Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.CO>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.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)Cc1ccccc1-c1ccc(C)cc1
Temperature: 85 °C

Procedure:
To a mixture composed of 243.1 mg (1 mmol) of ethyl 2-(2-bromophenyl)acetate, 3.7 ml of toluene, 57.8 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium and 127.2 mg (1.2 mmol) of anhydrous sodium carbonate are added 169.9 mg (1.25 mmol) of 4-methylphenylboronic acid, followed by addition of 2.21 ml (0.055 mmol) of methanol. The reaction medium is heated at 85° C. for 16 hours with stirring. After cooling, 10 ml of water and 8 ml of ethyl acetate are added with stirring, and the mixture is then filtered through a fluted filter paper. The organic phase is recovered and the aqueous phase is extracted again with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: ClCCCCCl
Reactant: Cc1nc2ccccc2[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1nc2ccccc2n1CCCCCl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 13.2 parts of 2-methyl-1H-benzimidazole, 3 parts of N,N,N-triethylbenzenemethanaminium chloride and 225 parts of a sodium hydroxide solution 60% are added 25 parts of 1,4-dichlorobutane. The whole is heated to about 100° C. and stirring is continued for one hour at this temperature. The reaction mixture is cooled and poured onto ice-water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and eluent is evaporated, yielding 1-(4-chlorobutyl)-2-methyl-1H-benzimidazole as a residue.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:21])=[C:7]([C:11]([I:20])=[C:12]([NH:15][CH2:16][C:17](=[O:19])[CH3:18])[C:13]=1[I:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+:26].[Cs+]>O>[C:1]([NH:4][C:5]1[C:6]([I:21])=[C:7]([C:11]([I:20])=[C:12]([NH:15][CH2:16][C:17](=[O:19])[CH3:18])[C:13]=1[I:14])[C:8]([O-:10])=[O:9])(=[O:3])[CH3:2].[Cs+:26]
Reactant: CC(=O)CNc1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(=O)CNc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Temperature: 50 °C

