Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[O:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23]C)=[O:22].[OH-].[Na+]>C1COCC1.O.Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[O:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 50 °C

Procedure:
A mixture of 1.6 g of methyl 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoate and 0.5 g of NaOH in 20 ml of THF and 5 ml of H2O is heated at 50° C. overnight. The reaction mixture is acidified to pH 4 in 1N HCl solution, filtered and dried to give 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid. (M.P. 149°-151° C.)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:45]([NH:47][CH3:48])=[O:46])=[N:41][C:42]=1[O:43][CH3:44].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:44][O:43][C:42]1[N:41]=[C:40]([C:45]([NH:47][CH3:48])=[O:46])[CH:39]=[CH:38][C:37]=1[NH:36][C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCOCC5)c34)cc2o1
Reactant: CNC(=O)c1ccc(N)c(OC)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(OC3CCOCC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(OC)n1
Temperature: 150 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
The solution of 6-(2-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 5-amino-6-methoxy-N-methylpicolinamide (1.05 equiv), xantphos (0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv) in 1,4-dioxane (0.16 M) was added cesium carbonate (1.4 equiv). The reaction mixture was stirred at 150° C. for 2 h under microwave irradiation. The reaction was filtered, and concentrated. The crude was purified using silica gel chromatography (0-90% ethyl acetate (with 10% 1N ammonia in methanol) in hexane) to give the title compound (82% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.11 (s, 9 H) 0.84-0.93 (m, 2 H) 1.63-1.76 (m, 2 H) 2.03-2.16 (m, 2 H) 2.64 (s, 3 H) 2.84 (d, J=4.69 Hz, 3 H) 3.49-3.65 (m, 4 H) 3.70-3.80 (m, 2 H) 4.12 (s, 3 H) 5.52-5.55 (m, 1 H) 5.58 (s, 2 H) 7.60 (s, 1 H) 7.65 (d, J=1.17 Hz, 2 H) 7.70 (d, J=8.20 Hz, 1 H) 7.91-7.99 (m, 1 H) 8.03 (s, 1 H) 8.41 (q, J=4.69 Hz, 1 H) 8.91 (d, J=7.81 Hz, 1 H); MS (ESI) m/z 660.5 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[C:14]([N+:19]([O-:21])=[O:20])[CH2:15][CH2:16][C:17](=O)[N:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[C:14]([N+:19]([O-:21])=[O:20])[CH2:15][CH2:16]/[C:17](=[N:23]\[OH:24])/[N:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCC([N+](=O)[O-])=C2N(Cc3ccc(Cl)nc3)CCN12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C1=C2N(Cc3ccc(Cl)nc3)CCN2/C(=N/O)CC1
Yield: 65 %

Procedure:
A mixture of 0.618 g (0.002 mol) of 1-((6-chloropyridin-3-yl)methyl)-8-nitro-2,3,6,7-tetrahydroimidazo[1,2-a]pyridin-5(1H)-one, 0.01 mol of hydroxylamine hydrochloride, 0.01 mol of potassium hydroxide and 20 ml of ethanol placed in a 100 ml of flask was refluxed for 24 hours. The solvent was removed and the residue was separated to give a product by column chromatography in 65% yield.
Reaction SMILES: [C:1]([C:3]12[CH2:10][CH2:9][N:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2)#[N:2]>C(Cl)Cl.CO>[NH2:2][CH2:1][C:3]12[CH2:10][CH2:9][N:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2
Reactant: N#CC12CCN(CC1)CC2
Solvent: ClCCl
Solvent: CO
Product: NCC12CCN(CC1)CC2

Procedure:
Colourless oil; Rf : 0.3 (trace of tailing; alumina; methylene chloride/methanol=7:3); Mass spectrum: M+=140; Prepared from 4-cyanoquinuclidine (see Example 3 of EP-A-0,213,337).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26]>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:40]([C:29]3[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=3)=[O:41])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCCCC3)c2)CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CCOCC1
Yield: 78 %

Procedure:
The title compound was prepared by the coupling procedure of Example 1, step (f) using 4-(4-amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 250 mg, 0.793 mmol), and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 266 mg, 0.872 mmol). Silica gel chromatography (20% EtOAc-hexane) afforded the title compound (348 mg, 78%) as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C30H40N4O5Si, 565.3 (M+H). found 565.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:8].[NH2:26][C:27]1[S:31][N:30]=[CH:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[CH2:5][NH:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:26][C:27]2[S:31][N:30]=[CH:29][N:28]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ncns1
Product: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Yield: 16 %

