Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])[CH3:20].[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][CH2:19][CH3:20])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: CCOc1ccccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)Nc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 2 h
Yield: 71.6 %

Procedure:
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 528 mg (2.11 mmol) was added at 0° C. to a solution of 2-ethoxybenzoic acid chloride 390 mg (2.11 mmol) in pyridine (25 ml) and stirring was performed for 2 h at 0° C. and then for 72 h at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 600 mg (1.51 mmol, 72% of theoretical) was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:5][CH2:6][OH:7].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH3:3][N:4]([C:8]1[N:9]=[CH:10][CH:11]=[CH:12][N:13]=1)[CH2:5][CH2:6][O:7][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Sodium hydride (60% in oil, 4.40 g) was added to a solution of 2-(methyl-2-pyrimidylamino)ethanol (15.3 g) in N,N-dimethylformamide (400 ml) at room temperature under nitrogen atmosphere and stirred for 1 hour. A solution of 4-fluorobenzaldehyde (13.6 g) in N,N-dimethylformamide (100 ml) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was poured onto ice (200 g) and concentrated. The residue was dissolved in ethyl acetate, washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzaldehyde (18.4 g, yield 72%) as crystals from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 74-75° C.
Reaction SMILES: [NH2:1][C:2]1[C:34]([N+:35]([O-])=O)=[CH:33][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=5[NH:21][C:20]4=[O:32])[CH2:15][CH2:14]3)[CH:8]=2)=[CH:4][C:3]=1[CH3:38]>CO.[Pd]>[NH2:35][C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([CH3:38])[C:2]=1[NH2:1])[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:32])[CH2:17][CH2:18]2)[CH:8]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c([N+](=O)[O-])c4)ncn3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2

Procedure:
830 mg (1.60 mmol) 3-{1-[6-(4-amino-3-methyl-5-nitro-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 20 mL MeOH were combined with 100 mg palladium on charcoal (Pd/C 10%) and hydrogenated for 8 h under a hydrogen atmosphere of 50 psi. After the catalyst had been removed by suction filtering, the filtrate was evaporated down and the residue was reacted further as the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](Cl)=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[N:11]1.[OH-:19].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([OH:19])=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[N:11]1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1Cl
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1O
Yield: 49 %

