Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1N)([CH3:4])([CH3:3])[CH3:2].N([O-])=[O:16].[Na+].NC(N)=O.OS(O)(=O)=O.O>OS(O)(=O)=O.O>[C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 61.5 %

Procedure:
To a mixture of 2-tert-butyl-5-nitroaniline (1.94 g, 10 mmol) in 40 mL of 15% H2SO4 was added dropwise a solution of NaNO2 (763 mg, 11.0 mmol) in water (3 mL) at 0° C. The resulting mixture was stirred at 0-5° C. for 5 min. Excess NaNO2 was neutralized with urea, then 5 mL of H2SO4—H2O (v/v 1:2) was added and the mixture was refluxed for 5 min. Three additional 5 mL aliquots of H2SO4—H2O (v/v 1:2) were added while heating at reflux. The reaction mixture was cooled to room temperature and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-10% EtOAc—Hexane) to give 2-tert-butyl-5-nitrophenol (C-1-a) (1.2 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=8.6, 2.2 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 5.41 (s, 1H), 1.45 (s, 9H); HPLC ret. time 3.46 min, 10-99% CH3CN, 5 min run.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2([OH:19])[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[C:5]([CH2:20][CH:21]=[CH2:22])[CH:4]=1)=O.[ClH:23].[O:24]([NH2:26])[CH3:25]>C(O)C>[ClH:23].[CH3:25][O:24][N:26]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2([OH:19])[CH:16]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]3)[CH2:12]2)=[C:5]([CH2:20][CH:21]=[CH2:22])[CH:4]=1
Reactant: CON
Reactant: C=CCc1cc(C=O)ccc1C#CC1(O)CN2CCC1CC2
Agent: Cl
Solvent: CCO
Product: C=CCc1cc(C=NOC)ccc1C#CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-[2-(4-formyl-2-allylphenyl)ethynyl]quinuclidin-3-ol (1.0 g) and methoxylamine hydrochloride were dissolved in ethanol (35 ml) and the mixture stirred at 25° C. for 12 hours. The ethanol was evaporated and the residue crystallised from ethyl acetate to give 3-[2-(4-methoxyiminomethyl-2-allylphenyl)ethynyl]quinuclidin-3-ol hydrochloride as a solid, m.p. 143° C.; microanalysis, found: C, 64.7; H, 7.0; N, 8.0% C20H24N2O2HCl. 0.5H2O requires C, 64.9; H, 7.0; N, 7.6% NMR ([CD3 ]2SO/CD3COOD): 1.5-2.3 (5H, m), 3.2 (4H, t), 3.4 (1H, d), 3.6 (1H, dd), 3.9 (3H, s), 5.1 (2H, m), 6.0 (1H, m), 7.5 (3H, m) and 8.2 (1H, s), m/z 325 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (165) (7.5 mg, 0.03 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (12 μl, 3 eq) followed by addition of DIEA (26 μl). The resulting solution was stirred at r.t. for 1 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (150 μl) at r.t. for 1 h before worked up with EA/brine. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (166) (8.3 mg, yield: 75.3%, purity>95%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O(7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl 3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:19]2[N:20]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:21]=[C:22]3[CH2:26][CH2:25][CH2:24][C:23]=23)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[CH:5][N:6]=3)=[C:23]3[CH2:24][CH2:25][CH2:26][C:22]3=[N:21]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)nc1

Procedure:
In analogy to the procedure described in example 2, 6-{2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-nicotinic acid methyl ester was hydrolysed using aqueous sodium hydroxide solution in MeOH to give the title compound as off-white solid. MS: m/e=466.2 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)/[C:7]1=[O:23])=[O:5])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[N:32][C:33]([O:35][Si](C)(C)C)=[CH2:34])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:35][C:33](=[O:34])[NH:32][CH:31]2[C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\C2CCCCC2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1ccc(Cl)cc1)NC(=O)CC2C1CCCCC1
Yield: 72 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.40 g, 1.20 mmol) prepared in example 6b was reacted with 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 7a, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a white solid (Yield 0.45 g, 72%).
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([S:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=C1.S1C=CC(SC2C=C[C:23]([N+:26]([O-])=O)=[CH:22]C=2)=C1.NC1C=CC=CC=1>>[N:26]1[CH:23]=[CH:22][CH:5]=[CH:4][C:3]=1[S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:11])=[CH:12][CH:13]=1
Reactant: Nc1ccc(Sc2ccsc2)cc1
Reactant: O=[N+]([O-])c1ccc(Sc2ccsc2)cc1
Solvent: Nc1ccccc1
Product: Nc1ccc(Sc2ccccn2)cc1

Procedure:
4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A1. A3j. General Method for Substituted Aniline Formation Via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[NH2:24][C:25]1[C:35]([Br:36])=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32][Cl:33])=[CH:27][C:26]=1[Br:37]>>[ClH:33].[NH2:24][C:25]1[C:26]([Br:37])=[CH:27][C:28]([O:29][CH2:30][CH2:31][CH2:32][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[C:14](=[O:15])[CH2:13][C:12]4[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=4[CH2:10][CH2:9]3)[CH2:2]2)=[CH:34][C:35]=1[Br:36]
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Reactant: Nc1c(Br)cc(OCCCCl)cc1Br
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCCOc3cc(Br)c(N)c(Br)c3)C1)CC2
Product: Cl