Procedure:
The title compound was prepared from 4-({[3-chloro-4-(trifluoromethyl)benzyl]amino}carbonyl)benzenesulfonyl chloride (Preparation 30) and 5-amino-1,2,4-thiadiazole in 16% yield following the Method H described for Example 6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)CCl>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([O:20][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Under argon, 10 g (20.11 mmol) of (−)-3-(2-benzyloxy-5-iodophenyl)-2(S)-tert-butoxycarbonylaminopropionic acid (Example (−)-6A) are dissolved in 200 ml of acetonitrile. To this are added 246 mg (2.01 mmol) of 4-dimethylaminopyridine and 4.16 ml (40.22 mmol) of benzyl alcohol. The mixture is cooled to −10° C., and 4.63 g (24.13 mmol) of EDC are added. The mixture is allowed slowly to reach RT and is stirred overnight. After about 16 h, the mixture is concentrated on a rotary evaporator in vacuo, and the residue is purified by column chromatography on silica gel (mobile phase: dichloromethane). Yield: 10.65 g (88% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:15](=O)[CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:21]([O:28][NH:29][CH:15]1[CH2:14][CH2:13][CH2:12][C:11]2[N:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=[CH:17][C:16]1=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCc2nc(OCc3ccccc3)ccc21
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(CONC2CCCc3nc(OCc4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
To the mixture of 2-benzyloxy-7,8-dihydro-6H-quinolin-5-one (37.8 g, 149 mmoL) in pyridine (300 mL) was added O-benzylhydroxylamine hydrochloride (26.2 g, 164 mmoL) and the resulting mixture was stirred at room temperature for 24 h. The reaction was concentrated, diluted with methylene chloride and washed with saturated sodium bicarbonate (×2) and brine (×2). The methylene chloride layer was dried, filtered and concentrated. Purification by column chromatography on silica gel with 5% ethyl acetate in hexane provided the desired product (51.0 g, 96%) as an offwhite solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.CN(C=O)C>O>[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(OCc2cccc(Br)c2)c1
Temperature: 60 °C

Procedure:
To tert-butyl 3-hydroxyphenylcarbamate (0.245 g, 1.17 mmol), K2CO3 (404 mg, 2.93 mmol), and 3-bromobenzyl bromide (322 mg, 1.29 mmol) was added anhydrous DMF (5 mL). The reaction mixture was heated to 60° C. for 18 hours. The reaction mixture was cooled to rt, poured into water and the resulting precipitate was collected by filtration and washed with water to provide the desired product tert-butyl 3-(3-bromobenzyloxy)phenylcarbamate (34A) with sufficient purity for subsequent use.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N+:18]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1>C(O)C>[NH2:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cc(Nc3cnccc3[N+](=O)[O-])ccc21
Solvent: CCO
Product: Cn1ccc2cc(Nc3cnccc3N)ccc21

Procedure:
A suspension of 1-methyl-N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N5 -oxide (6.8 g) in 250 ml ethanol containing 0.4 g platinum oxide was hydrogenated at 50 psi for twenty hours and thereafter filtered through Celite and concentrated to 3.5 g oil. This oil was purified by HPLC (silica 20% methanol in ethyl acetate) to give 2.5 g solid, m.p. 167°-169°. This solid was recrystallized from acetonitrile/ether to give 1.1 g solid, m.p. 168°-169°.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.[CH:15](O)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:4][CH:3]=1
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(Br)s1
Temperature: 0 °C
Yield: 90.2 %

