Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH3:31])[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH3:31])[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[N:23][N:24]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN(C)CCN(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Yield: 46 %

Procedure:
To a solution of Intermediate A (143 mg, 0.88 mmol) in DMF (3 mL) was added NaH (60% in oil, 96 mg, 2.4 mmol) and the mixture stirred at RT for 20 min, before Intermediate 43a (190 mg, 0.80 mmol) was added. This mixture was heated at 60° C. in the microwave for 1 h. The reaction mixture was applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-20% [2M NH3 in MeOH] in DCM, gave the title compound as a pale brown oil (140 mg, 46%). LCMS (Method 1): Rt 1.34 min, ink 381 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:18][CH2:17][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCN1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(NCCN1CCCC1)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
4-bromo-benzenesulfonyl chloride (3.36 g, 13.1 mmol, 1 equiv) was dissolved in 50 mL DCM and treated with TEA (9.16 mL, 65.7 mmol, 5 equiv). To this, while stirring the solution, was added 2-pyrrolidin-1-yl-ethylamine (3 g, 26.3 mmol, 2 equiv). After 3 h, reaction was poured onto DCM/water mixture and washed once. The aqueous phase was back extracted once with fresh DCM. Organic phases were combined, washed once with brine and dried over sodium sulfate. Filtration followed by rotary evaporation provided desired product. White needles (3.92 g, 90%). Rf=0.35 (10% MeOH/DCM)
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[CH3:10][C:11]([CH3:13])=O.C(O)(=O)C.C([O-])(=O)C.[NH4+]>CN(C)C=O.[C].[Pd]>[C:1]([CH:3]([CH:11]([CH3:13])[CH3:10])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: N#CCC(=O)NC(N)=O
Reactant: CC(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)C(C#N)C(=O)NC(N)=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
Cyanoacetylurea (78.6 g) was suspended in N,N-dimethylformamide (154.9 ml), and acetone (48.8 g), acetic acid (7.2 g) and ammonium acetate (4.6 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 10% palladium carbon (3.1 g, 50% wet product) under hydrogen pressure at 10 kg/cm2 and at 25° C. for 4 hours. The reaction mixture was heated to 70° C. to dissolve an insoluble matter, and the catalyst was filtered off. Water (390 ml) was added to the obtained filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyano-3-methylbutanoyl)urea (yield 89.7 g).
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][C:37]=1I)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cu][C:47]#[N:48]>CN(C)C=O>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][C:37]=1[C:47]#[N:48])[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1nc[nH]c1I)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1nc[nH]c1C#N)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Yield: 13.9 %

Procedure:
A solution of 335 mg (0.44 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-5-iodoimidazole-4-propionamide and 79 mg (0.88 mmol) of copper-(I) cyanide in 25 ml of dimethylformamide is stirred at 120° overnight under argon. Subsequently, the reaction mixture is evaporated under reduced pressure, the residue is suspended in 30 ml of a 95:5 mixture of methylene chloride and methanol and filtered over Dicalite. The filtrate is evaporated and, for purification, the residue is chromatographed on 50 g of silica gel using a 160:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. After precipitation from a methylene chloride-ether mixture there are obtained 40 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-5-cyanoimidazole-4-propionamide as a colourless powder; MS: 656 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6](=[NH:10])OCC.[NH3:14]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6](=[NH:10])[NH2:14]
Reactant: N
Reactant: CCOC(=N)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: N=C(N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
A 1-L round bottom flask was charged with ethyl 3-chlorobenzimidate hydrochloride (26.9 g, mmol, 122 mmol, 1 eq.) and NH3 (7N in methanol, 360 mL, 2.52 mol, 20 eq.) in methanol (270 mL). The resulting mixture was stirred at room temperature for 3 days. The volatile material was removed under reduced pressure and the resultant off-white solid was used in the next step without further purification (23.9 g, 89% yield). 1H NMR (DMSO-d6, 500 MHz) δ 9.48 (br s, 4H), 7.97-7.94 (m, 1H), 7.84-7.79 (m, 2H), 7.65 (t, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Mg].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH:20]=[O:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[OH:21])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Mg]
Product: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Yield: 59.5 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4,5-trimthoxy-phenyl)-methanol using 3,4,5-trimethoxy-bromobenzene (3.0 g, 12.1 mmol), magnesium turning (1.0 g, 24.3 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.8 g, 10.1 mmol). The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 7:3) to afford (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.1 g, 60%): 1H NMR (CDCl3) δ 7.82 (d, J=8 Hz, 1H), 7.23 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6,54 (s, 2H), 5,76 (s, 1H), 4.76 (s, 1H), 3.96 (s, 3H), 3.85 (s, 9H).
Reaction SMILES: [CH2:1]([C@@H:7]([C@@H:18]([O:39][Si](C(C)(C)C)(C)C)[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@H:7]([C@@H:18]([OH:39])[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@H](C[C@H](O)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Reaction time: 12 h
Yield: 60.4 %

