Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8](CC3C=CC(OC)=CC=3)[N:7]=[C:6]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH3:32])=[CH:20][N:19]=3)[C:5]=2[CH3:33])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>ClCCCl>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH3:32])=[CH:20][N:19]=3)[C:5]=2[CH3:33])[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c(C)c2C2CC2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
880 mg of 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2.0 mmol, 1.00 eq.) were dissolved in 7.8 mL of dry 1,2-dichloroethane. 4.6 mL trifluoroacetic acid (60 mmol, 30 eq.) and 1.8 mL trifluoromethanesulfonic acid (20 mmol, 10 eq.) were added at rt. The reaction mixture was stirred at 75° C. for 2 h. At 0° C. 2M sodiumhydroxide solution was added slowly. The solid was filtered off, dried in vacuo at 50° C. to provide 637 mg (1.96 mmol, 98%) of the analytically pure target compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[S:28]1(=[O:38])=[O:37].[Cl-].[Na+].Cl>CN(C)C=O.C1(C)C=CC=CC=1>[O:37]=[S:28]1(=[O:38])[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: COc1cccc2c1CC(CN)CC2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(CNCCCCN1C(=O)c3ccccc3S1(=O)=O)CC2

Procedure:
0.95 g of 2-aminomethyl-8-methoxytetralin (5 mmol), 0.70 ml of triethylamine (5mmol) and 1.59 g of 2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (5 mmol) are stirred at 40° C for 24 h in 19 ml of dimethylformamide. The reaction solution is then stirred into a mixture of 190 ml of 5% strength sodium chloride solution, 60 ml of toluene and 5 ml of 1N hydrochloric acid. After the organic phase has been separated off, the aqueous phase containing the final product precipitated as the resinous hydrochloride is stirred with 60 ml of toluene and 7 ml of triethylamine (50 mmol). The organic phase is separated off again, washed until neutral with water and dried over sodium sulphate. The solvent is distilled off in vacuo. The residue is chromatographed on silica gel 60 (Merck). Toluene/methanol 85:15 is in this case used as the eluent. The main fractions contain the two final products as yellow, viscous oils.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:22][N:23]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19](=[O:21])[CH2:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:14][CH:13]=1
Reactant: CNCCc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Product: CN(CCc1ccccc1)C(=O)Cc1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
When the procedure of Example 14 is followed, 5-benzyloxyindole-3-acetic acid and N-methyl-N-phenethylamine are reacted to give N-methyl-N-phenethyl-2-(5-benzyloxyindol-3-yl)acetamide. (m.p. 146° C. (dec.))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (940 mg, 3.03 mmol) was reacted with tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (830 mg, 86%) to afford the desired product as an orange solid: 1H NMR (300 MHz, CDCl3) δ 10.69 (s, 1H), 9.21 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.73 (dd, J=8.9, 2.0 Hz, 1H), 3.87 (dd, J=11.1, 5.5 Hz, 2H), 3.49 (t, J=4.9 Hz, 4H), 2.76-2.59 (m, 3H), 2.50 (t, J=4.9 Hz, 4H), 1.47 (s, J=11.3 Hz, 9H), 1.32-1.16 (m, 2H), 1.10-0.95 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:19][N:2]([CH2:3][C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1)[CH3:1]
Reactant: CN(C)C(=O)C1(C)Oc2ccccc2-n2cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)CC1(C)Oc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the amide of formula 3, N,N,4-trimethyl-4H-pyrrolo-[2,1-c][1,4]benzoxazine-4-carboxamide (3 g), described in Example 15 in 50 ml of ether is added dropwise to a suspension of lithium aluminum hydride (1.5 g) in anhydrous ether (100 ml) over a period of 30 min. The reaction mixture is stirred at room temperature for 16 hr. Decomposition of the mixture with 6 ml of water gives a white precipitate, which is collected on a filter and washed with ether. The filtrate is extracted with 2% aqueous HCl. The extract is rendered basic with a 10% solution of NaOH and extracted with chloroform. The chloroform extract is dried (MgSO4), filtered and evaporated to give the title compound, nmr (DMSO-d6) δ 1.85 (s, 3H), 2.78 (s, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([CH2:27][NH:28][C:29](=O)[CH2:30][CH3:31])=[N:26][C:22]=3[CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].O>C1COCC1>[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])=[N:26][C:22]=3[CH:21]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1)([CH3:8])[CH3:9]
Reactant: CCC(=O)NCc1nc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCNCc1nc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Temperature: 25 °C
Yield: 3.2 %

