Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl.C(N(CC)C(C)C)(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[C:66]([CH2:67][C:68](O)=[O:69])=[CH:65][CH:64]=[CH:63][N:62]=4)[C:56]([C:71]([F:74])([F:73])[F:72])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[NH2:2][C:68](=[O:69])[CH2:67][C:66]1[C:61]([CH2:60][CH2:59][C:57]2[C:56]([C:71]([F:73])([F:74])[F:72])=[CH:55][N:54]=[C:53]([NH:52][C:49]3[CH:48]=[CH:47][C:46]([CH:42]4[CH2:43][CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[CH2:41]4)=[CH:51][CH:50]=3)[N:58]=2)=[N:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(=O)O)n3)cc2)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)C1
Reaction time: 17 h

Procedure:
1-Hydroxybenzotriazole (20 mg, 0.15 mmol), EDCl.HCl (32 mg, 0.17 mmol) and N,N-diisopropylethylamine (45 μL, 0.26 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetic acid (1149) (29 mg, 0.051 mmol) in dry DMF (5 mL) under an atmosphere of nitrogen. Ammonium carbonate (50 mg, 0.52 mmol) was added in one portion after 10 minutes then stirring was continued at room temperature for 17 hours. Further portions of 1-hydroxybenzotriazole (20.0 mg, 0.15 mmol), EDCl.HCl (32 mg, 0.17 mmol) and N,N-diisopropylethylamine (45 μL, 0.26 mmol) were added, then ammonium carbonate (50 mg, 0.52 mmol) was added in one portion after 10 min. The resulting solution was stirred at 25° C. for 24 hours. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate (I0 mL) and saturated sodium hydrogen carbonate (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL) then the combined organic layers were washed with brine (10 mL), dried (MgSO4) and evaporated to dryness. The residue was chromatographed (Biotage Isolera: 10 g silica cartridge, 0-100% EtOAc/petroleum benzine 40-60° C. then 10 g silica cartridge, 50-100% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I150) (0.023 g, 77%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.77 (br s, 1H), 7.57-7.44 (m, 3H), 7.19 (d, J=8.5 Hz, 2H), 7.14 (dd, J=7.6, 4.8 Hz, 1H), 5.63 (d, J=22.0 Hz, 2H), 4.35-3.96 (m), 3.67 (s, 2H), 3.41-3.33 (m, 2H), 3.27 (t, J=6.9 Hz, 2H), 2.83-2.58 (m, 3H), 2.01-1.99 (m, 1H), 1.80-1.71 (m, 1H), 1.68 (s, 3H), 1.65-1.52 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]12[CH2:78][CH2:77][CH:74]([CH2:75][CH2:76]1)[CH:73]([NH2:79])[CH2:72]2>CN1C(=O)CCC1>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:79][CH:73]5[CH:74]6[CH2:77][CH2:78][N:71]([CH2:76][CH2:75]6)[CH2:72]5)=[O:34])=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:18][CH2:17]1
Reactant: NC1CN2CCC1CC2
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)NC2CN3CCC2CC3)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 40 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to according to example 68 with quinuclidin-3-amine (79 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (24.3 mg, 40% yield); MS (ESI) m/z=614.7
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:31]>C(O)CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:2])[NH:31][C:6](=[O:7])[C:5]3=[CH:10][C:11]=2[NH:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:16][CH:17]=1
Reactant: N
Reactant: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21

Procedure:
Analogously to Example 1, 290 mg (0.7 mmol) of 4,5-bis(4-fluoroanilino)phthalic acid dimethyl ester in 22 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of orange crystals, m.p.>220° C., FAB-MS: 366 [M+ +H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=2[F:30])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:30])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2F)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc(N)ccc2F)cc1

Procedure:
Following a reaction and purification procedure similar to those described in Example (59b), 800 mg of N-[1-(3,4-difluorophenyl)ethyl]-N-[(2-fluoro-5-nitrophenyl)-(4-methoxyphenyl)methyl]amine [prepared as described in step (a) above], 1.05 g of nickel chloride hexahydrate and 306 mg of sodium borohydride were reacted, to obtain 330 mg of isomer A and 350 mg of isomer B of the title compound as yellow oils, respectively.
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.[H-].[Na+]>C(N)CN>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: NCCN
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 75 %