Procedure:
To a solution of tert-butyl 5-bromothiazol-2-ylcarbamate (3 g, 10.7 mmol), isopropanol (6.40 g, 107.4 mmol) and triphenylphosphine (5.63 g, 21.5 mmol) in THF (30 mL) was added diethyl azodicarboxylate dropwise at 0° C. The mixture was stirred at 0° C. and slowly warmed up to room temperature overnight. The solvent was evaporated. The residue was redissolved in dichloromethane (20 mL) and filtered to get rid of the undissolved solid. The filtrate was concentrated and purified by column chromatography on silica gel using 100% hexane to give a light yellow oil (3.10 g, 90% yield). LCMS (Conditions C): 4.19 min (RT); (M+H)+=267.01 (100%), 265.01 (95%), 224.95 (60%), 222.95 (60%). 1H NMR, 400 MHz, CDCl3: δ 7.34 (s, 1 H), 5.29 (m, 1 H), 1.59 (s, 9 H), 1.45 (d, 6.8 Hz, 6 H).
Reaction SMILES: [H-].[Na+].C([C:5]1([O:16]C(=O)C)[CH2:10][CH:9]=[CH:8][CH2:7][CH:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C>C(O)C>[OH:16][C@@H:5]1[CH2:10][CH:9]=[CH:8][CH2:7][C@H:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1CC=CCC1(CC)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC=CC[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Sodium hydride (200 mg) was added to a mixture of the cis and trans isomers of ethyl 1-acetoxy-2-carboethoxycyclohex-4-ene (1.60 g, 7.55 mmol) in absolute ethanol (50 ml), and the mixture was stirred for 1 hour at RT. The reaction mixture was neutralized with Dowex W 50 cation exchange resin (acid form), the resin removed by filtration, the solvents removed under vacuum, and the residue chromatographed on silica gel (hexane:EtOAc 7:3, Rf=0.40) to yield 1.2 g (94%) trans 1-hydroxy-2-carboethoxycyclohex-4-ene (IR CCl4, 1732 cm-1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([C:20]2[C:21]3[CH:33]=[CH:32][C:31]([CH2:34]OS(C)(=O)=O)=[CH:30][C:22]=3[S:23][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[CH:15]=[CH:16][CH:17]=1>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([C:20]2[C:21]3[CH:33]=[CH:32][C:31]([CH2:34][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[CH:30][C:22]=3[S:23][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Oc1cccnc1
Reactant: CCOC(=O)c1sc2cc(COS(C)(=O)=O)ccc2c1S(=O)c1cccc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(COc3cccnc3)ccc2c1S(=O)c1cccc(OC)c1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
3-Hydroxypyridine (57 mg, 0.6 mmol) was added to a stirred suspension of sodium hydride (24 mg of 60% dispersion in mineral oil, 0.6 mmol) in anhydrous dimethylformamide (2 ml), under a nitrogen atmosphere. After 30 minutes, ethyl 3-[(3-methoxyphenyl)sulfinyl]-6-[(methylsulfonyloxy)methyl]benzo[b]thiophene-2-carboxylate (Preparation 18, 234 mg, 0.5 mmol) was added to the mixture, and the mixture was stirred for 3 hours. The reaction was partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 2% ethanol in dichloromethane as eluant The semi-pure product was re-chromatographed on silica gel using ethyl acetate, and then crystallised from diethyl ether, to give the title compound as a colourless solid (110 mg).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:31]1[N:36]=[C:35]([NH:37][C:38]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:39]=2[C:40]([NH:42][CH3:43])=[O:41])[C:34]([Cl:49])=[CH:33][N:32]=1>C(O)(C)C>[Cl:49][C:34]1[C:35]([NH:37][C:38]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:39]=2[C:40]([NH:42][CH3:43])=[O:41])=[N:36][C:31]([NH:29][C:27]2[CH:26]=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:32][CH:33]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21
Yield: 42.5 %

Procedure:
10-Camphorsulfonic acid (91 mg, 0.39 mmol) was added to 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (65 mg, 0.34 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (110 mg, 0.34 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 40 min). Complete conversion was achieved. The reaction was diluted with 5 mL satd. sodium bicarbonate and the ppt collected. The ppt was purified by ISCO (12 g SiO2, 0-100% EtOAc:Hex) to afford 2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a green foam (68 mg, 43%). LCMS: 471 (M+H), 1H-NMR (CDCl3): 8.64 (s, 1H), 8.03 (s, 1H), 7.29 (m, 3H), 7.10 (s, 1H), 6.88 (m, 1H), 6.68 (m, 2H), 6.07 (q, 1H, J=4.5 Hz), 4.03 (t, 2H, J=5.6 Hz), 3.17 (m, 4H), 2.91 (d, 3H, J=4.5 Hz), 1.99 (m, 2H), 1.16 (t, 3H, J=7.0 Hz); 19F-NMR: −112
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].C[Al](C)C.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.O.CC(=O)OCC>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:10][C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=2)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCCCCCCOc1ccc(CC(=O)OC)cc1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCOc1ccc(Cc2nc3cc(C#N)ccc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a stirred solution of 3,4-diaminobenzonitrile (1.08 g, 8.10 mmol) in THF (20 mL) at 0° C. was added trimethylaluminum (4.86 mL, 9.72 mmol, 2 M in hexanes). After 10 min, methyl 2-(4-(heptyloxy)phenyl)acetate (2.36 g, 8.91 mmol) was added and the cooling bath removed. After stirring for 48 h at 60° C., the reaction mixture was allowed to cool to room temperature then poured into a mixture of Rochelle's salt (6.86 g, 24.31 mmol) in water (150 mL) and EA (100 mL) and stirred for 2 h. The layers were split and the aqueous layer further extracted with EA (50 mL). The combined organics were washed successively with water (100 mL) and brine (50 mL), dried over MgSO4 and evaporated. The residue was taken up in xylenes (50 mL), treated with toxic acid (0.154 g, 0.810 mmol) and heated under reflux for 18 h. The reaction mixture was allowed to cool, diluted with EA (100 mL), washed with NaHCO3 (100 mL), dried over MgSO4 and evaporated. The crude material was purified by chromatography (EA/isohexanes) then re-slurried from isohexanes to afford 2.19 g, (78%) of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile as a white solid INT-46. LCMS-ESI (m/z) calculated for C22H25N3O: 347; found 348 [M+H]+, tR=2.82 min (Method 5).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:24]1([C:34]2[N:39]=[N:38][N:37]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([O:46]CCO)=[CH:42][C:41]=3[OH:50])[C:35]=2[C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([C:34]2[N:39]=[N:38][N:37]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:42][C:41]=3[OH:50])[C:35]=2[C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1

