylethylamine (0.063 ml) in dichloromethane (2 ml). The solution was stirred for 16 h at 23° C. The solvent was removed in vacuo and the residue purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol, to give the title compound as a clear gum (0.035 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.S(Cl)([Cl:52])=O>ClC(Cl)C>[O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([Cl:52])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)Cl)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 73.2 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (200 mg, 0.289 mmol) and thionyl chloride (0.211 mL, 2.89 mmol) in dichloroethane (5 mL) was refluxed for 30 h. The reaction mixture was concentrated under reduced pressure to provide the title compound as a white solid (150 mg, 73%). LCMS: m/e 705.46 (M−Cl+OMe+H)+, 3.0 min (method 10).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O:24][CH2:25][CH2:26]Br)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:25]([O:24][C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:26].[OH:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(C=Cc1ccccc1)OCCBr
Agent: O=C(O)c1ccc(C(=O)O)c(O)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccccc1

Procedure:
33.44 g (0.75 mol) of 2-dicesium salt of 2-hydroxy terephthalic acid, 38.27 g (0.15 mol) of 2-bromoethyl cinnamate and 200 mL of DMF were placed in a reaction vessel and reacted at 110° C. for 5 hours under a nitrogen atmosphere. After reaction, the precipitated CsBr was filtered out and the filtrate was poured into 800 mL of water to form a precipitate. The precipitate was separated from the solution and then dried. Thus 32 g (0.06 mol) of 2-hydroxy terephthalic acid ethyl cinnamate was obtained.
Reaction SMILES: [H-].[Na+].[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C)C=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=[O:11])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(F)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Sodium hydride (1.66 g) was added in portions to a stirred solution of salicylaldehyde (8.06 g) in N,N-dimethylformamide (100 mL) under nitrogen. To the resulting yellow solution was added 2,5-difluoro-1-nitrobenzene (10.0 g) and N,N-dimethylformamide (10 mL). The reaction was heated at 50° C. for 18 hours and evaporated under vacuum. The oily mixture was taken up in chloroform, and washed with 1 M NaOH, water, 1 M HCl, and brine, dried over magnesium sulfate, and evaporated under vacuum to an orange oil. The oil was treated with ethyl ether, cooled in an ice bath, and the precipitated product was collected by filtration to yield the title compound as white crystals. Mp: 94°-95° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[C:15](OC(=O)C)(=O)C.[ClH:22].O1CCOCC1>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6](=[O:5])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 5.04 mmol) in DCM (15 mL) is added acetic anhydride (0.52 mL, 5.55 mmol) and the reaction stirred at about 25° C. for 72 hours. The reaction is concentrated, and the residue dissolved in DCM (15 mL) and treated with 4M HCl in 1,4-dioxane (5.04 mL, 20.2 mmol). The reaction is stirred overnight, and the solid filtered to afford the title compound (O).
Reaction SMILES: F[C:2]1C=C(F)C=CC=1[N+]([O-])=O.CN1CCNCC1.[CH2:19]([NH:21][C:22]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:24][C:23]=1[N+:34]([O-:36])=[O:35])[CH3:20]>>[CH2:19]([NH:21][C:22]1[CH:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:2])[CH2:32][CH2:33]2)[CH:25]=[CH:24][C:23]=1[N+:34]([O-:36])=[O:35])[CH3:20]
Reactant: CCNc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CN1CCNCC1
Product: CCNc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
N-ethyl-5-(4-methyl-1-piperazinyl)-2-nitroaniline was prepared from 2,4-difluoro-1-nitrobenzene and methylpiperazine using the same method described for N-ethyl-2-nitro-5-(1-piperazinyl)aniline and was obtained as yellow solid (99%). 1H NMR (CDCl3) δ 8.30 (br s, 1H), 8.08–8.04 (m, 1H), 6.25–6.20 (m, 1H), 5.89–5.86 (m, 1H), 3.45–3.39 (m, 4H), 3.35–3.25 (m, 2H), 2.56–2.50 (m, 4H), 2.35 (s, 3H), 1.37 (tr, J=7.2 Hz, 3)); 13C NMR δ(CDCl3) 155.92, 147.72, 128.99, 124.19, 104.30, 94.37, 54.78, 47.05, 46.25, 37.73, 14.43; MS (posESI) m/z=found 264.1575, calc 264.1586. Anal. (C13H20N4O2,0.5 H2O) C, H, O.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:13](C(OOCC)=O)=[O:14])[C:6]([O:8][CH:9]([CH2:11][CH3:12])[CH3:10])=[O:7].[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:13](=[O:14])[NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)[C:6]([O:8][CH:9]([CH2:11][CH3:12])[CH3:10])=[O:7]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)CC)=C1SCS1
Reactant: Cc1csc(N)n1
Product: CCC(C)OC(=O)C(C(=O)Nc1nc(C)cs1)=C1SCS1

