Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[CH3:39])[CH:2]=C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:39][CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: C=CCC1C(C)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A solution of 4-allyl-3-methyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (38) (0.29 g) in ethyl acetate (25 ml) was treated with trifluoroacetic acid (0.4 ml) and then cooled to -78°. Ozone was bubbled through the solution until it just became pale blue in colour. The excess ozone was blown off in a stream of argon and an ethyl acetate solution of triphenylphosphine (0.14 g) was then added. After a further 10 minutes the reaction flask was transferred to an ice bath and saturated aqueous sodium bicarbonate (45 ml) was added with vigorous stirring. This was continued for 30 minutes and the ethyl acetate solution was then separated, washed with brine and dried over sodium sulphate. The solution was concentrated and chromatographed on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether mixtures grading from 3:7 to 6:4. This gave the trans-isomer of benzyl 6-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene- 2-carboxylate (39) (0.08 g, 55%); νmax (CHCl3) 3000, 1780, 1725 and 1615 cm-1 ; δ ppm (CD3)2CO) 1.34 (3H, d, J 7 Hz, CH3), 2.85 (2H, dd, J 9 and 2 Hz, C4-H2), 3.24 (1H, dq, J 3 and 7 Hz, C6-H), 3.91 (1H, dt, J 3 and 9 Hz, C5-H), 5.20 (2H, s, benzyl CH2), 6.45 (1H, t, J 2 Hz, C3-H) and 7.2-7.5 (5H, m, phenyl); (M+ at m/e 257.1052 C15H15NO3 requires 257.1051 ).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[NH2:19])[CH:13]=[C:12]2[NH:21][C:22]([N:24]1[C@H:29]([C:30](=[O:40])[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH2:28][C@@H:27]2[C@H:25]1[CH2:26]2)=[O:23])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:41])=[O:5])=[CH:17][CH:16]=2)[C:12]([NH:21][C:22]([N:24]2[C@H:29]([C:30](=[O:40])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[CH2:28][C@@H:27]3[C@H:25]2[CH2:26]3)=[O:23])=[CH:13]1)(=[O:20])[NH2:19]
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)c(NC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1ccccc1F)cn2C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)n1cc(NC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2ccccc2F)c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1-carbamoyl-3-{[(1R,3S,5R)-3-(2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carbonyl]-amino}-1H-indol-5-yloxy)-acetic acid tert-butyl ester Example 390 (18 mg, 0.032 mmol) in CH2Cl2 (0.5 mL) was added TFA (97 μL, 1.27 mmol) and the mixture was stirred at RT overnight. Then concentrated, taken up in CH2Cl2 and filtered-off to give the desired material which was further dried under high vacuum. MS (LC-MS): 510.1 [M+H]+, 532.2 [M+Na]+, 508.1 [M−H]−, 465.1 [M−CONH2]−; tR (HPLC conditions f): 1.52 min.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:14][C:13](=[O:29])[NH:12]2)=[CH:4][C:3]=1[O:30][CH3:31].[NH4+].[Cl-].CCN(CC)CC.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>CCO.[Zn].C1COCC1.O>[OH:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([CH:11]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:14][C:13](=[O:29])[NH:12]2)=[CH:6][C:7]=1[NH:8][S:41]([CH3:44])(=[O:43])=[O:42]
Reactant: COc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(NS(C)(=O)=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 9 %

