Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.Cl[C:35]1[N:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=2)[C:38]([Cl:54])=[CH:37][N:36]=1>>[Cl:54][C:38]1[C:39]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=2)=[N:40][C:35]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:36][CH:37]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: Cn1ccnc1-c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 33.5 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) was combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine (93 mg, 0.290 mmol) to yield -Chloro-N*4*-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-N*2*-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-pyrimidine-2,4-diamine (52.73 mg, 47% yield) as a white powder. 1H-NMR (CDCl3) δ 10.71 (s, 1H), 8.56 (d, J=8.7 Hz, 1H), 8.01 (s, 1H), 7.41 (m, 2H), 7.39 (s, 1H), 7.23 (m, 1H), 7.18 (m, 1H), 7.02 (m, 3H), 3.76 (s, 3H), 3.24 (q, J=9.4, 18.8 Hz, 2H), 2.82 (m, 3H), 2.68 (m, 2H), 2.05 (m, 2H), 1.31 (m, 2H), MP=154-156° C.
Reaction SMILES: C1COCC1.[C:6]1([C@H:16]([N:18]([CH2:26][CH:27]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][NH:29][CH2:28]2)C(=O)OC(C)(C)C)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(CC)CC)C>O>[C:6]1([C@H:16]([NH:18][CH2:26][CH:27]2[CH:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:30][N:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:28]2)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CC(CN[C@H](C)c2cccc3ccccc23)C(c2ccccc2)C1
Temperature: 50 °C