Procedure:
To a suspension of lithium-aluminiumhydride (180 mg, 4.79 mmol) in THF (5 ml, dried Al2O3) at −5-0° C. a solution of N-[5-(4-isopropyl-benzenesulfonylamino)-1H-benzoimidazol-2-ylmethyl]-propionamide (320 mg, 0.80 mmol) in THF (5 ml) was added. After complete addition the mixture was allowed to warm to room temperature and was heated to reflux for 2 h. At 0° C. THF and then water were added. The mixture was dried with Na2SO4. The filtered solution was evaporated in vacuo and the residue was purified by preparative HPLC (water/5% acetonitrile/0.1% acetic acid) to give the product as a yellow oil (10 mg, 3%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[Na+]>CN(C=O)C>[CH3:12][N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][O:20][C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[CH:15][CH:16]=2)[CH2:7][CH2:8]1
Reactant: Nc1ccc(O)cc1
Reactant: CN1CCN(CCCCl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.2 %

Procedure:
1-(3-Chloro-propyl)-4-methyl-piperazine hydrochloride (1.7 g, 9.6 mmol, 1.2 eq.) is added in one portion to a mixture of 4-aminophenol (893 mg, 8.0 mmol) and finely powdered sodium hydroxide (808 mg, 20 mmol, 2.5 eq.) in DMF (27 ml). The reaction mixture is stirred for 17 h at RT. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2×50 ml). The aqueous layer is back-extracted with DCM. The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3) provides 1.86 g of the title compound as a yellow-brown oil: ESI-MS: 250.2 [MH]+; TLC: Rf=0.31 (DCM/MeOH, 7:3).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[C:13]([Cu])#N.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: N#C[Cu]
Reactant: CON(C)C(=O)c1cccnn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)c1cccnn1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 168.4 %

Procedure:
To a solution of compound 2 (100 mg, 0.22 mmol) in DMF (10 mL) was added CuCN (40 mg, 0.44 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) under N2 at room temperature. The resulting mixture was stirred 30 min at 180° C. in a microwave reactor. Water (15 mL) was added and the mixture was extracted with EtOAc (3×20 mL), and the combined organic layers were dried over Na2SO4 and concentrated to give the residue which was purified by preparative TLC on silica gel (petroleum ether:ethyl acetate=5:1) to give compound 3 (46 mg, 52%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccc2ccccc2c1
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In analogy to the procedure described in Example 3(c) by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 474 (M+H)+.
Reaction SMILES: C(OC(NCCNCCNC(OC(C)(C)C)=O)=O)(C)(C)C.C(C1C=CC(CBr)=CC=1)#N.C([O-])([O-])=O.[K+].[K+].C(OC(NCCN(C1C=C(C)C=CC=1C#N)CCNC(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:68].CCOCC.[C:74]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=1)(=[O:76])C.[BH4-:83].[Na+:84]>CO.CC#N>[N:78]1[CH:79]=[CH:80][CH:81]=[CH:82][C:77]=1[CH:74]=[O:76].[BH4-:83].[Na+:84].[ClH:68]
Reactant: CC(=O)c1ccccn1
Agent: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(C#N)c(N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC#N
Product: O=Cc1ccccn1
Temperature: 60 °C

Procedure:
A mixture of bis(2-tert-butoxycarbonylaminoethyl)amine (0.01 mol), 4-cyanobenzyl-bromide (0.01 mol), K2CO3 (0.05 mol), and CH3CN (70 mL) was heated at 60° C. for 10 hours. The resultant bis(2-tert-butoxycarbonylaminoethyl)amino-4-methylphenylcyanide was deprotected using HCl/ether, condensed with 2-acetyl pyridine (0.01 mol) in MeOH, and then reduced by NaBH4. After sequential treatments with pyridine-2-carboxaldehyde, NaBH4, and HCl, compound 110 was obtained in 75% overall yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][C:20]([CH3:23])=[C:19]3[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:27]1([S:24]([C:19]2[C:18]3[C:22](=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:15]=[CH:16][CH:17]=3)[NH:21][C:20]=2[CH3:23])(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2c1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2c(N3CCNCC3)cccc2c1S(=O)(=O)c1ccccc1
Yield: 17.9 %