Procedure:
4-(4-Hydroxy-3-methoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (Compound 9) (100 mg, 0.24 mmol) was dissolved in an EtOH:H2O:THF (4 mL, 2:1:1) mixture. To this was added Zn dust (26 mg, 0.40 mmol) and NH4Cl (26 mg, 0.48 mmol) and stirred at room temperature for 1 day, followed by stirring at 50° C. for 1 day. The solution was filtered through a celite pad followed by a solvent swap to DCM (5 mL). Excess Et3N (0.1 ml, 0.72 mmol) was added and stirred for 15 minutes, followed by excess addition of mesyl chloride (50 μL, 0.3 mmol) and stirring over night. The crude mixture was directly purified by silica-gel column chromatography (0 to 5% MeOH in EtOAc) to yield 10 mg of Compound 76 as a faint yellow solid. 1H NMR (CD3OD 300 MHz): δ 7.27 (m, 5H), 7.06 (m, 1H), 7.04 (d, 2H), 6.91 (m, 2H), 6.61 (d, 1H), 6.38 (d, 1H), 5.51 (s, 1H), 5.14 (s, 1H), 3.77 (s, 3H)); MS (ESI): m/z 466.17 [M+1]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Si]([O:12][CH:13]1[CH2:17][CH2:16][NH:15][CH:14]1[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])=[CH:20][C:19]=1[F:33])(C(C)(C)C)(C)C>>[C:13]([O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:25](=[O:26])[CH3:27])[CH:14]1[C:18]1[CH:23]=[C:22]([N+:1]([O-:4])=[O:2])[C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])=[CH:20][C:19]=1[F:33])(=[O:12])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)[Si](C)(C)OC1CCNC1c1ccc(NC(=O)c2ccccn2)cc1F
Product: CC(=O)OC1CCN(C(C)=O)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1 ml of fuming nitric acid was added to 57 mg of N-(4-(3-((t-butyl(dimethyl)silyl)oxy)pyrrolidin-2-yl)-3-fluorophenyl)pyridine-2-carboxamide, and the reaction liquid was stirred at room temperature for 40 minutes. The reaction liquid was poured into a mixed solution of ice-aqueous saturated sodium bicarbonate, extracted with chloroform, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain diastereomer A and diastereomer B of the entitled compound each as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.S([CH2:32][N+:33]#[C-:34])(C1C=CC(C)=CC=1)(=O)=O.COCCOC>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:6]=[C:7]([C:9]2[O:10][CH:34]=[N:33][CH:32]=2)[N:8]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(CCNc2cc(C=O)nc(OC)n2)cc1
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CCNc2cc(-c3cnco3)nc(OC)n2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 8.5 %

Procedure:
In a tube is combined 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carbaldehyde [120 mg, 0.42 mmol, Intermediate (59)], tosylmethylisocyanide (90 mg, 0.46 mmol), Ambersep 900 OH resin (800 mg), ethylene glycol dimethyl ether (3.5 mL) and water (3.5 mL). The tube is sealed and the mixture is heated to 90° C. and stirred for 18 hours. The mixture is allowed to cool to ambient temperature and filtered to remove the resin, and the resin is washed with MeOH (10 mL). The combined filtrate and washings are concentrated by rotary evaporator and the residue is subjected to flash column chromatography on silica gel eluting with 0 to 40% EtOAc in heptane gradient) to afford (2-methoxy-6-oxazol-5-yl-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine [11.6 mg, 8.5%, Example 45]. LCMS: RT=2.57 minutes, MS: 327 (M+H). IC50=7.8 nM
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][C:20]=3[CH3:24])=[CH:15][CH:14]=2)[CH2:10][CH2:9]1.Cl[C:33]1[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=1>CN1CCCC1=O>[Cl:39][C:36]1[CH:35]=[N:34][C:33]([N:29]2[CH2:30][CH2:31][CH:26]([N:11]([CH:8]3[CH2:10][CH2:9]3)[C:12](=[O:25])[C:13]3[CH:14]=[CH:15][C:16]([C:19]4[O:23][CH:22]=[N:21][C:20]=4[CH3:24])=[CH:17][CH:18]=3)[CH2:27][CH2:28]2)=[N:38][CH:37]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1ncoc1-c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-(4-methyl-oxazol-5-yl)-N-piperidin-4-yl-benzamide trifluoroacetic acid salt and 2,5-dichloro-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 6): tR=1.92 min; Mass spectrum (ESI+): m/z=438/440 (Cl) [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[NH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1>C(O)C>[OH:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([N:16]1[CH2:14][CH2:13][N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[CH2:3][CH2:2]1)[CH2:26][CH2:25]2
Reactant: COc1ccccc1N(CCCl)CCCl
Reactant: NC1CCc2cc(O)ccc2C1
Solvent: CCO
Product: COc1ccccc1N1CCN(C2CCc3cc(O)ccc3C2)CC1

Procedure:
2.48 g of N,N-Di(2-chloroethyl)-2-methoxyaniline are dissolved together with 1.63 g of 2-amino-1,2,3,4-tetrahydro-6-hydroxynaphthalene in 100 ml of ethanol and finally refluxed for 20 hours. The solvent is evaporated off and the residue recrystallized from methanol/ether to yield the title compound. M.P. 282°-286° [Hydrochloride salt form].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:22])[C:28]=4[Cl:29])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4Cl)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.15 mmol) and 2,3-dichlorophenylboronic acid (329 mg, 1.72 mmol) the subtitle compound was obtained (288 mg, 60%). MS 415 m/z (M+H)+.
Reaction SMILES: N1[CH2:12][CH2:11]NCCNCCNCC1.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:15][CH2:14][CH2:13][CH2:18][CH2:17][CH2:13][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:11][CH3:12]
Reactant: C1CNCCNCCNCCN1
Reactant: c1ccccc1
Product: CCCCCCCCCCCCC