Procedure:
A 10 ml THF solution of 500 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(4-phenylpyrrolidin-3-yl)methyl]carbamate was mixed with 0.34 ml of ethyl chloroformate and stirred at 50° C. A 0.24 ml portion of triethylamine and 20 ml of water were added thereto, and the solvent was evaporated. This was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate, and the solvent was evaporated. The thus obtained residue was treated with 4 M hydrogen chloride/ethyl acetate solution and recrystallized from ethyl acetate-hexane to obtain 312 mg of ethyl 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as colorless crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14](Cl)=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1.[CH2:22]([N:24]1[C:28]([OH:29])=[CH:27][CH:26]=[N:25]1)[CH3:23].C(N(CC)CC)C>ClCCCl>[CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14]([C:27]3[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[C:28]=3[OH:29])=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Reactant: CCn1nccc1O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc(Cl)c(Cn3nnn(C4CC4)c3=O)c2Cl)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
A 1,2-dichloroethane solution of 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl chloride (0.70g) was added drop by drop to the solution of 1-ethyl-5-hydroxypyrazole (0.24 g) and triethylamine (0.24 g) in 1,2-dichloroethane (4 ml) at 5° C. and the mixture was stirred at room temperature for 6 hours. After reaction it was extracted with dichloromethane (100 ml), washed with diluted hydrochloric acid and aqueous solution of sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The residue, obtained by distilling off the solvent, was dissolved in 1,4-dioxane (8 ml), added with potassium carbonate (0.38 g) and refluxed by heating for 3 hours. After the solvent was distilled off, the residue was teated with an aqueous solution of potassium carbonate and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate (150 ml). The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective 4-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl}-5-hydroxy-1-ethylpyrazole (0.73 g, 88% yield from 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) methyl]-2,4-dichlorobenzoic acid) was obtained. nD20: 1.5510.
Reaction SMILES: C([Al]([CH2:6][CH3:7])CC)C.[C:8]([O:11][CH:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH:24]=[CH:25]1)[CH2:20][CH2:19]3)(=[O:10])[CH3:9].[Cu](C#N)C#N.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:8]([O:11][CH:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][C@@H:25]1[CH2:6][CH3:7])[CH2:20][CH2:19]3)(=[O:10])[CH3:9]
Reactant: CC[Al](CC)CC
Reactant: CC(=O)OC1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@H]1CC(=O)C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(OC(C)=O)CC[C@@H]34)[C@@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
5.78 ml (11 mmol) of a 1.9 molar solution of triethyl aluminum in toluene is added at room temperature to 3.3 g (10 mmol) of 17-acetoxy-5α-androst-1-en-3-one in 15 ml of ethyl acetate and 44.78 mg (0.5 mmol) of copper cyanide (CuCN). It is stirred 12 hours more at 25° C. The reaction solution is hydrolyzed with 1 ml of water and stirred again for 15 minutes. The inorganic solid is filtered off. The solid is washed again with ethyl acetate. After evaporation of the solvent and chromatography of the substance on silica gel with hexane/ethyl acetate as eluent, 1.44 g (39% of theory) of 17-acetoxy-1α-ethyl-5α-androstan-3-one is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=2)[N:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:3]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:4][C:5]3[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=4)[N:10]=3)[N:7]=2)=[CH:33][CH:32]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
To a flame-dried round bottom flask was placed 6-chloro-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (44 mg, 0.1 mmol), 4-chlorophenylboronic acid (31 mg, 0.2 mmol), K3PO4 (42.5 mg, 0.2 mmol) and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (1:1) (16 mg, 0.02 mmol). The flask was purged with argon for 15 min before addition of degassed anhydrous THF (1 mL). The reaction mixture was stirred at 70° C. under argon for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL), washed with 1 N aqueous NaOH, water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 8 min gradient, hold at 100% B for 6 min (A=90% H2O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H2O, 90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 18.2 mg (35%) of the title compound as a yellow powder. LC/MS (method A): retention time=3.94 min, (M+H)+=516. 1H NMR (CDCl3, 400 MHz): δ 8.83 (d,J=1.71 Hz, 1H), 7.98 (dd, J=7.95, 2.08 Hz, 1H), 7.69 (d,J=8.07 Hz, 1H), 7.41 (s, 1H), 7.25-7.32 (m, 4H), 7.20-7.23 (m, 2H), 7.00-7.04 (m, 2H), 5.33 (s, 2H).
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH3:40])([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.N>ClCCl.CO>[C:37]([C:34]1([CH3:40])[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]1)(=[O:38])[NH2:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.284 g) was added to a mixture of 1-hyroxybenzotriazole hydrate (0.227 g) and 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.300 g) in dichloromethane (6 mL). Diisopropylethylamine (0.644 mL) was added and the reaction was stirred overnight. Ammonia (7 mol/L; 5.28 mL) in methanol was syringed in and the reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo. The residue was suspended in ethyl acetate (500 mL) and stirred for 15 minutes with a saturated ammonium chloride solution (250 mL). The layers were separated and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (300 mL). The aqueous phase was extracted once with ethyl acetate (200 mL). The combined organics were dried with magnesium sulfate, and then concentrated to afford the title compound as a tan solid (0.299 g) with the following physical data.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]([CH2:26][C:27]#[C:28][CH3:29])[C:17](=[O:25])[N:18]3[CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH2:26]([N:16]1[C:15]2[C:19](=[N:20][C:21]([Cl:23])=[N:22][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:18]([CH3:24])[C:17]1=[O:25])[C:27]#[C:28][CH3:29]
Reactant: CC#CCn1c(=O)n(C)c2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(=O)n(C)c2nc(Cl)nc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[7-(2-Butynyl)-2-chloro-9-methyl-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (compound 1f) (15 mg) was dissolved in trifluoroacetic acid (1 mL). This reaction solution was stirred at room temperature for five minutes, and then concentrated. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (11.07 mg).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:42][CH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][N:48](C(OCC2C=CC=CC=2)=O)[CH2:47][CH2:46]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:42][CH2:43][CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{3-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperidinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:29]#[N:30])=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: N#CC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
2-Fluorobenzoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.2 mL of 2-fluorobenzoyl chloride (97%, Aldrich) (10 mmol), 26 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.55 mL of trimethylsilyl cyanide (12 mmol) were placed in a 100-mL round bottom flask. To this solution 0.25 mL of tin (IV) chloride (2.1 mmol) was added. On addition of the tin (IV) chloride, the color of the solution changed from yellow to dark brown. The reaction mixture was stirred for 2 hr at room temperature, then quenched with 75 mL of ice-cold water, and finally extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield a dark brown oil which was purified by Kugelrohr vacuum distillation to yield 0.711 g (47%) of 2-fluorobenzoyl cyanide as a colorless oil: IR (CH2Cl2) (partial) 2225, 1695, 1670, 1610, 1489, 1484, 1457 cm-1.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([N+:19]([O-:21])=[O:20])=[C:2]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c([N+](=O)[O-])cc2c1=O
Temperature: 95 °C
Yield: 54 %

Procedure:
A mixture of 9.3 g (0.03 mol) of 7-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid and 12.9 g (0.15 mol) of piperazine is warmed at 120° C. in 60 ml of dimethylsulphoxide for 15 minutes. After a short time, a precipitate separates out from the hot solution. The mixture is concentrated under a high vacuum, the residue is stirred with 30 ml of water and the mixture is heated again at 95° C. for 30 minutes. The mixture is brought to pH 8 with 2N hydrochloric acid, and the precipitate is filtered off with suction and washed with water and methanol. 5.8 g (54% of theory) of 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 296°-298° C. are isolated.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:14][C:15]1[C:20](Cl)=[CH:19][C:18]([NH2:22])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.C(O)(C(F)(F)F)=O.O>CN(C=O)C.O>[NH2:22][C:18]1[C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]([Cl:14])=[C:20]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[CH2:2][OH:1])[CH:19]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: OC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N2CCC[C@@H]2CO)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Hydroxymethyl-pyrrolidine (202 mg, 2.0 mmol) followed by potassium carbonate (304 mg, 2.2 mmol) were added to a mixture of 4,5-dichloro-2-nitro-phenylamine (414 mg, 2.0 mmol) in DMF (10 mL) and stirred at rt overnight. The reaction mixture was diluted with water, acidified with TFA:H2O 1:1 and filtered. The filtercake was washed with DMF:H2O 1:1 and dried to give the sub-title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CN(C)C=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C(=O)O)Cc1ccccc1-3
Temperature: 50 °C
Yield: 96.9 %