Procedure:
A suspension of 3-acetylamino-5-(acetylmethylamino)-2,4,6-triiodobenzoic acid (50.0 g, 79.62 mmol) in water (170 ml) was stirred and heated to 50° C. Cesium carbonate (12.8 g, 39.81 mmol) in water (20 ml) was added dropwise to the suspension until pH 7 was reached. Water was removed under reduced pressure to give a residue which was washed twice with ethanol and dried at 60° C. for 7 days.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>ClCCl.N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:25]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(C#Cc3cccc(N)c3)CCC(=O)CC2)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2(C#Cc3cccc(NC(C)=O)c3)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)cyclohexan-1-one (0.07 g, 0.18 mmol) in dichloromethane (2 mL) under an argon atmosphere. were added pyridine (three drops) and acetic anhydride (0.05 mL, 0.53 mmol) and the reaction was stirred at room temperature for 2 h. Hydrochloric acid (1N) was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetamidophenylethynyl)cyclohexanone as a white solid. mp 63°-64° C.; Anal. (C28H31NO4.1.75 H2O) calcd: C, 70.49; H, 7.29; N, 2.94; found: C, 70.09; H, 6.94; N, 2.83.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[N:5]=1)=[C:2]=[S:3].[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH:24]([CH3:29])[C:25]([NH:27][NH2:28])=[O:26])[N:19]=1>C(Cl)Cl>[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH:24]([CH3:29])[C:25]([NH:27][NH:28][C:2](=[S:3])[NH:1][C:4]2[CH:8]=[CH:7][N:6]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:5]=2)=[O:26])[N:19]=1
Reactant: Cc1cc(C)n(C(C)C(=O)NN)n1
Reactant: Cc1cccc(Cn2ccc(N=C=S)n2)n1
Solvent: ClCCl
Product: Cc1cccc(Cn2ccc(NC(=S)NNC(=O)C(C)n3nc(C)cc3C)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Intermediate 74 2-[(3-isothiocyanato-1H-pyrazol-1-yl)methyl]-6-methylpyridine (101 mg, 0.439 mmol) was dissolved in 4 mL of DCM, and then Intermediate 102 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanohydrazide (80 mg, 0.439 mmol) was added. The mixture was stirred at room temperature for 2 h. Solvent was evaporated under vacuum to give 2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl]-N-{1-[(6-methyl-2-pyridinyl)methyl]-1H-pyrazol-3-yl}hydrazinecarbothioamide (181 mg, 0.439 mmol, 100% yield) as yellow solid. [ES+MS] m/z 413 (MH+)]. Solid was dissolved in 5 mL of POCl3 and the mixture was stirred at 100° C., until no starting material was detected (1 h 30 minutes). Crude of reaction was partitioned between DCM and distilled water. Organic layer was dried over MgSO4 (anh), filtered and concentrated to give a light yellow solid. This solid was purified by HPLC preparative using X-Terra chromatography column (30 mm×150 mm), gradient 0% to 40% ACN/H2O, in neutral conditions to yield the title compound as a white solid (22 mg, 12.7%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.87 (br s, 1H), 7.77 (d, 1H), 7.59-7.65 (m, 1H), 7.15-7.17 (m, 1H), 6.77-6.80 (m, 1H), 6.01 (d, 1H), 5.83 (br s, 1H), 5.77 (q, 1H), 5.26 (s, 2H), 2.45 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.78 (d, 3H). [ES+MS] m/z 395 (MH+).
Reaction SMILES: C(O[C@H]1[C@@H](OC(=O)C)[C@H](COC(=O)C)O[C@@H]1N1C=NC(C(OC)=O)=N1)(=O)C.O.[CH:29]1[N:33]([C@@H:34]2[O:38][C@H:37]([CH2:39][OH:40])[C@@H:36]([OH:41])[C@H:35]2[OH:42])[N:32]=[C:31]([C:43]([NH2:45])=[O:44])[N:30]=1>CO.N>[C@H:34]1([N:33]2[CH:29]=[N:30][C:31]([C:43]([NH2:45])=[O:44])=[N:32]2)[O:38][C@@H:37]([CH2:39][OH:40])[C@H:36]([OH:41])[C@@H:35]1[OH:42]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Agent: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: N
Solvent: CO
Solvent: O
Product: NC(=O)c1ncn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The substrate (20) (1.1 g) was dissolved in CH3OH/NH3 at 0° C. and placed in a steel bomb. The bomb was closed and stirred at room temperature for 18 h. The steel bomb was cooled, opened and evaporated to dryness. The residue was tried to crystallization with little ethanol. The product crystallized, but on filtration, the crystals re-absorbed water and became a paste. The crystallization repeated several times. Finally it crystallized from Methanol/Ethanol mixture. The colorless crystals was filtered, washed with methanol and dried in vacuo. The filtrate was evaporated again which on standing gave further crystals. Total yield 0.5 g (72%); mp: 177-179° C.; [a]D =+38.33 (c 3 mg/mL H2O); D form of Ribavirin [a]D =-36.0 (c 3.0 mg/mL H2O); 1H NMR (Me2SO-d6) δ 3.46 (m, 1H, C5'H), 3.60 (m, 1H, C5 h), 3.92 (q, 1H, C4H), 4.12 (q, 1H), 4.34 (q, 1H), 4.88 (t, 1H, C5'OH), 5.20 (d, 1H), 5.58 (d, 1H), 5.80 (d, 1H, C1'H), 7.60 (bs, 1H, NH), 7.82 (bs, 1H, NH), and 8.82 (s, 1H, C3H). Anal. Calc. for C8H12N4O5 (244.20): C, 39.34; H, 4.95; N, 22.94. Found: C, 39.23; H, 4.97; N, 22.91.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([OH:12])(=[O:11])[CH:9]=[CH2:10]>N1(C2CCCCC=2)CCCC1.O>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:10][CH2:9][C:8]([OH:12])=[O:11]
Reactant: C=CC(=O)O
Reactant: O=C1CCCCC1
Agent: C1=C(N2CCCC2)CCCC1
Solvent: O
Product: O=C(O)CCC1CCCCC1=O
Temperature: 25 °C
Yield: 59.9 %