Procedure:
9.11 g of acetic anhydride, 18.1 g of triethylamine and 0.73 g of dimethylaminopyridine in 400 ml of anhydrous dichloromethane are added to the product from Example A9. The reaction mixture is heated to boiling. When the reaction is complete (monitoring by TLC), the solvent is removed in vac. and the residue is taken up in dichloromethane. The organic phase is washed with water and dried with magnesium sulfate. After removal of the solvent, the residue is chromatographed on silica gel, yielding the product having the following NMR data:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(O)(=O)C.O.[Zn]>[Br:19][C:7]1[CH:6]=[C:5]([NH2:8])[C:4]([NH2:9])=[CH:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)c(N)cc1Br
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
To the solution of 4-methyl-2-nitro-phenylamine (1 g, 1 eq.) in 15 mL of acetic acid was added NBS (1.4 g, 1.2 eq.). The reaction was allowed to stir for 2.5 hours. Reaction was then diluted with 15 mL of water and Zn dust (1.29 g, 3 eq.) was added. Reaction was stirred for 1 hour, filtered and then pH was adjusted to ˜7 with ammonia. The aqueous layer was extracted with CH2Cl2 twice, dried over Na2SO4, concentrated and adsorbed on silica. Purification by flash column chromatography (60:40 hexanes/EtOAc) afforded 1.1 g (83 %) of product as off-white solid. MS (electrospray): mass calculated for C7H9BrN2, 201.06; m/z found 202.2, [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl.[NH2:19][OH:20]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=[N:19][OH:20])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(O)cc2)c(Cl)c1Cl
Agent: Cl
Product: ON=Cc1ccc(-c2ccc(O)cc2)c(Cl)c1Cl

Procedure:
The title compound was prepared by reacting 48 (140 mg, 0.526 mmol) with hydroxylamine hydrochloride (110 mg, 1.58 mmol) according to method F to yield 148 mg (100%) of off white solid: mp 208-210° C.; 1H NMR (DMSO-d6): δ 6.84-6.87 (2H, m), 7.26-7.29 (2H, m), 7.36 (1H, d, J=7.94 Hz). 7.80 (1H, d, J=8.20 Hz), 8.41 (1H, s), 9.72 (1H, s), 11.83 (1H, s); MS (ESI) m/z 280/282/284 (M−H)−, 282/284/286 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:33]([O-:35])=[O:34])=[C:15]([CH:32]=1)[C:16]([NH:18][C:19]1[CH:24]=[C:23]([C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])[CH:22]=[CH:21][C:20]=1[CH3:31])=[O:17]>>[CH:28]1([NH:27][C:25]([C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]3[CH:32]=[C:11]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)[CH:12]=[CH:13][C:14]=3[N+:33]([O-:35])=[O:34])[CH:24]=2)=[O:26])[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN(C(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (3) in the portion of Example 1 which is concerned with the preparation of starting materials, N-isopropylpiperazine was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-isopropylpiperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 0.99 (d, 6H), 2.29 (s, 3H), 2.54 (m, 4H), 2.68 (m, 1H), 2.83 (m, 1H), 3.48 (m, 4H), 7.05 (m, 2H), 7.27 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.03 (d, 1H), 8.35 (d, 1H), 9.90 (s, 1H); Mass Spectrum M+H+ 466.