Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:34])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3.[OH-].[Na+]>O.Cl>[C:2]([NH:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:34])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)(=[O:1])[NH2:3]
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3ccccc3C)n(CCN)c(=O)n1CC2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3ccccc3C)n(CCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
Sodium cyanate (0.64 g, 9.8 mmol) in water (13 ml) was added dropwise to a stirred solution of amine 3 (2 g, 4.9 mmol) in water (63 ml) and 1M HCl (9.8 ml) at 80° C. After stirring for 3 h at 80° C. the mixture was cooled and basified with 2M NaOH. The mixture was extracted with CH2Cl2 until no more product remained in the organic phase. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography [dichloromethane/methanol (97:3)] and the product triturated with ether to afford the title compound (1.0 g, 45%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C1COCC1>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:17])=[O:18])=[CH:20][CH:21]=2)=[CH:38][CH:37]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
In a 100 ml RBF combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (2.5 g, 6.62 mmol) and THF (25 ml). Cool the solution in an ice water bath and add 4-methylmorpholine (0.73 ml, 7.29 mmol) follow by the portion wise addition of CDMT (1.16 g, 7.29 mmol). Stir the solution in an ice water bath for one hour. Add dropwise, a solution of 4-fluorobenzylamine (0.83 ml, 7.29 mmol) in THF (8 μl) to the reaction at 0° C. Stir the solution at 0° C. for five hours, and quench with 1N HCl (50 ml). Extract the reaction MTBE (2×50 ml), filter and wash with saturated aqueous sodium chloride (50 ml). Dry the organics over magnesium sulfate, filter and concentrate to give N-(4-fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide (2.43 g) as a white solid. HPLC=95.5%, MS (ESI) m/z observed 485.1334 calculated 485.1335 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:40][C@@H:39]2[C@@H:10]([CH2:11][C:12]3[N:13]([CH2:38]2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]=3[C:21]2[C:22](=[O:37])[O:23][C:24](=O)[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:42](C=O)C>N>[C:1]([O:5][C:6]([N:8]1[CH2:40][C@@H:39]2[C@@H:10]([CH2:11][C:12]3[N:13]([CH2:38]2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]=3[C:21]2[C:22](=[O:37])[NH:42][C:24](=[O:23])[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3C4)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 700 mg of cis-3-[2-(tert.butoxy-carbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 6 ml of DMF and 6 ml of 33% aqueous ammonia was heated to 100° C. for 2.5 hours in a sealed vessel. The mixture was left to cool and the solid formed was filtered off and dried to give 400 mg of cis-3-[2-(tert.butoxycarbonyl)-2,3,3a,4, 11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]-indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 173°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7](C1C=CC=CC=1)[CH2:6][C:5]2=O.[C:20](=[N:26][Si](C)(C)C)=[N:21][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:26][C:20]#[N:21]
Reactant: O=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CCOc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of 6-bromo-7-fluoro-2-phenylchroman-4-one (289.3 mg, 1.28 mmol) in DCM (10 mL) was added TiCl4 (2.6 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.63 mL, 2.82 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried and concentrated to give crude N-(6-bromochroman-4-ylidene)cyanamide (300 mg, 94%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])([F:7])[F:6].[CH2:11]([Mg]Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH3:9][O:8][C:5]([F:7])([F:6])[C:4]([F:10])=[CH:3][CH2:2][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(F)(F)C(F)=CCBr
Reactant: CCCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCC=C(F)C(F)(F)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 118.9 %

Procedure:
To a solution of 1.0 g (4.5 mmol) 4-bromo-1-methoxy-1,1,2,-trifluoro-2-butene in 15.0 mL tetrahydrofuran at -60° C. in a 50 mL round-bottom flask was added a solution of n-hexylmagnesium bromide (2M, 5.0 mL, 10.0 mmol) in diethyl ether and followed by addition of 100 mg dilithiumcupric tetrachloride. The reaction mixture was stirred for two hours at 0° C. The contents of the flask were poured into a large excess of an aqueous ammonium chloride solution, and the liquid extracted twice with diethyl ether. The ether layers were combined, washed once with brine, then dried over anhydrous magnesium sulfate. Evaporation of solvent gave 1.20 g of 1-methoxy-1,1,2,-trifluoro-2-decene. 1H NMR (CDCl3 300 MHz): 0.85(3H,t), 1.23(10H,bs), 2.12(2H,m), 3.60(3H,s), 5.39(1H,dt,J=8,34Hz). Without further Purification this crude oil was transformed to the ester as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:20]=1B(O)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:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:20]4[CH:21]=[C:22]([CH:23]=[CH:24][C:19]=4[F:18])[CH:25]=[O:26])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(F)c(B(O)O)c1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1ccc(F)c(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Temperature: 75 °C
Yield: 53.3 %