Procedure:
29.4 Grams (0.300 mol; 31.1 mL) cyclohexanone, 14.4 grams (0.200 mol; 13.7 mL) of acrylic acid, 1.6 mL (9.6×10-3 mol) of 1-pyrrolidino-1-cyclohexene and 0.09 grams (5×10-3 mol) of water were added to a 250 mL round bottomed flask equipped with a reflux condenser, thermometer, and magnetic stirrer. The mixture was stirred and heated under reflux for four hours. The mixture was then cooled to room temperature resulting in a slushy mixture. Next, the reaction product was subjected to fractional distillation using a 1×20 cm Vigreux column and 0.3 mm Hg vacuum. The fraction taken at 145-151° C. yielded 20.4 g of 91 percent 3-(2-oxocyclohexyl)-propanoic acid (54 percent yield). This fraction was recrystallized in 40 mL CHCl3 /200 mL petroleum ether to give 15.4 grams of 3-(2-oxocyclohexyl)propanoic acid at 99 percent purity.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH:20]5[CH2:22][CH2:21]5)[CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:28])[CH:16]([CH:20]5[CH2:21][CH2:22]5)[CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C4CC4)C3)c(F)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C1CC1
Temperature: 100 °C

Procedure:
A mixture of 210 mg of 1-cyclopropyl-7-(3-cyclopropyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.24 ml of 37% formaldehyde and 0.30 ml of 90% formic acid was heated at 100° C. for 4 hours, then allowed to cool and the excess reagents removed under reduced pressure. Water was added and the pH adjusted to 7 with 1N sodium hydroxide. The mixture was then extracted several times with chloroform:methanol (95:5), the extracts combined, dried, filtered and evaporated. The resulting oil was triturated with ether, giving 170 mg of the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=4)(=[O:38])=[O:37])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:14](OC)=[O:15].O>CCCCCC.C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:14]([CH2:2][C:1]#[N:3])=[O:15]
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(=O)CC#N)cc1OC
Reaction time: 1 h

Procedure:
Dry acetonitrile (1.8 ml) was added to a solution of n-butyl lithium (a 2.5M solution in hexane, 13.8 ml) in dry THF (30 ml) at -78° C. and the mixture was stirred at the same temperature for 1 hour to which was subsequently added a solution of methyl 3,4-dimethoxybenzoate (6.42 g) in dry THF (15 ml). The mixture was stirred at -78° C. for 3 hours and then at room temperature for 1 hour. Water (100 ml) was added to the reaction solution and the resultant mixture was extracted with ethyl ether (100 ml). After the aqueous layer was acidified with 6 N hydrochloric acid, it was extracted with ethyl acetate (200 ml×3). The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. Then, the solvent was distilled away under a reduced pressure. The resultant residue was crystallized from ethyl acetate-hexane to obtain the title compound (3.6 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccc(C2(CCCS(=O)(=O)[O-])CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Agent: Cl
Product: COc1ccc(C2(CCN3CCC(C(N)=O)(c4ccccc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
Prepared by the method of example 3.3 using 2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.55 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (175 mg, 0.73 mmol). Chromatography on silica gel (30 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and 10% methanol in dichloromethane gave the title compound: Rf =0.39 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]=[O:26])[N:22]([CH2:27][CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH:35]OS([O-])=O.[K+].O>CN(C=O)C>[CH:32]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([C:25]([OH:35])=[O:26])[N:22]([CH2:27][CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: O=S([O-])OO
Reactant: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-formyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101C, 27 mg, 0.059 mmol) and OXONE (79 mg, 0.129 mmol) in DMF was stirred at room temperature for 20 hrs. Water was added and the mixture was extracted with dichloromethane 3 times. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified with preparative HPLC to give 3-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-1-ethyl-1H-pyrazole-5-carboxylic acid (20 mg, 98% yield)
Reaction SMILES: Cl.NO.[OH-].[Na+].C(O)(=O)C.C[N:11](/[CH:13]=[N:14]/[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)C>O1CCOCC1>[O:23]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:13]=[N:11]1
Reactant: CN(C)/C=N/C(=O)c1ccc(O)cc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ncno2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of hydroxylamine hydrochloride (354 mg, 5.1 mmol) in an a mixture of aqueous 5N sodium hydroxide solution (1 mL, 5 mmol), acetic acid (10 mL) and dioxane (8.5 mL) was added the N-[(1E)-(dimethylamino)methylene]-4-hydroxybenzamide from step 1 of this Example (815 mg, 4.24 mmol). The reaction was stirred at 90° C. for 3 hrs. Upon cooling to room temperature, the solvent was removed under vacuum and residue was purified by column chromatography on an 80 gram biotage silica gel cartridge eluting with 20-50% ethyl acetate/hexanes (gradient) to give the product as white solid. LRMS calc: 162.0; obs: 163.2 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: O=CCN1CCOCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2CCNC2)cn1
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A vial was charged with (R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 233, 700 mg, 1.14 mmol) and morpholin-4-yl-acetaldehyde monohydrate hydrochloride (250 mg, 1.37 mmol) in methanol (10 mL). MP-cyanoborohydride (730 mg, 1.71 mmol) beads were added and the resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered and the beads were washed with more methanol. The filtrate was concentrated under reduced pressure and purified by Analogix SF15-24 g in dichloromethane/methanol system to give a light yellow solid (320 mg, 38.6%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[ClH:11].[F:12][C:13]1[CH:18]=CC(ON)=[CH:15][CH:14]=1>Cl>[ClH:11].[F:12][C:13]1[CH:18]=[CH:2][C:3]2[O:4][C:5]3[CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[C:15]=2[CH:14]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: NOc1ccc(F)cc1
Agent: Cl
Product: Fc1ccc2oc3c(c2c1)CNCC3
Yield: 43.9 %