Procedure:
480 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyl-dimethylsilyl)oxy]-5 -[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate and 350 mg of tetrabutylammonium fluoride trihydrate are dissolved in 8 ml of THF and stirred for 12 hours. After evaporation the residue is dissolved in 50 ml of ether and washed with water. The ethereal phase is dried and evaporated. The crude product is chromatographed on silica gel. There are obtained 240 mg of benzyl (2S,3S,5R)-2-hexyl-3-hydroxy-5 -[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate,, MS: 463 [(M+H)+ -dihydro-2H-pyran-2-yl].
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1=COCCC1
Reactant: Cc1ccc(CO)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(COC2CCCCO2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 9.85 g of 4-methyl-3-nitrobenzyl alcohol in 200 ml of dichloromethane is admixed successively with 10.9 ml of 3,4-dihydro-2H-pyran and 1.12 g of p-toluenesulphonic acid monohydrate. The reaction mixture is stirred at room temperature over 18 hours. The solution is poured onto 1M sodium hydrogencarbonate solution (300 ml) and extracted with tert-butyl methyl ether (2×300 ml). The organic phase is washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.49 (1:2 EtOAc-heptane); Rt=4.73.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: COc1cc2nc(CO)[nH]c2c(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(CO[Si](C)(C)C(C)(C)C)[nH]c2c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxymethyl-4,5,6-trimethoxybenzimidazole (354 mg) was dissolved in dry DMF (2 mL), tert-butyldimethylchlorosilane (270 mg) and imidazole (45 mg) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (chloroform:methanol=12:1) to obtain the title compound.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([C:33]([F:36])([F:35])[F:34])[CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][C:26]=3[C:33]([F:34])([F:35])[F:36])[CH2:18][CH2:19]2)[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C(F)(F)F)CC2)c1
Reaction time: 1 h

Procedure:
To a stirred solution of N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.99 mmol, 1.1 g), 4-nitro-2-(trifluoromethyl)benzoic acid (3.83 mmol. 0.9 g) and triethylamine (28.7 mmol, 4 mL. 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (8.94 mmol, 5.3 mL, 5.69 g, 50% solution in ethyl acetate) dropwise. After 1 hour stirring, ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate (×2), water (×2) and finally brine. The organic mixture was dried with sodium sulfate and concentrated under vacuum to give the intermediate N-tert-butyl-3-((4-(4-nitro-2(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH2:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:22][C:21]1[CH:23]=[C:17]([O:16][CH3:15])[CH:18]=[CH:19][C:20]=1[CH3:24])=[O:11]
Reactant: COc1ccc(C)c(N)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C)c(NC(=O)c2cc(C(N)=O)ccc2OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 5-methoxy-2-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].[C:13]([OH:22])(=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(Cl)Cl>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:13]([O-:22])(=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=N)NC(=N)N
Product: O=C([O-])CCCCC(=O)[O-]
Yield: 119.1 %