Procedure:
4-(3-Benzenesulfonyl-2-methyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.25 g) was dissolved in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid was added. After 10 min the mixture was concentrated in vacuo, taken into water, and washed with ether. The aqueous layer was basified with ammonium hydroxide, extracted with dichloromethane, and the extract was dried (sodium sulfate) and evaporated to afford the crude free base which was crystallized from dichloromethane-ether to afford 35 mg of 3-benzenesulfonyl-2-methyl-7-piperazin-1-yl-1H-indole (601), m.p. 188-190° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][C@H:18]3[CH2:58][N:21]4[C:22](=[O:57])[C@@H:23]([NH:49]C(=O)OC(C)(C)C)[C@H:24]([CH3:48])[CH2:25][CH:26]([CH3:47])[CH2:27][CH2:28][CH:29]=[CH:30][C@@H:31]5[CH2:36][C@@:32]5([C:37](=[O:46])[NH:38][S:39]([C:42]5([CH3:45])[CH2:44][CH2:43]5)(=[O:41])=[O:40])[NH:33][C:34](=[O:35])[C@@H:20]4[CH2:19]3)[CH:14]=[C:13]([C:59]3[CH:64]=[N:63][CH:62]=[CH:61][N:60]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(Cl)Cl.[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71]>C1(C)C=CC=CC=1>[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71].[NH2:49][C@@H:23]1[C:22](=[O:57])[N:21]2[CH2:58][C@H:18]([O:17][C:15]3[CH:14]=[C:13]([C:59]4[CH:64]=[N:63][CH:62]=[CH:61][N:60]=4)[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[CH:16]=3)[CH2:19][C@H:20]2[C:34](=[O:35])[NH:33][C@:32]2([C:37]([NH:38][S:39]([C:42]3([CH3:45])[CH2:44][CH2:43]3)(=[O:40])=[O:41])=[O:46])[CH2:36][C@H:31]2[CH:30]=[CH:29][CH2:28][CH2:27][CH:26]([CH3:47])[CH2:25][C@H:24]1[CH3:48]
Reactant: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](N)[C@H](C)C1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](N)[C@H](C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25 mL round-bottom flask equipped with a stir bar and charged with tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((2-(4-isopropoxyphenyl)-6-(pyrazin-2-yl)pyridin-4-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (all material from Step 1) was added CH2Cl2 (1 mL), then trifluoroacetic acid (1.0 mL, 13 mmol). The solution was stirred at room temperature for 2 h. The reaction solution was diluted with toluene (2 mL) and then concentrated in vacuo to afford (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((2-(4-isopropoxyphenyl)-6-(pyrazin-2-yl)pyridin-4-yl)oxy)-7,9-dimethyl-N-((1-methylcyclopropyl)sulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide trifluoroacetic acid salt as an amber solid residue. MS: MS m/z 800.5 (M++1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH:18]([CH3:20])[CH3:19].C[O-].[Na+].[CH:24]([C:26]([CH3:28])=[O:27])=[CH2:25].C(O)(=O)C>CO.C1C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:18]([CH3:20])[CH3:19])[CH2:25][CH2:24][C:26](=[O:27])[CH3:28]
Reactant: CC(C)C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: C=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)CCC1(C(C)C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred solution of (1-oxo-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (3.17 g., 0.01 mole) and sodium methoxide (3.2 g., 0.05 mole) in methanol (100 ml.) and benzene (100 ml.) in an inert atmosphere is cooled to 0° C. and treated with methyl vinyl ketone (2.0 g., 0.029 mole) in methanol (10 ml.) during a 1/2 hour period then stirred 72 hours at 25° C. The reaction mixture is acidified with acetic acid, evaporated to dryness, extracted with chloroform, washed with water, dried over magnesium sulfate and evaporated to dryness affording [1-oxo-2-isopropyl-2-(3-oxobutyl)-6,7-dichloro-5-indanyloxy]acetic acid which melts at 125°-128° C. after recrystallization from methanol.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1ccc(F)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(F)ccc(F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3-chloro-1,4-difluorobenzene and isolated as white solid (8.0 mg, 44%). MS(m/e): 443.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:12])=O>N>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(N)cc(O)n1
Agent: N
Product: Cc1nc(N)cc(Cl)n1
Temperature: 20 °C