Procedure:
Following the procedure of Example 22, the titled compound was prepared as a white solid (67%) from sec-butyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and 2-amino-4-methylthiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])[C:10](O)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])[C:10]([Cl:17])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C(=O)O)c1cc(Cl)cc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)c1cc(Cl)cc(Br)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-bromo-5-chloro-phenyl)-propionic acid (0.87 g, 3.3 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride (0.63 mL, 6.6 mmol) and DMF (2 drops), and the reaction was stirred for 15 minutes and then concentrated to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10]1.C(=O)([O-])O.[Na+]>C1COCC1>[C:5]([CH:4]([C:3]#[N:7])[C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10]1)#[N:6]
Reactant: N#CCC#N
Reactant: COC(=O)C1(Br)CCOC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(C#N)C#N)CCOC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
440 mg (11.00 mmol) of sodium hydride (60% in mineral oil) were initially charged in 30 ml of THF, and 726 mg (11.00 mmol) of malononitrile were added in portions. Thereafter, 2.3 g (11.00 mmol) of the compound obtained in example 11A in THF (50 ml) were added. The mixture was stirred at RT for 6 h and then heated to 50° C. overnight. After cooling, the mixture was admixed with saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated. The residue (2.66 g) was dried under high vacuum for 1 h and then converted without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH:11]([C:13]2[N:17]3[C:18]4[CH:24]=[CH:23][N:22]([S:25]([C:28]5[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=5)(=[O:27])=[O:26])[C:19]=4[N:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH:10]([CH2:35][CH3:36])[CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[CH2:35]([CH:10]1[CH:11]([C:13]2[N:17]3[C:18]4[CH:24]=[CH:23][N:22]([S:25]([C:28]5[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=5)(=[O:27])=[O:26])[C:19]=4[N:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:12][CH:8]([NH2:7])[CH2:9]1)[CH3:36]
Reactant: CCC1CC(NC(=O)OC(C)(C)C)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CC(N)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 40 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A round-bottomed flask was charged with tert-butyl-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (1.7 g, 3.2 mmol) and 1,4-dioxane (20 mL) to give a brown solution. HCl (4 N in 1,4-dioxane, 4.05 mL, 16.2 mmol) was added and the mixture was stirred at about 40° C. for about 3 h. The solvent was removed under reduced pressure. EtOAc (50 mL) and saturated aqueous NaHCO3 (20 mL) were added. The resulting solid was collected by vacuum filtration and dried on the lyophilizer to give a grey solid (0.93 g). The layers of the filtrate were partitioned and the aqueous layer was extracted with EtOAc (3×40 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give a brown residue (0.52 g). The material obtained was combined to give 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclopenta amine (1.45 g, 80% UV purity, 84%): LC/MS (Table 2, Method a) Rt=1.76 min; MS m/z: 425 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 4-fluorobenzylamine (0.114 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidine carboxylate. Yield: 130 mg. To a solution of tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((4-fluorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((4-Fluorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 45 mg; 13C-NMR (CD3OD, rotamers): δ 26.1, 27.5, 40.1, 43.6, 43.8, 44.0, 51.6, 53.6, 54.6, 113.77, 113.84, 114.0, 114.1, 114.7, 114.9, 115.3, 115.6, 126.8, 127.2, 128.1, 128.6, 128.7, 129.8, 130.0, 130.1, 130.6, 131.0, 133.8, 159.1, 173.3, 173.6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:38][C:39]1[C:40]([N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([NH2:45])[CH:44]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:43]3[CH:44]=[C:39]([CH3:38])[C:40]([N:49]4[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 34.5 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) (200 mg, 0.385 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (Example 248, Step B) (200 mg, 0.586 mmol) in trifluoroethanol (10 mL) was added p-toluene sulfonic acid (200 mg, 1.05 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and silica was added. The solvent was removed on a rotovap and the product purified on a 12 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (110 mg, 0.133 mmol, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.34 (d, J=7.0 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.75-7.73 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.46-7.34 (m, 2H), 7.29 (d, J=8.8 Hz, 1H), 7.19 (t, J=8.0 Hz, 2H), 6.95 (t, J=7.1 Hz, 1H), 6.74 (s, 1H), 6.61 (d, J=5.2 Hz, 1H), 4.91-4.81 (m, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.39-3.28 (m, 2H), 3.06 (s, 3H), 2.88-2.81 (m, 4H), 2.77 (t, J=6.8 Hz, 2H), 2.67-2.53 (m, 4H), 2.13 (s, 3H), 1.39 (d, J=5.8 Hz, 6H), 1.25 (t, J=7.0 Hz, 3H). MS (ESI) m/z=412 [M+2H]+2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O>N1C=CC=CC=1>[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A suspension of pyrazole (1 g) and 4-toluenesulfonyl chloride (2.8 g) in pyridine (10 ml) was stirred at 130° C. for 1 hour. After the reaction mixture was cooled, water was added to the reaction mixture, resulting in a white suspension. The resultant suspension was filtered, and the obtained white solids were washed three times with water. Drying at room temperature under reduced pressure gave white solids (500 mg).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:9])[CH2:6][CH2:7]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][C:15]#[N:16].[OH-].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]2([C:15]#[N:16])[CH2:7][CH2:6][N:5]([CH3:9])[CH2:4][CH2:3]2)[CH:17]=[CH:18][CH:19]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: CN(CCCl)CCCl
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: CN1CCC(C#N)(c2cccc(Cl)c2)CC1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
The starting material, 4-(3-chlorophenyl)-1-methylpiperidine-4-carbonitrile was prepared as follows by the procedure of T. Cammack and P. C. Reeves, J. Heterocycl. Chem., 23, 73 (1986): a mixture of 100 g (0.52 mole) of N,N-bis(chloroethyl)methylamine hydrochloride, 80 g (0.53 mole) of 3-chlorobenzyl cyanide, 13 g of hexadecyltributylphosphonium bromide and 750 mL of 50% aqueous sodium hydroxide was stirred at 100° internal temperature for 1 hour. Water (750 mL) was added to the cooled mixture which was then extracted with 500 mL and three 100-mL portions of toluene. Removal of the solvent from the dried solution and rapid short-path distillation of the residue (160° bath temperature, 0.1 mm) gave 107.2 g (88% yield) of 4-(3-chlorophenyl)-1-methylpiperidine-4-carbonitrile as a colorless oil which slowly crystallizes. NMR (CDCl3): δ7.5 (s,1H); 2.3 (m,3H); 3.0 (d,2H); 2.5 (m,2H); 2.4 (s,3H) and 2.1 (m,4H). The hydrochloride had m.p. 235°-236° after crystallization from isopropyl alcohol.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1C(=O)NC(=O)N([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])C=1>P([O-])([O-])([O-])=O>[CH:2]1[N:3]=[C:4]2[N:5]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]3[OH:27])[CH:6]=[N:7][C:8]2=[C:9]([NH2:10])[N:1]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 51.3 %