Procedure:
3.3 g of 1-(2,4,6-trichlorophenyl)-4-nitro-5-chloropyrazole are suspended in 10 ml of methanol, and 20 ml of 1N methanolic potassium hydroxide solution are added. The mixture is refluxed for 12 hours. In order to achieve complete reaction, a further 10 ml of 1N methanolic potassium hydroxide solution are added to the reaction mixture, which is refluxed for a further 12 hours. For work-up, the mixture is filtered, the solvent is stripped off in vacuo, the residue is taken up in hot water, and the product is precipitated by acidification with 2N hydrochloric acid. After filtering off and drying, 1.5 g (49% of theory) of 1-(2,4,6-trichlorophenyl)-4-nitro-5-hydroxypyrazole of melting point 106°-115° C. are obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[N:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[NH:8][CH:9]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1COCC1.O.[Cl-].[Na+].O>[F:16][C:4]([F:3])([F:15])[C:5]1[N:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[NH:8][CH:9]=1.[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:8]1[CH:9]=[C:5]([C:4]([F:3])([F:15])[F:16])[N:6]=[C:7]1[C:10]1[S:11][CH:12]=[CH:13][N:14]=1
Reactant: COC(=O)CBr
Agent: FC(F)(F)c1c[nH]c(-c2nccs2)n1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cn1cc(C(F)(F)F)nc1-c1nccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (109 mg of a 60% dispersion in mineral oil, 2.74 mmol) in THF (10 mL) at 0° C. under N2 is added a solution of 2-(4-trifluoromethyl-1H-imidazol-2-yl)-thiazole (500 mg, 2.28 mmol) in THF (4 mL) via cannula, followed by a 1 mL rinse. The mixture is stirred at 0° C. for 30 min and then treated with methyl bromoacetate (0.28 mL, 2.97 mmol). The reaction mixture is stirred overnight while slowly warming to rt. It is then diluted with H2O (10 mL) and the resulting mixture stirred vigorously for 5 min. The mixture is further diluted with some brine and then extracted twice with EtOAc. The combined extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 4:1 hexanes-EtOAc followed by 3:1 hexanes-EtOAc affords unreacted 2-(4-trifluoromethyl-1H-imidazol-2-yl)-thiazole as well as (2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetic acid methyl ester. 1H NMR (CDCl3, 400 MHz) δ 7.82 (d, J=3.2 Hz, 1H), 7.40 (d, J=3.2 Hz, 1H), 7.35 (s, 1H), 5.41 (s, 2H), 3.77 (s, 3H) ppm.
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(Cl)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
Triethylamine (2.09 mL, 15.0 mmol) was added to a cold (0° C.) solution of (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (3.05 g, 10.0 mmol) in DCM (100 mL), followed by methanesulfonyl chloride (0.929 mL, 12.0 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then quenched with water (50 mL). The layers were separated, and the organic layer was washed with saturated NaHCO3, dried, filtered and concentrated to give the crude product. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (25:1) to give (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (3.80 g, 99%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 1H), 7.20 (m, 1H), 7.12 (m, 1H), 5.50 (m, 1H), 3.91 (m, 1H), 3.80 (m, 1H), 2.98 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:46][C:47](=[O:51])[C@H:48]([CH3:50])[NH2:49])C>CCOCC>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:49][C@H:48]([C:47]([OH:51])=[O:46])[CH3:50])=[O:11])=[CH:13][CH:14]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCC#Cc2ccc(Cl)cc2)C(=O)C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of 4-[N-trifluoroacetyl-13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the N-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}alanine as a white, crystalline solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][CH:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)[CH3:12])(=[O:9])[CH3:8].Cl>CO>[C:7]([NH:10][CH:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1)[CH3:12])(=[O:9])[CH3:8]
Reactant: COC(=O)C1CCC(C(C)NC(C)=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](C(C)NC(C)=O)CC1
Temperature: 0 °C

Procedure:
Potassium tert-butoxide (37.7 g) was added to a solution (200 ml) of a cis- and trans- mixture of methyl (+)-4-(1-acetamidoethyl)cyclohexanecarboxylate (38.0 g) in methanol and the mixture was refluxed under heating for 60 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue obtained was poured into ice water, neutralized with conc. hydrochloric acid and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure to give 21 g of methyl (+)-trans-4-(1-acetamidoethyl)cyclohexanecarboxylate. [α]D =+41.6° (methanol, c=1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]1[CH2:16][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([I:18])=[C:8]1I.CC[Mg+].[Br-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]1[CH2:11][CH:10]([CH2:16]1)[N:9]1[C:5]2=[N:6][C:7]([I:18])=[CH:8]1
Reactant: Brc1ccc2c(c1)-c1nc(I)c(I)n1C1CC2C1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)-c1nc(I)cn1C1CC2C1
Temperature: -40 °C
Yield: 285.3 %

Procedure:
Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tetrahydrofuran (1200 mL), 9-bromo-3,4-diiodo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene (119.3 g, 226.40 mmol, 1.00 equiv), followed by the addition of EtMgBr (90.7 mL, 1.20 equiv) dropwise with stirring at −40° C. The resulting solution was stirred at −40° C. for 1 h. This reaction was repeated for 2 more times. The reaction was then quenched by the addition of 500 mL of 5% hydrogen chloride and extracted with 3×500 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 259 g (97%) of 9-bromo-4-iodo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene as a brown solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1.[C:16]([CH2:18][C:19]([NH:21][CH:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:20])#[N:17].O>CS(C)=O>[Br:7][C:8]1[N:13]=[C:12](/[CH:14]=[C:18](\[C:16]#[N:17])/[C:19]([NH:21][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:29][CH:30]=2)[CH2:23][CH3:24])=[O:20])[CH:11]=[CH:10][CH:9]=1
Reactant: CCC(NC(=O)CC#N)c1ccc(OCCOC)cc1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOC)cc1
Yield: 90 %