Procedure:
800 mg of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, 437 mg of 2-fluoro-5-formylbenzeneboronic acid and 150 mg of tetrakis(triphenylphosphine)palladium are placed under a stream of argon in a round-bottomed flask comprising a mixture, degassed beforehand under a stream of argon, of 8 ml of acetonitrile, 8 ml of toluene and 10 ml of a 0.5M sodium carbonate solution. The mixture is heated at 75° C. for 5 hours and then diluted, after cooling, with a mixture of water and ethyl acetate. The organic phase is separated, dried and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/ethyl acetate mixture. 486 mg of compound are obtained.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[N:9][CH:8]=1
Reactant: OCc1ccc(O)cn1
Reactant: Fc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OCc1ccc(OCc2cccc(F)c2)cn1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A mixture of 6-hydroxymethyl-pyridin-3-ol hydrochloride (1:1) (6.29 g, 38.9 mmol), 3-fluorobenzyl bromide (8.1 g, 42.8 mmol), potassium carbonate (10.76 g, 77.9 mmol) and 2-butanone (200 ml) was heated to 80° C. for 5 h. After cooling, water was added, and the mixture extracted with ethyl acetate. After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, CH2Cl2—MeOH 95:5) to give the title compound as a brown solid (6.12 g, 67%). MS: m/e=234.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.[OH-].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:23])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 99 %

Procedure:
6-Methyl-5-nitroisoquinoline (43.3 g, 0.230 mol) obtained in Step (2) above was dissolved in dichloromethane (650 mL), and the temperature of the reaction solution was cooled to 0° C. or lower. The reaction solution was slowly added with mCPBA (67.5 g, 0.390 mol), followed by stirring for 10 hours or more at 0° C. The reaction mixture was adjusted to have a pH value of 10 by adding 1N aqueous NaOH solution and extracted with dichloromethane. The combined organic layer thus obtained was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (46.5 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].ClCC#N.[CH3:14][C:15]([NH:17][CH2:18][CH2:19]C1C2C=C(OC)C=CC=2NC=1)=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH2:19][CH2:18][NH:17][C:15](=[O:16])[CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: N#CCCl
Product: COc1cccc(NCCNC(C)=O)c1

Procedure:
N-cyanoalkylation of 3-methoxyaniline (3l) using chloroacetonitrile, followed by hydrogenation and N-acetylation of the intermediate nitrile 4l [Yield (4l): 58%; 1H-NMR (CDCl3): δ 3.80 (s, 3H), 4.05 (s, 2H), 6.25-6.48 (m, 2H), 7.18 (t, 1H)], according to the procedure previously described for the preparation of 5a, provided the title compound 5l; oil. 1H-NMR (CDCl3): δ 2.00 (s, 3H), 3.27 (m, 2H), 3.53 (m, 2H9, 3.78 (s, 3H), 5.84 (brs, 1H), 6.17-6.32 (m, 3H), 7.09 (t, 1H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:20]([NH:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:21])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: S=C=Nc1ccccc1
Reactant: CC(=O)NNc1ccc(N)cc1
Solvent: CC#N
Product: CC(=O)NNc1ccc(NC(=S)Nc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
1-Acetyl-2-(4-aminophenyl)hydrazine (8.25 g, 0.05 mole) and phenyl isothiocyanate (6.8 g, 0.05 mole) were suspended in acetonitrile (100 ml). The resulting mixture was heated at reflux with stirring for 5 minutes. The product separated from solution as a white solid. After chilling, the product was removed from the reaction mixture by filtration and washed thoroughly with ether. Yield 14.5 g (96%), m.p. 205°-207° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][C:5]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccnc2)cc1C(=O)Nc1ccccc1
Temperature: 170 °C
Yield: 61.3 %