Procedure:
0.720 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone, 0.144 g (6 mmole) of sodium hydride and 10 ml of ethylene-diamine were heated at 100° for 4 hours, then cooled, extracted and finally distilled as indicated hereinabove to afford the desired compound in a 75% yield.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C>[Br:46][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one (1.20 g, 3.53 mmol) in DMF (10 mL) were added PPh3 (1.02 g, 3.88 mmol) and CBr4 (1.29 g, 3.88 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried under vacuum and purified by the Simpliflash system, using 2% methanol in CH2Cl2 as eluent, to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one as a white solid. Yield: 0.547 g (38%).
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1)[CH3:3].C1C[O:23][CH2:22]C1.Cl>O>[CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH:22]=[O:23])[CH2:7][CH2:6]1)[CH3:3]
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: CN(C)C(c1cccc(F)c1)C1CCC(CC=O)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The aldehyde 34 (13.69 g, 52 mmol) dissolved in abs. THF (90 ml) was then added dropwise at RT, and stirring was carried out overnight at RT. Hydrolysis was carried out dropwise with water (50 ml) and 6N HCl (150 ml), while cooling with ice-water. After 1 hour's stirring at RT, extraction with ether was carried out ten times (50 ml each time). The aqueous phase was adjusted to pH 11 with 5N NaOH, extracted by shaking three times with ethyl acetate (100 ml each time), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/cyclohexane (1:1).
Reaction SMILES: [P:1](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)[C@@H]1O)([OH:4])([OH:3])=[O:2].[P:25]([O:29][C@@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C@@H:32]([N:37]2[CH:44]=[CH:43][C:41]([NH2:42])=[N:40][C:38]2=[O:39])[C@@H:31]1[OH:45])([OH:28])([OH:27])=[O:26]>>[P:25]([O:29][C@@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C@@H:32]([N:37]2[CH:44]=[CH:43][C:41]([NH2:42])=[N:40][C:38]2=[O:39])[C@@H:31]1[OH:45])([O:27][P:1]([OH:4])([OH:3])=[O:2])(=[O:28])[OH:26]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)O)[C@H]2O)c(=O)[nH]1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)O)[C@H]2O)c(=O)n1
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)OP(=O)(O)O)[C@H]2O)c(=O)n1

Procedure:
Cytidine-3'-diphosphate was prepared by repeating the procedure of Example 1 except that guanosine-3'-monophosphate was replaced by cytidine-3'-monophosphate.
Reaction SMILES: CC(N(C)C)C(O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(NC1C=CC=CC=1)C.[CH:29]1([CH:35]=[C:36]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)[C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.Cl>C(OCC)C.O>[CH:29]1(/[CH:35]=[C:36](/[N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)\[CH:37]([OH:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Agent: CC(C(O)c1ccccc1)N(C)C
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: CCOCC
Solvent: CCNc1ccccc1
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 12.5 g (70 mmols) of the (+)-antipode of N-methyl-ephedrine in 140 ml of absolute diethyl ether is added dropwise, at 20° C., to a stirred suspension of 2.7 g (70 mmols) of lithium aluminum hydride in 70 ml of diethyl ether. The mixture is heated under reflux for 30 minutes and then cooled to 20° C., 17 g (140 mmols) of N-ethylaniline are added dropwise, and the mixture is allowed to boil under reflux for one hour. Thereafter, the reaction mixture is cooled to -70° C. A solution of 5.2 g (20 mmols) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene-3-one in 50 ml of absolute diethyl ether is added dropwise at this temperature. Stirring is continued for a further 4 hours at -70° C., and the reaction mixture is then allowed to stand for a further 16 hours at - 70° C. Water is then added slowly. The resulting reaction mixture is acidified with 10% strength aqueous hydrochloric acid so that the pH value is about 4. Thereafter, the organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed twice with 5% strength aqueous hydrochloric acid, dried over magnesium sulphate and then evaporated down under reduced pressure. The crystalline residue which remains is stirred with cyclohexane, and the product is filtered off under suction, washed with cyclohexane and dried. 3.2 g (61% of theory) of the (+)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in the form of a crystalline product in this manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:14][O:15][CH2:16][CH2:17]Br>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[N:9]2[CH2:17][CH2:16][O:15][CH3:14])=[CH:5][CH:4]=1
Reactant: COCCBr
Reactant: COc1ccc2c(c1)NC(=O)C2=O
Product: COCCN1C(=O)C(=O)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a red solid, using 6-methoxy-isatin prepared as described in Pavlidis et al. and 2-bromoethyl methyl ether following Method B. Pavlidis, V. H., et al., The Synthesis of a Novel Series of Substituted 2-Phenyl-4H-3,1-benzoxazin-4-ones, Synthetic Communications, 1994, 24:4, 533-548. NMR (CDCl3): δ 3.35 (s, 3H), 3.65 (t, 2H), 3.87 (s, 3H), 3.94 (t, 2H), 6.64 (d, 1H), 7.58 (t, 1H), 7.79 (d, 1H), 13.93 (br s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:20][CH2:17][CH2:18][CH3:19])[C:11]=1[I:12]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and propylamine in THF. ES-MS m/e (%): 345 (M+H+, 100).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1)=[O:16]
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: O=C(O)Cc1ccc(C(=O)c2cccc(C(F)(F)F)c2)s1