Procedure:
reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][C:5](=[S:8])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH2:3]1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:4]1[CH2:3][C:2]([CH3:19])([CH3:1])[CH2:7][O:6][C:5]1=[S:8]
Reactant: CC1(C)COC(=S)N(Cc2ccccc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1(C)COC(=S)N(Cc2ccccc2N)C1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
5,5-Dimethyl-3-(2-nitrobenzyl)-[1,3]-oxazinan-2-thione (1.06 g, 3.79 mmol), iron powder (1.06 g, 19.0 mmol), ammonium chloride (0.10 g, 1.87 mmol) were suspended in ethanol (20 ml) and water (10 ml) and heated to reflux for one hour. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-(2-aminobenzyl)-5,5-dimethyl-[1,3]-oxazinan-2-thione (0.60 g).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.C([O:30][C:31]1[CH:44]=[CH:43][C:34]([O:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:33][CH:32]=1)C1C=CC=CC=1>>[N:38]1([CH2:37][CH2:36][O:35][C:34]2[CH:33]=[CH:32][C:31]([OH:30])=[CH:44][CH:43]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: c1ccc(COc2ccc(OCCN3CCCC3)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: Oc1ccc(OCCN2CCCC2)cc1

Procedure:
Compound 106B was prepared in a similar manner to the synthesis of compound 31F by substituting compound 31E with compound 106A: 1H NMR (DMSO-d6): δ 8.88 (s, 1H), 6.72-6.75 (m, 2H), 6.64-6.67 (m, 2H), 3.94 (d, J=6.1 Hz, 2H), 2.72 (d, J=5.95 Hz, 2H), 2.48-2.51 (m, 4H), 1.65-1.68 (m, 4H) ESI (+)/MS: 208 (M+H)+.
Reaction SMILES: Cl.COC[O:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:16])[CH2:13][NH:14][CH3:15])[CH:9]=[CH:10][CH:11]=1>CO>[OH:16][CH:12]([C:8]1[CH:7]=[C:6]([OH:5])[CH:11]=[CH:10][CH:9]=1)[CH2:13][NH:14][CH3:15]
Reactant: CNCC(O)c1cccc(OCOC)c1
Agent: Cl
Solvent: CO
Product: CNCC(O)c1cccc(O)c1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
Concentrated hydrochloric acid (0.1 mL) was added to 1-(3-methoxymethoxy-phenyl)-2-methylamino-ethanol (300 mg, 1.42 mmol) dissolved in methanol (3 mL). The resulting mixture was heated at reflux for about 30 minutes, and then cooled to ambient temperature. The mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (1×16 cm, dichloromethane/methanol/ammonium hydroxide=45/8/1 elution) to give the title compound (160 mg, 67%). 1H NMR (300 MHz, CD3OD) δ 7.14 (t, 1H, J=8.1 Hz), 6.81-6.80 (m, 2H), 6.69-6.66 (m, 1H), 4.71-4.67 (m, 1H), 2.78-2.66 (m, 2H), 2.41 (s, 3H); LC-MS: m/z=168 (MH)+; HPLC: 98% (Purity).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH:10][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=2)[CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(N)ccc1Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(=O)c2cccc(Cl)c2)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Amino-2-phenoxy-benzoic acid methyl ester (972 mg, 4.00 mmol) (prepared according to WO 01/046171) was dissolved in a biphasic mixture of ethyl acetate (10 ml) and aqueous sodium bicarbonate (1N) (10 ml). 3-Chloro-benzoylchloride (770 μl, 6 mmol) was added under vigorous stirring. The mixture was stirred for 18 hours at ambient temperature. The phases were separated, the organic phase was dried over sodium sulfate and concentrated. The residue was used without further purification.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N-]=[N+]=[N-].[Na+].[N:16]([CH2:19][C:20]1([CH3:35])[CH2:24][C:23]2[CH:25]=[C:26]([Cl:34])[CH:27]=[C:28]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:22]=2[O:21]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pt]>[Cl:34][C:26]1[CH:27]=[C:28]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[O:21][C:20]([CH2:19][NH2:16])([CH3:35])[CH2:24][C:23]=2[CH:25]=1
Reactant: CC1(CN=[N+]=[N-])Cc2cc(Cl)cc(-c3cccs3)c2O1
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [N-]=[N+]=[N-]
Product: CC1(CN)Cc2cc(Cl)cc(-c3cccs3)c2O1