Procedure:
A mixture of 2-amino-5-bromo-N-phenyl-pyridine-3-carboxamide (230 mg, 0.5511 mmol), 3-pyridylboronic acid (74.45 mg, 0.6057 mmol), tetrakis(triphenylphosphine) palladium(0) (31.85 mg, 0.02756 mmol) and potassium carbonate (551.5 μL of 2 M, 1.103 mmol) in dioxane (1.40 mL) was heated in the microwave at 170° C. for 10 minutes. The reaction was filtered to remove Pd residues and partitioned between EtOAc and water. The organic phase was dried (Na2SO4), filtered and concentrated and triturated with MeCN. The resultant solid was crystallised from EtOAc to give the pure product as a pale brown solid (98 mg, 43% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.12 (1H, t), 7.23 (2H, brs), 7.38 (2H, t), 7.48 (1H, dd), 7.69 (1H, s), 7.72 (1H, s), 8.14 (1H, dt), 8.42 (1H, d), 8.54 (1H, dd), 8.56 (1H, d), 8.98 (1H, d), 10.28 (1H, s) ppm; MS (ES+) 290.7.
Reaction SMILES: C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:11])(=O)=O)=CC=1.[CH2:21]([N:23]([CH2:36][CH3:37])[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([CH:34]=[O:35])[CH:28]=[CH:27]2)[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:36]([N:23]([CH2:21][CH3:22])[C:24]1[C:25]([F:11])=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([CH:34]=[O:35])[CH:28]=[CH:27]2)[CH3:37]
Reactant: CCN(CC)c1ccc2cc(C=O)ccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc2cc(C=O)ccc2c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
N-fluorobenzenesulfonimide (57.0 milligrams, 0.18 millimole) was added to a solution of 6-diethylamino-naphthalene-2-carboxaldehyde (1, 40.0 milligrams, 0.18 millimole) in 5 milliliters of anhydrous N,N-dimethylformamide under argon at −40° C. The mixture was allowed to warm up to room temperature slowly. After 3 hours, 10 milliliters of 10% K2CO3 aqueous solution was added and the product was extracted with ethyl acetate (3×50 milliliters). Solvent was removed by rotary evaporation and the residue was purified by chromatography (SiO2, 1:1 hexane/CH2Cl2) to give 2 as yellow needles (35.0 milligrams, 79%). Rf (silica gel, 1:1 Hex/CH2Cl2)=0.74; 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J=7.0 Hz, 6 H), 3.45 (q, J=7.0 Hz, 4 H), 7.25 (t, J=8.8 Hz, 1 H), 7.65 (d, J=8.8 Hz, 1 H), 7.89 (dd, J=1.2 Hz, 8.8 Hz, 1 H), 8.00 (d, J=8.8 Hz, 1 H), 8.19 (s, 1 H), 10.06 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][N:18]([CH3:19])[CH3:17])=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: CNC
Reactant: Cc1ccccc1-c1ccc(Cl)cc1C#N
Solvent: ClCCl
Product: CN(C)Cc1ccccc1-c1ccc(Cl)cc1C#N

Procedure:
The starting material is prepared as follows: 3.8 g of 3-chloro-6-o-tolyl-benzonitrile (described in Example 3) is brominated as described in Example 2, and the residue dissolved in 25 ml of methylene chloride. The solution is added slowly to that of 14 g of liquid dimethylamine in 100 ml of methylene chloride while stirring at 0°. The mixture is stirred at room temperature for 16 hours, evaporated and the residue stirred with diethyl ether and 1 N hydrochloric acid. The aqueous phase is separated, combined with methylene chloride and basified with cold 2 N aqueous sodium hydroxide. The organic layer is separated, dried and evaporated to yield the 3-chloro-6-(o-dimethylaminomethyl-phenyl)-benzonitrile.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:32].C([O-])(O)=O.[Na+]>>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([CH2:13][N:6]3[CH:5]=[CH:4][C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[I:32])[C:7]3=[O:12])=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: I
Reactant: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1Cc1ccc2c(c1)OCCO2
Reaction time: 1 h