Procedure:
Using the procedure of Example 1, 7.1 gm of thiophene-2-acetic acid and 10.40 gm of m-trifluoromethyl-benzoyl chloride were reacted to obtain 5(m-trifluoromethyl-benzoyl)-thiophene-2-acetic acid melting at 120° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)C)=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[ClH:18]>>[ClH:18].[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(NC(C)=O)ccc2o1
Agent: Cl
Product: CCCCc1cc2cc(N)ccc2o1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A mixture of N-(2-butyl-5-benzofuranyl)acetamide [10a] (1.16 g, 5.0 mmol) and 15% hydrochloric acid (10 mL) was stirred overnight under reflux conditions and 2 hours at 0-5° C. The precipitated crystals were filtered off, washed on the filter with cold water and ethyl acetate and dried under reduced pressure at 50° C. (water bath) to a constant weight to give 1.00 g (88.6%) of 2-butyl-5-benzofuranamine hydrochloride [12a] as off-white crystalls with mp 189-192° C. (with decomposition).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:25])[CH2:23][N:24]=2)=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>O1CCCC1>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([O:25][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:23][N:24]=2)=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 50 °C
Yield: 67.7 %

Procedure:
Phenyl isocyanate (0.95 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-acetylphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (2 g) in tetrahydrofuran (25 cc). The solution obtained is heated to 50° C. for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization in ethanol, (5RS, 6SR)-2-(4-acetylphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.9 g), m.p. 168° C., is obtained.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]4[C:33](=O)[CH2:32][CH2:31][CH2:30][C:27]=4[CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1>COCCOC>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]4[C:33](=[CH:5][C:3]#[N:4])[CH2:32][CH2:31][CH2:30][C:27]=4[CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 12.0 g, 300 mmol) in DME (600 mL) was added diethyl (cyanomethyl)phosphonate (53.1 g, 300 mmol) at a dropwise rate under nitrogen. After gas evolution ceases (about 30 min), 1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[f]indazol-5(6H)-one (4, R1=4-Fluorophenyl) (42.0 g, 150 mmol) was added in portions. The reaction was stirred at rt for about 3 h, then the reaction was concentrated under reduced pressure and the residue was dissolved with EtOAc (1000 mL) and sat. aq. NH4Cl (500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (330 g) using a gradient of 70-100% DCM in heptane. Product fractions were combined and concentrated under reduced pressure to yield 2-(1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[f]indazol-5(6H)-ylidene)acetonitrile (27, R1=4-Fluorophenyl) as a 2:1 mixture of isomers (42.9 g, 94%); LC/MS, method 3, Rt=2.57 min, MS m/z 304 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.60 (bs, 0.33H), 8.50 (d, J=0.9 Hz, 0.33H), 8.42 (bs, 0.67H), 8.40 (d, J=0.9 Hz, 0.67H), 7.88-7.76 (m, 2H), 7.67 (bs, 0.33H), 7.64 (bs, 0.67H), 7.52-7.36 (m, 2H), 6.32 (t, J=1.6 Hz, 0.67H), 5.73 (t, J=1.5 Hz, 0.33H), 3.03-2.95 (m, 2H), 2.90-2.83 (m, 1H), 2.71-2.64 (m, 1H), 1.93-1.81 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:31]#[C:32][CH2:33][OH:34])[CH:14]=2)[N:9]=1.Cl>CO.O1CCOCC1>[OH:34][CH2:33][C:32]#[C:31][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[N:17]=[C:16]2[NH:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OCC#Cc1ccc2nc(-c3ccccc3O)nc(N[C@H]3CCNC3)c2c1
Reaction time: 12 h
Yield: 27.3 %