Procedure:
10.00 g of metformin hydrochloride, 2.40 g of sodium hydroxide and 2.20 g of adipic acid were stirred in 150 ml of ethyl alcohol at 70° C., and then methylene chloride was added thereto. Then, the produced inorganic salt was filtered, and ethyl acetate was added to the filtrate. The produced crystal was filtered and dried in hot air, thus obtaining 4.90 g (yield: 80.5%) of metformin adipate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Br:16][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][N:11]2[CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: Fc1ccc(-c2cc3n(n2)CCC3)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nn3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (44.5 g, 0.22 mol) in 600 mL chloroform is added at 0° C. N-bromosuccinimide (117 g, 0.66 mol). The mixture is stirred 17 h at RT. Thereafter, the mixture is diluted with water and extracted with dichloromethane. The combined organic phases are dried and evaporated. The obtained crude material is purified by column chromatography on silica (6 cm×40 cm, eluent dichloromethane). The obtained product is further purified by trituration with a MTBE-hexane mixture and 38.2 g (61%) of the product are obtained as solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])(O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>[Zn].C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN(C)C(=O)CC1C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A flask is charged with 2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 19) (10.0 g, 30.8 mmol), acetic acid (250 mL), acetic anhydride (100 g), and Zn-dust (20 g). The mixture is kept under reflux, until all of the starting material is consumed (3 h). The solids are then filtered off, and from the filtrate the solvent is removed to leave an oil which crystallizes to a pale brown solid on treatment with di-iso-propyl ether. Yield of the title compound: 9.2 g (96.8%). 1H-NMR (CDCl3, 300 MHz) δ 2.73 (dd, 1, 2J=16.5 Hz, J=9.4 Hz, CH2NMe2); 3.00, 3.01 (2 s, 6, N(CH3)2); 3.20 (dd, 1, J=3.2 Hz, CH2NMe2); 4.06 (dd, 1, H-3); 4.90, 4.97 (AB, 2, 2J=15.6 Hz, CH2N); 6.70 (d, 1, J=7.9 Hz, H-7); 6.97 (“dtr”, J=7.5 Hz, J=1.2 Hz, H-5); 7.13 (“dtr”, J=7.8 Hz, J=1.2 Hz, H-6); 7.22-7.29, 7.29-7.33 (m, 5, 5 Ph-H); 7.38 (br d, 1, J=7.5 Hz, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.25 (CH2NMe2); 36.07, 37.51 (N(CH3)2); 42.59 (C-3); 44.28 (NCH2Ph); 109.12 (C-7); 122.66 (C-5); 124.85 (C-4); 127.49 (Ph meta-C); 127.71 (Ph para-C); 128.04 (C-6); 128.92 (Ph ortho-C); 129.63 (C-9); 136.19 (Ph ipso-C); 143.52 (C-8); 170.00 (CONMe2); 178.02 (C-2),
Reaction SMILES: O.O.[OH-].[Li+].[F:5][CH:6]([F:25])[O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10](C(OCC)=O)[N:9]=1>C1COCC1>[F:25][CH:6]([F:5])[O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)n1nc(OC(F)F)c2cc([N+](=O)[O-])ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2[nH]nc(OC(F)F)c2c1
Temperature: 80 °C
Yield: 106.2 %

Procedure:
Water (6 ml) and lithium hydroxide monohydrate (640 mg) were added to a THF (19 ml) solution containing ethyl 3-(difluoromethoxy)-5-nitro-1H-indazol-1-carboxylate (1.14 g) obtained in the 1st step, followed by reflux at 80° C. for 3 hours. THF was distilled away under reduced pressure and a saturated ammonium chloride aqueous solution was added. An insoluble precipitate was removed by filtration. The obtained residue was washed with water, dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. A yellow solid of 3-(difluoromethoxy)-5-nitro-1H-indazole (921 mg) was thus obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH:15]([NH2:18])([CH3:17])[CH3:16]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH3:16][CH:15]([NH:18][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:17]
Reactant: CC(C)N
Reactant: O=S(=O)(CCCCCl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)NCCCCS(=O)(=O)c1ccccc1
Product: Cl
Yield: 30 %