Procedure:
5-Amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-2H-isoquinolin-1-one (260 mg, 0.00084 mol) was added to a solution of sodium nitrite (200 mg, 0.003 mol) in dimethyl sulfoxide (4 mL, 0.06 mol) at 35° C. Aqueous hydrogen iodide (0.5 mL, 0.004 mol) in dimethyl sulfoxide (4 mL, 0.06 mol) was added, and the reaction mixture was stirred for 1 hour. The cooled reaction mixture was neutralized with sat. aq. NaHCO3 and extracted with methylene chloride (3×50 mL). The combined methylene chloride extracts were washed with brine, dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified via flash column chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) gave a light yellow solid. MS m/z (M+H) 420.0.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[Cl:18])=[N:6][CH:5]=1.[AlH4-].[Li+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:7]1[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(NCc2ccncc2Cl)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(NCc2ccncc2Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester (555, 1.00 g, 3.60 mmol) in tetrahydrofuran (120 mL) was added a solution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 5.00 mL) under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature overnight, followed with addition of sodium sulfate decahydrate. After 1 hour, the reaction mixture was filtered, concentrated, and purified with silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound as a white solid (556, 0.5 g, 56%). MS (ESI) [M+H+]+=250.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1c(OCCN(Cc2ccccc2)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CNc1c(N)cccc1OCCN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a mixture of N-benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acid tert-butyl ester (520 mg, 1.30 mmol) and 10% palladium on carbon (120 mg ) in ethanol (40 mL) at 50° C. was added a solution of hydrazine hydrate (1.3 g) in ethanol (10 mL). The reaction was allowed to stir for 3 hr then the catalyst filtered through celite and the solvent removed. Purification by chromatography (30% ethyl acetate-hexane) afforded 380 mg (78.9%) of a clear oil; MS EI m/e 371 (M+); IR (film) 3400,3350,1680 cm-1.
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[CH3:23])[C:3]1[N:4]=[CH:5][N:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:13][N:11]([CH3:12])[S:8]([N:6]1[CH:7]=[C:3]([CH2:2][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=2[CH3:23])[N:4]=[CH:5]1)(=[O:9])=[O:10]
Reactant: Cc1c(C(O)c2cn(S(=O)(=O)N(C)C)cn2)cccc1[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2cn(S(=O)(=O)N(C)C)cn2)cccc1[N+](=O)[O-]

Procedure:
A solution of Example 28B in trifluoroacetic acid (15 mL) was treated with triethyl silane (1.5 mL), heated to reflux for 16 hours, cooled, concentrated, tritrated with hexanes, treated with sodium bicarbonate solution and extracted with dichloromethane (×2). The combined dichloromethane layers were dried (MgSO4), filtered and concentrated. Purification of the residue on silica gel with ether provided the desired product enriched in the 3-nitro isomer.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(F)c1
Reactant: CN1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(COc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1-Methylpiperidin-4-yl)methanol (0.500 g, 3.87 mmol) was dissolved in dry DMF (8 mL), cooled (<0° C.), NaH (0.232 g, 5.80 mmol, 55% in oil) added and stirred for 30 minutes. 3-fluorobenzonitrile (0.492 g, 4.06 mmol) was added and the reaction mixture allowed to warm to r.t. over 1 hour. Due to excessive foaming the reaction mixture was diluted with dry DMF to 20 mL and stirred over night at r.t. The reaction was quenched by addition of water portionwise, and the mixture was extracted with EtOAc. The organics were dried (MgSO4) and concentrated in vacuo. The product was purified by flash chromatography using a step gradient of EtOAc:MeOH:TEA (100:10:2) in EtOAc to give the title compound as an oil. Yield: 0.417 g (44%). 1H NMR (400 MHz, CDCl3) δ 7.29-7.35 (m, 1H), 7.19 (m, 1H), 7.05-7.10 (m, 2H), 3.78 (d, 2H, J=6.1 Hz), 2.83-2.90 (m, 2H), 2.26 (s, 3H), 1.89-1.98 (m, 2H), 1.70-1.84 (m, 3H), 1.33-1.46 (m, 2H).
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=[O:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[N+:25]([CH3:28])([O-:27])=[O:26]>C1COCC1>[O:1]([C:9]1[CH:10]=[C:11]([C@@H:12]([OH:13])[CH2:28][N+:25]([O-:27])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: C[N+](=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
105 mg (0.28 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.31 ml of rare earth metal complex solution D1 was mixed into the solution. After stirring for 30 minutes, 85.5 mg (1.40mmol) of nitromethane was added dropwise to the mixture. After 61-hour reaction time, (R)-1-(3,4-di(t-butyldimethylsilxy)phenyl)-2-nitroethanol with an optical purity of 87% e.e. was obtained in a yield of 86%.