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 3-(4-amino-3,5dibromo-phenoxy)-propyl chloride analogously to Example 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)[CH2:16][CH2:15]1)=[O:19]
Reactant: O=C(O)C1CCC(Cc2nc3ncccc3[nH]2)CC1
Reactant: NCc1ccccc1F
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ncccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid (Compound AAB) (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the resulting reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. Preparative chromatography eluting with chloroform:methanol gave the cis 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 367 [(M+H)+; calcd for C21H24N4OF: 366].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[C:10]([OH:13])=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH2:14]1COCC1.N1CCCC1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27](S(O)(=O)=O)=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH3:14][C:24]([CH3:25])([CH3:34])[CH2:29][CH2:28][CH:27]=[CH:26][C:9]1[C:7](=[O:8])[C:5]2[C:4]([C:11](=[O:12])[C:10]=1[OH:13])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCOC1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: CC(C)(C)CCC=CC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
The aldehyde (8.46 mmol) was coupled to lawsone following the procedure set out in Example 42 using lawsone (1.18 g),THF (20 ml), pyrrolidine (672 μl), benzene (40 ml) and p-toluenesulphonic acid (1.95 g). 391 mg of the title compound was isolated after purification.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[C:8]([C:14]#[N:15])[C:7]=1[Cl:16].[OH-:18].[Na+]>O>[C:14]([C:8]1[C:7]([Cl:16])=[C:6]([C:11]([Cl:12])=[CH:10][C:9]=1[Cl:13])[O:5][CH2:4][C:3]([OH:2])=[O:17])(=[O:18])[NH2:15]
Reactant: COC(=O)COc1c(Cl)cc(Cl)c(C#N)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Cl)cc(Cl)c(OCC(=O)O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
29.4 g (0.1 mol) of 3-cyano-2,4,6-trichlorophenoxyacetic acid methyl ester are suspended in 300 ml of water. After addition of 35 ml of concentrated sodium hydroxide, the reaction mixture is heated at 60° C. until a clear solution is obtained. After filtration over active carbon, the solution is cooled and brought to pH 2 by dropwise addition of 50% concentrated hydrochloric acid. The mixture is stirred for 2 hours in an ice bath, after which the resultant precipitate is vacuum-filtered, washed with water and dried at 50° C., thus producing 25.4 g (85% of theory) of 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid as a white powder, mp 261°-262° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:32]=[CH:31][C:12](/[CH:13]=[CH:14]/[C:15]2[N:23]([CH3:24])[C:22]3[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH3:30])[C:17]=3[N:16]=2)=[CH:11][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[OH-].[Na+]>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:13]=[CH:14]/[C:15]2[N:23]([CH3:24])[C:22]3[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH3:30])[C:17]=3[N:16]=2)=[CH:31][CH:32]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN=[N+]=[N-])cc3)n2C)n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN)cc3)n2C)n(CC)c1=O

Procedure:
Compound 178 (75 mg, 0.17 mmol) obtained in Reference Example 117 was dissolved in 7.5 ml of tetrahydrofuran. To the solution was added 90 mg (0.34 mmol) of triphenylphosphine, and the mixture was heated under reflux for 3 hours. Water (5 ml) was added thereto and the mixture was heated under reflux for further one hour. After cooling, a 2N aqueous solution of sodium hydroxide was added thereto, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform/methanol/triethylamine) to give 74 mg (yield quant.) of Compound 179. The obtained crude crystals were further recrystallized from 2-propanol/water.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH3:24])[C:5](=[O:23])[C:6]2[C:7]([N:22]=1)=[C:8]([OH:21])[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([CH2:17]O)=[N:13][C:14]=1[C:15]=2[OH:16].[Li+].[Cl-:26].CS([Cl:31])(=O)=O.[K+].[Br-]>CN(C)C=O.O>[Cl:26][CH2:2][C:3]1[N:4]([CH3:24])[C:5](=[O:23])[C:6]2[C:7]([N:22]=1)=[C:8]([OH:21])[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([CH2:17][Cl:31])=[N:13][C:14]=1[C:15]=2[OH:16]
Reactant: CS(=O)(=O)Cl
Reactant: [Cl-]
Reactant: Cn1c(CO)nc2c(O)c3c(=O)n(C)c(CO)nc3c(O)c2c1=O
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(CCl)nc2c(O)c3c(=O)n(C)c(CCl)nc3c(O)c2c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 105 mg (0.313 mmol) of 20 in 10 mL of dry dimethyl formamide, were added 66 mg (1.56 mmol) of LiCl and 191 mg (1.56 mmol) of dimethylaminopyrldine. To this mixture was added 120 μL (1.56 mmol ) of methanesulfonyl chloride and the resulting solution gently heated with a heat gun until it became homogenous. After stirring this mixture at room temperature for 6 h, it was combined with 100 mL of water and the resulting mixture allowed to stir for an additional 2 hours. The resulting yellow precipitate was filtered, rinsed with water, and dried: 99 mg (85%) yield; mp >275° C. dec; IR (KBr pellet) 3036, 1645, 1603, 1421, 1372, 1343, 1270, 1240, 1015, 794 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ11.84 (2H, s, 5- and 10-hydroxyl) 4.95 (4H, s, methylenes), 3.65 (6H, s, 3- and 8- methyls); mass spectrum (EI, solids probe), m/z 370 (P+, 35Cl35Cl), 372 (P+, 37Cl35Cl), 374 (P+, 37Cl37Cl). Anal. Calcd for C14H12Cl2N4O4 : C, 45.30, H, 3.26; N, 15.09. Found: C, 45.76; H, 3.47; N, 13.99.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[NH2:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=1.C[N:20](C=O)C>O>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][N:20]=[C:17]3[C:16]([CH3:18])=[N:15][N:14]=[C:13]3[NH2:12])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CN(C)C=O
Reactant: Nc1cccc2cnccc12
Solvent: O
Product: CC1=NN=C(N)C1=NNc1cccc2cnccc12