Procedure:
A solution of 105.95 g (0.456 mole) [(4-chlorobutyl)sulfonyl]benzene was heated overnight at 75° C. on an autoclave in 200 ml of isopropylamine. The reaction mixture was stripped to dryness. The residue obtained was dissolved in chloroform and the chloroform layer was extracted with water. The chloroform layer was dried, filtered, and solvent removed to give a dark brown oil. The oil was dissolved in methanol and converted to the hydrochloride salt. This salt was recrystallized from methanol-diethyl ether and dried in vacuo overnight at 80° C. This gave white crystalline product, m.p. 155°-157.5° C. in 30% yield.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[C:8]([CH2:11][C:12](=[O:14])[CH3:13])(=[O:10])[CH3:9]>>[C:8]([C:11]1[C:1]([OH:6])=[CH:2][C:3](=[O:4])[O:14][C:12]=1[CH3:13])(=[O:10])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: O=C(Cl)CC(=O)Cl
Product: CC(=O)c1c(O)cc(=O)oc1C
Temperature: 25 °C
Yield: 15.3 %

Procedure:
When 7.0 mL (72.0 mmol) of malonyl chloride was added to 7.0 mL (67.8 mmol) of acetylacetone, a violent exothermic reaction occurred to give a black solid within a few minutes. The solid was cooled to room temperature, washed with ether and then ethyl acetate, and filtered. The thus-obtained brown solid was recrystallized from ethyl acetate/methanol to give 1.75 g (10.4 mmol, 15.3%) of 5-acetyl-4-hydroxy-6-methyl-2-pyrone as brown crystals. The filtrates from washing and the recrystallized mother liquor were combined and concentrated; the residue was purified by silica gel column chromatography to give 2.87 g (17.1 mmol, 25.2%) of 5-acetyl-4-hydroxy-6-methyl-2-pyrone as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:3]1[C:2]([Cl:1])=[C:7]([C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:5][N:4]=1)[C:8]#[N:9].[Cl:26][C:5]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[C:7]([C:2]([Cl:1])=[CH:3][N:4]=1)[C:8]#[N:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(Cl)c[n+]([O-])cc1-c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cnc(Cl)c1Cl
Product: N#Cc1c(Cl)cnc(Cl)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 100 °C

Procedure:
A suspension of 3-chloro-4-cyano-5-(4-phenoxyphenyl)pyridine 1-oxide (0.3068 g, 0.951 mmol) in phosphorus oxychloride (5 mL, 53.6 mmol) was heated to 100° C. for 1 h. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (30 mL) and brine (30 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 5-15% ethyl acetate in hexanes, gave 2,3-dichloro-5-(4-phenoxyphenyl)isonicotinonitrile (156.6 mg), 2,5-dichloro-3-(4-phenoxyphenyl)isonicotinonitrile (89.4 mg) and a 2:3 mixture of the two isomers (65.4 mg). Characterization of 2,3-dichloro-5-(4-pherioxyphenyl)isonicotinonitrile: 1H NMR (400 MHz, CDCl3) δ ppm 8.49 (1H, s), 7.48-7.59 (2H, m), 7.35-7.46 (2H, m), 7.21 (1H, t, J=7.40 Hz), 7.05-7.18 (4H, m); MS (ES+) m/z: 341 (M+H); LC retention time: 4.601 min (analytical HPLC Method A). Characterization of 2,5-dichloro-3-(4-phenoxyphenyl)isonicotinonitrile: 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (1H, s), 7.33-7.48 (4H, m), 7.21 (1H, t, J=7.40 Hz), 7.07-7.18 (4H, m); MS (ES+) m/z: 341 (M+H); LC retention time: 4.438 min (analytical HPLC Method A).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C@@H:16]([NH2:18])[CH3:17].Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:29]1[C:21]([NH:18][CH:16]([C:8]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1ccccc1-n1c([C@H](C)N)nc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccccc1-n1c(C(C)Nc2ncnc3[nH]cnc23)nc2cccnc21
Temperature: 90 °C
Yield: 31.9 %

Procedure:
A mixture of (S)-1-(3-o-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (330 mg, 1.31 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (430 mg, 1.83 mmol) and DIPEA (0.41 mL, 2.35 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 168 as a white solid (155 mg, 32%). LCMS (Method K): RT 2.70 and 2.83 min [M+H]+ 371.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (1H, s), 8.30-7.86 (4H, m), 7.69-7.08 (5H, m), 5.47 (1H, s), 1.96 (3H, s), 1.68 (1.5H, d, J=6.77 Hz), 1.50 (1.5H, d, J=6.84 Hz). Signals split due to presence of rotamers/tautomers.