Procedure:
Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.90 g, 5.8 mmol), thiophene-2-boronic acid (1.11 g, 8.7 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.47 g, 0.58 mmol), and potassium carbonate (1.6 g, 11.6 mmol) generally according to the procedure described for Intermediate 35 gave (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (2.00 g, 30.7 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.250 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.58 g of (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 251-252° C.; Anal. calcd. for C14H14ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 51.17; H, 4.48; N, 4.32.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([NH:29][C:8]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1)N[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
A solution of pyridin-3-yl-carbamic acid phenyl ester (1.6 g) in dry THF (20 ml) is treated with (R)-1-benzyl-pyrrolidin-3-ylamine (1.9 g, 1.05 eq) and then heated using microwave radiation at 110° C. for 1000 s. The solvent is removed in vacuo and purification of the crude product by chromatography on silica eluting with DCM followed by EtOAc and EtOH affords the title compound as an oil. (MH+ 297).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]([N:23]1[CH2:29][CH2:28][C:27]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1)[CH3:22].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:34][C:31]2[CH:32]=[CH:33][C:26]3[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:29][CH2:28][C:27]=3[CH:30]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (99 mg, 0.29 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55.0 mg, 0.289 mmol) in 2-Methoxyethanol (3 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After overnight stirring, Macroporous carbonate resin (3.16 mmol/g loading; 150 mg, 0.474 mmol) was added and the reaction was cooled to room temperature, then was concentrated in vacuo onto Celite, and chromatographed (14 g ISCO Amine column, DCM) to isolate N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo-[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}methane-sulfonamide as a beige foam (40 mg, 28%). LCMS (m/e) 493 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.24 (m, 2H), 7.04 (d, 1H, J=8.8 Hz), 6.76 (s, 1H), 5.38 (d, 1H, J=7.6 Hz), 5.28 (s, 1H), 3.87 (m, 1H), 3.22 (m, 1H), 2.91 (m, 4H), 2.77 (s, 3H), 2.64 (m, 3H), 2.57 (t, 2H, J=7.0 Hz), 2.21 (m, 2H), 1.82 (m, 2H), 1.37 (m, 4H), 1.10 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:14][CH:15]([CH3:17])[CH3:16])([C:12]#[N:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N.O>CO.[Ni]>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][C:9]([CH2:12][NH2:13])([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C#N)(CC(C)C)CC1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)N1CCC(CN)(CC(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a heavy wall flask was placed 1-(ethylsulfonyl)-4-isobutylpiperidine-4-carbonitrile (4, 1.4 g, 5.42 mmol) 2N ammonia in methanol (50 ml). To this was added commercially available Raney nickel slurry in water (1.393 g, 16.26 mmol). This was then agitated under hydrogen atmosphere (45 psi) at room temp for 12 hours. The catalyst was filtered off using celite and washed with MeOH (200 ml). The organics were concentrated in vacuo to give 1-[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methanamine (5) as a clear oil. MS 263 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:14]([C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][C:8]=2[CH:10]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc2ccccc2o1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)c1cc2cc(C(C)=O)ccc2o1

Procedure:
To a solution of 2-benzofuranoic acid methyl ester in carbon disulphide (240 ml) cooled to 5° C. was added acetyl chloride (70 ml) followed portionwise over 1 hour by aluminium trichloride (40 g). The mixture was heated under reflux for 42 hours before cooling and decanting the carbon disulphide. The residual complex was destroyed by the addition of iced water (50 ml) and 2N HCl (50 ml). The resulting mixture was extracted with ethyl acetate (3×200 ml). The organic layers were combined, washed with water (100 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography, eluting with ethyl acetate/hexane (10:90 to 40:60, v/v), to give methyl 5-acetylbenzofuran-2-carboxylate as a solid (3.099 g); NMR 2.68(3H,s), 4.00(3H,s), 7.6-8.35(4H,m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1C.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:12]([OH:13])=[O:15]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Br)cccc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
To a mixture of 2-bromo-6-nitrotoluene (8 g), sodium carbonate (18.1 g) and water (500 mL) was added potassium permanganate (23.4 g), and the mixture was heated for reflux overnight. The insoluble material was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (three times). The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-bromo-6-nitrobenzoic acid (2.78 g). Tin (II) chloride dihydrate (9.18 g) was dissolved in concentrated hydrochloric acid (30 mL). To the solution was added 2-bromo-6-nitrobenzoic acid (2.78 g), and the mixture was stirred at 80° C. for 1.5 hours. The insoluble material was collected by filtration, washed with 2 mol/L hydrochloric acid and dried under reduced pressure. The obtained crystal (2.05 g) was suspended in concentrated hydrochloric acid (35 mL). To the suspension was added a solution of sodium nitrite (0.79 g) in water (6 mL) under ice-cooling, and the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of tin (II) chloride dihydrate (5.78 g) in concentrated hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (1.27 g)