Procedure:
50 kg of wet cell paste obtained by fermenting E. aerogenes were resuspended in approximately 200 liters of 30 mM phosphate buffer at pH 7 and mixed with 800 liters of phosphate buffer in which had been dissolved at elevated temperature 5.4 kg of adenine (final concentration 40 mM) and 8.9 kg of Ara-U (final concentration 40 mM). The mixture was maintained at 60° C., with agitation, for 20 hours, diluted to approximately 3000 liters with hot H20 and subjected to diafiltration on a membrane, collecting approximately 5000 liters of ultrafiltrate. The bioconversion yield determined by RP-HPLC was approximately 55%. The residue containing the cell paste is used for a subsequent reaction. The ultrafiltrate was concentrated to approximately 1000 liters and cooled to collect the precipitate constituted by Ara-A contaminated with non-reacted adenine (approximately 30 g of adenine per 100 g of Ara-A). 5 kg of Ara-A (total yield approximately 46%) with a degree of purity higher than 99.5% were finally obtained after crystallisation with H2O.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[C:16]([N+:31]([O-])=O)[CH:15]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:31][C:16]3[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][C:17]=3[S:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CCCOc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Product: CCCOc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (250 mg, 1.56 mmol) was reacted with the product from Example 55a (273 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (187 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.62-1.79 (m, 2H) 2.34 (s, 3H) 2.76 (s, 3H) 3.86 (t, J=6.43 Hz, 2H) 6.27 (d, J=6.99 Hz, 1H) 6.84 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.24 (d, J=8.46 Hz, 2H) 7.29 (s, 1H) 7.80 (d, J=8.46 Hz, 1H) 8.42 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.46 Hz, 1H) 11.01 (s, 1H) 14.39 (s, 1H); MS (ESI+) m/z 416 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)[C:8]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:6][CH:7]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C1Nc2cc(Br)cnc2C12CCOCC2
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cnc2c(c1)NCC21CCOCC1

Procedure:
Prepared according to procedure K using 6′-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one (138 mg, 0.487 mmol) and sodium bis(2-methoxyethoxy)aluminium hydride (304 μL, 1.560 mmol) in toluene (3 mL). After purification 6′-bromo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] was obtained as a white solid.
Reaction SMILES: [Na].C([O:4][C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:9]=1[C:21](=O)[CH3:22])C>C(O)C>[CH3:22][C:21]1[C:9]2[CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:5]([OH:4])=[O:24]
Reactant: CCOC(=O)COc1ccc(Cc2cccnc2)cc1C(C)=O
Agent: [Na]
Solvent: CCO
Product: Cc1c(C(=O)O)oc2ccc(Cc3cccnc3)cc12
Yield: 18.7 %

Procedure:
Sodium (0.50 g.) was dissolved in ethanol (10 ml.) and a solution of 2-acetyl-4-(3-pyridylmethyl)phenoxyacetic acid ethyl ester (4.70 g.) in ethanol (15 ml.) was added. The mixture was heated under reflux for 3 hours and then evaporated. The residue was dissolved in water and the solution was washed several times with ether. The aqueous layer was acidified with glacial acetic acid to give a gummy solid which was filtered off, washed with water, dried and chromatographed on silica gel. Elution with chloroform gave some impurity and then further elution with chloroform/methanol (9:1) gave a solid which was crystallized from ethanol to give 3-methyl-5-(3-pyridylmethyl)benzofuran-2-carboxylic acid (0.75 g.), m.p. 223°-225° C.