Procedure:
1,4-dioxa-8-azaspiro[4,5]decane (0.12 mol) was added dropwise to a mixture of O-(4-fluorophenyl)hydroxylamine hydrochloride (1: 1) (0.1 mol) in a mixture of HCl and 1,1-oxybisethane (150 ml). The reaction mixture was stirred and refluxed for 4 hours and then cooled. The precipitate was filtered off and dried, then recrystallized from water, yielding 10 g (43.9%) 1,2,3,4-tetrahydro-8-fluorobenzofuro[3,2-c]pyridine hydrochloride (interm. 2; mp. >300° C.).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[O:12]1.C(=O)([O-])[O-].[K+].[K+].[CH:40](I)([CH3:42])[CH3:41]>C(#N)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH:40]([CH3:42])[CH3:41])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[O:12]1
Reactant: CC(C)I
Reactant: CCOC(=O)CCC1CC(NC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCC1CC(N(C[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C(C)C)C1
Temperature: 90 °C
Reaction time: 17.5 h
Yield: 15 %

Procedure:
A solution of the above crude ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate in acetonitrile (30 mL) was treated with potassium carbonate (6.3 g, 46 mmol) and isopropyl iodide (3.9 mL, 39 mmol). The reaction mixture in a sealed tube was heated at 90° C. for 6.5 h; HPLC indicated a 4:1 mixture of product to starting material. The reaction mixture was stirred overnight (17.5 h) at rt, treated with additional isopropyl iodide (2.0 mL, 20 mmol), and heated at 90° C. for 3 h; HPLC/LC MS indicated nearly complete conversion. The reaction mixture was cooled to rt and the solids were removed by vacuum filtration, rinsing with CH3CN, and the filtrate was concentrated in vacuo to afford a dull orange oil with precipitate. Purification by column chromatography (5×14.5 cm silica; 0-10% 7 N methanolic NH3/CH2Cl2) afforded the title compound (0.49 g, 15%) as a white foam/colorless oil. The mixed fractions containing product were repurified by column chromatography (4×10.5 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) to afford the title compound (1.66 g, 40%) as a white foam/colorless oil contaminated with the bisreductive amination byproduct from Step 1: MS (ESI+) for C25H38N6O5 m/z 503.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:26])[N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc(SCc2ccccc2)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(SCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9 %

Procedure:
6-Amino-9-benzyl-2-benzylthiopurine (176 mg, 0.51 mmol) and bromine (1 ml) were dissolved in 160 ml of methylene chloride and the solution was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (19 mg, yield 9%).