Procedure:
4-(isoquinolin-5-ylhydrazono)-5-methyl-4H-pyrazol-3-ylamine was prepared from 5-aminoisoquinoline (0.7 g, 4.9 mmol) and 3-amino-5-methylpyrazole (0.6 g, 6.2 mmol) according to the procedure described above except that the substituted aniline was initially dissolved in a mixture of water (6.0 mL) and DMF (6.0 mL) prior to being acidified. The crude material was purified by chromatography eluting with (CH2Cl2:MeOH=6:1) to yield 0.089 g (7%) of the compound as a red solid. MS (m/z, ES+): 253.2 (M+1, 50%), 129 (M−123, 100%).
Reaction SMILES: [CH3:1][NH2:2].O.CS[C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]>C(O)C>[CH3:1][NH:2][C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]
Reactant: COc1ccnc(CSCCNC(=C[N+](=O)[O-])SC)c1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1cc(OC)ccn1
Reaction time: 0.33 h

Procedure:
Methylamine in ethanol (33%, 20 cc) was added to 1-methylthio-1-[2-(4-methoxy-2-pyridylmethylthio)ethylamino]-2-nitroethylene monohydrate (2.01 g) and the mixture was stirred at 18° for 20 minutes and evaporated to an oil which was crystallised from propan-2-ol to give the title product (1.1 g) m.p. 107°-108.5°.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:15]([C:17]1([CH2:27][CH3:28])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][OH:25])[NH:18]1)[CH3:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:27]([C:17]1([CH2:15][CH3:16])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][O:25][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[NH:18]1)[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC1(CC)NC(C)(CO)COC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(CC)NC(C)(COC(=O)C(C)(C)C)COC1=O
Reaction time: 20 h

Procedure:
2.4 ml (0.017 mol) of triethylamine and then 2.15 g 2 (0.018 mol) of pivaloyl chloride are added dropwise to a solution of 3.45 g (0.017 mol) of 3,3-diethyl-5-methyl-5-hydroxymethylmorpholin-2-one and 0.1 g of 4-dimethylaminopyridine in 20 ml dichloromethane at 15° C. After stirring for 20 hours, the precipitated triethylaminehydrochloride is removed by filtration and the filtrate is washed with water, dried over MgSO4 and concentrated by evaporation in a rotary evaporator. The residue is recrystallised from hexane. This gives 3.9 g (77%) of compound (217), m.p. 51-53° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1>>[ClH:20].[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][N:33]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32]1
Reactant: FC1(F)CCCNC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCCC(F)(F)C3)cc12

Procedure:
6-[2-(3,3-difluoro-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 72% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 3,3-difluoro-piperidine.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:15][CH3:16])=[O:14].[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:17]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:15][CH3:16])=[O:14])#[N:18]
Reactant: [C-]#N
Reactant: CNC(=O)c1cnn(-c2ccccc2)c1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Temperature: 100 °C
Yield: 39.8 %

Procedure:
A solution of 5.6 g of 5-bromo-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide and 2 g of sodium cyanide in 30 ml of DMF was heated at approximately 100° C. for 24 hours. An additional 2 g of sodium cyanide was next added to the reaction mixture which was then heated for an additional 24 hours at 100° C. The solution was poured into ice water and the precipitated solid was collected by filtration. The product thus isolated was recrystallized from 3A ethanol to provide 1.8 g of 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. MP=203°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: O
Solvent: COCCOC
Product: Cc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 29.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.020 g (30%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution containing carbazole (20 g; 0.12 mol) in DMF (130 ml) was added portionwise sodium hydride (50% suspension) (6.9 g; 0.14 mol); the suspension thus obtained was stirred at room temperature for 30 minutes and then heated to 60° C. A solution containing ethyl 2-bromoacetate (24 g; 0.14 mol) in DMF (20 ml) was added dropwise, and the resulting mixture was stirred for 16 hours. The mixture was poured into H2O (0.5 L) and filtered, and the solid obtained was crystallized from hexane to give ethyl 9H-carbazol-9-ylacetate (20 g).