Procedure:
150 g (1.2 mol) of anhydrous 2-methyl-4-amino6-hydroxypyrimidine are added little by little, with good stirring, to 720 ml of phosphorus oxychloride. The mixture is refluxed gently for 5 hours. A yellow solution is obtained. After cooling to 20° C., the precipitate formed is drained. An oily residue is recovered by evaporating the filtrate almost to dryness. This oily residue is poured, little by little, onto 500 g of ice, with stirring and while cooling the vessel in ice. The precipitate is introduced little by little into the solution obtained after some time. The addition is exothermic and the mixture must be cooled well in an ice bath. All of the solid dissolves. The solution is cooled to 0° C. and is rendered alkaline to pH 8 by the addition of 20% ammonia (850 ml). The formation becomes very thick. The solid is drained and washed on the filter with 100 ml of 10% aqueous sodium chloride solution and then with 200 ml of water. 144.2 g of crude product are obtained, which are recrystallised from acetonitrile. 97 g (0.676 mol) of pure product having a melting point of 191° C. are recovered. The yield of recrystallised product is 56.3%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]2[O:13][CH3:14])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:24]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].CS(C)=O>[CH3:14][O:13][C@@H:12]1[C@H:15]([OH:16])[C@@H:17]([CH2:19][OH:20])[O:18][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:24])[C:5]=2[N:6]=[CH:7]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
2,6-Diamino-9-(2′-O-methyl-β-D-ribofuranosyl) purine (9.5 g) in 0.1M sodium phosphate buffer (200 ml, pH 7.4) and DMSO (25 ml) was treated with adenosine deaminase (Type II Sigma) at RT for 4 days. The resulting suspension was cooled and filtered and the resulting filter cake washed with H2O and dried to a white solid (4.0 g). The solid was recrystallized from hot H2O to yield 2.9 g of product. m.p. 236-238° C. 1H NMR (DMSO-d6) δ 3.3 (s, 3, OCH3), 3.53 and 3.6 (ABX, 2, H-5′), 3.87 (m, 1, H-4′), 4.15 (m, 1, H-2′), 4.25 (m, 1, H-3′), 5.13 (t, 1, 5′—OH), 5.23 (d, 1, 3′—OH), 5.8 (d, 1, H-1′), 6.48 (br s, 2, NH2), 7.96 (s, 1, H-8) and 10.68 (br s, 1, NH). Anal. Calcd. for C11H15N5O5.½H2O: C, 43.14; H, 5.26; N, 22.86. Found: C, 43.59; H, 5.34; N. 23.04.
Reaction SMILES: Cl.[NH2:2][OH:3].C(O)C.N1C=CC=CC=1.[OH:13][C:14]1[C:23]2[O:22][C@@H:21]([CH2:24][OH:25])[CH2:20][O:19][C:18]=2[CH:17]=[CH:16][C:15]=1[C:26](=O)[CH3:27]>C(O)C>[OH:13][C:14]1[C:23]2[O:22][CH:21]([CH2:24][OH:25])[CH2:20][O:19][C:18]=2[CH:17]=[CH:16][C:15]=1[C:26](=[N:2][OH:3])[CH3:27]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1O)O[C@@H](CO)CO2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1O)OC(CO)CO2

Procedure:
A solution of hydroxylamine hydrochloride (2.38 g, 34.2 mmole) in 1:1 ethanol/pyridine (100 mL) was added to a solution of 1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone (1.92 g, 8.57 mmole) in ethanol (200 mL). It was then heated to reflux under nitrogen for 5 hours. Upon cooling, the solvent was removed and replaced with ethyl acetate. The solution was then washed with water (200 mL) and with aqueous 2N HCl (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuum to give 1.89 g (93%) of the (S)-enantiomer of the title compound as a gray solid, m.p. 162° C. MS (ESI) m/z 240 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C1COCC1>[N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][NH:8][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14])([O-:3])=[O:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(CN)c(C)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Nitro-2,4-dimethyl-benzylamine (1.40 g, crude) is added to a mixture of 2,2-dimethyl-propionic acid chloride (0.682 mL, 5.5 mmol) and TEA (1.92 mL, 13.8 mmol) in THF (30 mL) and it is stirred overnight. The reaction mixture is concentrated, diluted with EtOAc, washed successively with 2 M HCl-solution, 5% aq. NaHCO3 solution and water, dried with Na2SO4 filtered and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][C:7]=1[Br:22]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)c2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN(c2cnc(Br)c(Br)c2)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 1-(5-bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (2.68 g, 7.5 mmol), N-bromosuccinimide (1.34 g, 7.5 mmol) and acetonitrile (75 ml) was stirred for 30 minutes. The crude mixture was evaporated and purified by chromatography on silica gel using ethyl acetate: petroleum (2:1) as solvent. Yield 3.0 g, 92%.