Procedure:
(S)-tert-Butyl 3-(2-(2-hydroxyphenyl)-6-(3-hydroxyprop-1-ynyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.028 g, 0.061 mmol) was dissolved in methanol (1 mL) and 4 M HCl in dioxane (2 mL) added. After stirring for 12 hours, the solution was concentrated and purified by ion exchange chromatography on SCX-2 (solute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by preparative thin layer chromatography, eluting with 20% methanol in dichloromethane, gave the title compound as a yellow solid (0.006 g, 27%).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:18])[CH:4]=1)=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:19]([NH:23][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:18])[CH:4]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1C
Reactant: CCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNCc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
To a solution of ethyl 2-(4-formyl-2-methylphenoxy)-2-methylpropanoate (0.56 g, 2.25 mmol) in anhydrous CH2Cl2 (10 mL) was added n-butylamine (0.33 mL, 3.38 mmol). After stirring for 90 mins under nitrogen at room temperature, sodium triacetoxyborohydride (0.668 g, 3.15 mmol) was added and stirring continued for 18 h. The reaction was quenched by cautious addition of sat. sodium carbonate aq. (20 mL) and then extracted CH2Cl2 (2×40 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow oil (0.48 g).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH2:8]([NH:10][C:11]([NH2:13])=[NH:12])[CH3:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](Cl)=[O:31]>CC(C)=O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([NH:13][C:11]([NH:10][CH2:8][CH3:9])=[NH:12])=[O:31]
Reactant: COc1ccccc1CC(=O)Cl
Reactant: CCNC(=N)N
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCNC(=N)NC(=O)Cc1ccccc1OC
Reaction time: 1 h

Procedure:
8.80 g of a 50% aqueous sodium hydroxide solution, ethylguanidine sulfate (14.98 g) and 100 ml of acetone, are stirred for 21/2 hrs at RT. The resulting mixture is treated with anhydrous sodium sulfate (6.0 g) and stirring continued for 1 hr. A solution of 2-methoxyphenylacetyl chloride (9.23 g) in 50 ml of acetone is added to the mixture dropwise and stirring is continued overnight at RT. The reaction mixture is filtered, the filtrate diluted with 100 ml of saturated aqueous sodium bicarbonate and the acetone evaporated in vacuo. The residue is diluted with 100 ml H2O and extracted with two 100 ml portions of methylene chloride. The extract is dried with sodium sulfate, filtered and concentrated in vacuo. The concentrate is acidified with ethereal hydrochloric acid and the solvent evaporated in vacuo. After stirring the residue with 200 ml of diethyl ether, the solid is collected, washed with diethyl ether and dried in air. The residual solid is recrystallized from acetone affording a white solid, M.P. 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Cl:13]Cl>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Cl:13])=[CH:11][NH:10][N:9]=1
Reactant: ClCl
Reactant: Clc1ccccc1-c1cc[nH]n1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccccc1-c1n[nH]cc1Cl
Temperature: 25 °C
Yield: 44.5 %

Procedure:
6.8 g (0.038 mol) of 3-(2'-chlorophenyl)-1H-pyrazole, prepared as in Example 9, are dissolved, at temperature and with stirring, in 30 ml of acetic acid. 2.9 g (0.0409 mol) of chlorine are then introduced into the reaction mixture. Stirring is maintained for 1 hour at room temperature and then the acetic acid is driven off under reduced pressure. The residue is taken up in methylene chloride and this organic solution is washed with in aqueous bicarbonate solution, then with water and then dried over Na2SO4 before being concentrated to dryness. The residue is chromatographed on a silica column (eluent: heptane/ethyl acetate 60/40). 3.6 g of 3-(2'-chlorophenyl)-4-chloro-1H-pyrazole (compound 96) are obtained, which is of honey-like consistency (yield 44%).