Procedure:
Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (308 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (5 mL) and treated with LiOH (173 mg, 7.2 mmol). The mixture was heated at 50° C. for 4 hr, after which the solvent was removed in vacuo. The residue was dissolved in H2O (5 mL) and the resultant mixture was acidified by the addition of a 10% aqueous HCL solution. A precipitate formed which was collected by filtration and air dried to afford the title compound as a bright yellow solid (290 mg, 97%). ESI-MS m/z [M+1]=415.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using 2-aminoethyl-methyl-sulfone (258 mg, 2.096 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-thiophenesulfonamide (100 mg, 0.210 mmol) the title compound was obtained as a light yellow solid (20 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H) 8.07 (d, J=4.9 Hz, 1H) 7.82-7.92 (m, 1H) 7.46-7.52 (m, 1H) 7.37-7.46 (m, 1H) 7.28-7.36 (m, 1H) 7.12-7.25 (m, 3H) 7.04-7.12 (m, 1H) 6.04-6.14 (m, 1H) 3.55-3.69 (m, 2H) 3.30-3.37 (m, 3H) 2.97 (s, 3H) 1.32 (d, J=6.8 Hz, 6H). MS (ESI): 564.1[M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)[C:4]1=[O:16].[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([S:29](Cl)(=[O:31])=[O:30])=[CH:26]2)=[CH:21][CH:20]=1>C(Cl)Cl>[C:14]([C:12]1[O:13][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:29]([C:25]3[CH:24]=[CH:23][C:22]4[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)[CH:26]=3)(=[O:31])=[O:30])[C:4]2=[O:16])=[CH:10][CH:11]=1)#[N:15]
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: N#Cc1ccc(CN2CCC(N)C2=O)o1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(C#N)o4)C3=O)cc2c1
Reaction time: 16 h
Yield: 45.5 %

Procedure:
7-Methoxynaphthalene-2-sulfonic acid [1-(2-cyanofuran-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide is prepared as described in EXAMPLE 125, Part C from of 5-(3-amino-2-oxopyrrolidine-1-ylmethyl)furan-2-carbonitrile hydrochloride (1.1 g, 4.55 mmol), and 7-methoxynaphthalene-2-sulfonyl chloride (1.52 g, 5.9 mmol). After 16 hours, the solution is diluted with CH2Cl2. The organic layer is washed with 0.5 N HCl, water and sat NaCl. The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 10% EtOAc/CH2Cl2 to afford the title compound (0.88 g, 2.07 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)CCC>>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[N:4][CH:3]=2)[CH:26]=1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(-c2cccnc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from 3′-(5-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 3-(tri-n-butylstannyl)pyridine. The title compound (87 mg) was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=5)[C:19]([CH3:30])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:30])=[C:20]([C:22]5[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCC5)CC3)ccc2C)cn1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCC4)CC2)nc1-c1ccc(=O)[nH]c1
Temperature: 55 °C
Reaction time: 6.5 h
Yield: 78.5 %

Procedure:
To a suspension of 1-(2,3-dihydro-1H-inden-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.127 g, 0.3172 mmol) in CH3CN (6.7 mL) was added TMSI (254 mg, 180.5 μL, 1.27 mmol) drop-wise. The suspension became a clear solution upon TMSI addition. The reaction was stirred at 55° C. for 6.5 hours. The reaction was allowed to cool down to room temperature. Methanol (2.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,3-dihydro-1H-inden-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a yellow solid (0.096 g, 78.5%). ESI-MS m/z calc. 385.46. found 386.5 (M+1)+. Retention time 1.58 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([OH:13])[C:9]=1[CH:14]([CH3:16])[CH3:15].[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:13][C:10]1[C:9]([CH:14]([CH3:16])[CH3:15])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:12][N:11]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)c1c(O)noc1-c1ccccc1Cl
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1Cl
Yield: 72 %

Procedure:
5-(2-Chlorophenyl)-3-hydroxy-4-isopropylisoxazole (0.13 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.1 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.15 g, 72%) as a colorless powder.