Procedure:
Potassium t-butoxide (0.014 g, 0.127 mmol) was added to a stirred solution of 6-bromo-2-pyridinecarboxaldehyde (0.094 g, 0.51 mmol) and 2-cyano-N-(1-(4-(2-methoxyethoxy)-phenyl)propyl)acetamide (0.07 g, 0.25 mmol) in dimethylsulfoxide (10 mL) under nitrogen at room temperature. After 26 hours the mixture was shaken with water and then extracted with ethyl acetate several times. The combined extracts were washed with water and then dried over sodium sulfate. The solvent was removed in vacuo leaving 0.10 g of a clear amber syrup, which was flash chromatographed on a column (5×10 cm) of silica gel with gradient elution utilizing dichloromethane/EtOAc (10:0 gradually changing to 12:1) to afford 0.040 g of the product as a clear pale yellow syrup; mass spec ES+m/z=444, 466 (m+1, m+23).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]#[N:21])[CH:16]=[N:15]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:33]=[N+:34]=[N-:35])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]2[N:33]=[N:34][NH:35][N:21]=2)[CH:16]=[N:15]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(CC#N)cn1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(Cc2nn[nH]n2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To N-[3-tert-butylsulfanylmethyl-4-(4-cyanomethyl-pyrazol-1-ylmethyl)-phenyl]-2,2-dimethyl-propionamide (0.015 g, 0.04 mmol) in toluene (1 mL) was added trimethylsilyl azide (0.02 mL, 0.1 mmol), followed by dibutyltin oxide (0.001 g, 0.004 mmol), and the reaction was stirred at 80° C. overnight. Starting material was still present, so additional trimethylsilyl azide (0.20 mL, 1.1 mmol) and dibutyltin oxide (0.005 g, 0.02 mmol) were added, and the reaction was stirred for 6 hours at 100° C. After work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC(O)CC>[C@@H:20]1([NH:19][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([C@H:11]4[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(Cl)ncnc32)C[C@@H]1O
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 55 °C
Yield: 77.3 %

Procedure:
A jacketed reactor was charged with (1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (30.8 Kg, 115.05 mol), 2-butanol (198.5 Kg), (S)-(+)-1-aminoindane (16.95 Kg, 127.26 mol) and diisopropylethylamine (19.45 Kg, 150.50 mol). The mixture was heated to 55±5° C. and then moved to a mobile vessel. The reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which was moved to the mobile vessel. The mobile vessel contents were then transferred to a pressure reactor and 2-butanol (51 L) was used to rinse the mobile vessel. The reaction mixture was then heated to 135±5° C. and adjusted to a pressure of 8 bar. The mixture was then stirred until reaction was complete by HPLC analysis. The mixture was cooled to 30±10° C. and transferred to a mobile vessel via a plate filter. The pressure reactor was rinsed with 2-butanol (43.1 L). The contents of the mobile vessel were then charged to a jacketed reactor via an in-line filter and the vessel rinsed with 2-butanol (39.2 Kg). The mixture was heated to 50±5° C. and concentrated under reduced pressure to about 50 L. The mixture was cooled to 20±5° C. and then dichloromethane (256 Kg) added over a period of about 3 hours. The mixture was stirred for a further 9.5 hours and then further cooled to 0±5° C. and stirred for about 4 hours. The solid product was isolated by filtration and washed with dichloromethane (82 Kg) at 0±5° C. The solids were then dried under reduced pressure at 40±5° C. to constant weight. A reactor was charged with water (371 Kg) and the dried solids and the mixture stirred at 20±5° C. for about 14.5 hours. The solid product was isolated by filtration and washed with water (371 Kg). The solids were then dried under reduced pressure at 50±5° C. to afford the title compound (32.4 Kg) as a white solid. 1H NMR (300 MHz, DMSO, 6): 8.15 (s, 1H), 7.71 (d, 1H), 7.07-7.29 (m, 5H), 6.61 (d, 1H), 5.88 (dd, 1H), 5.24-5.38 (m, 1H), 4.60 (d, 1H), 4.26-4.37 (m, 2H), 3.53-3.65 (m, 1H), 3.35-3.46 (m, 1H), 2.90-3.04 (m, 1H), 2.75-2.90 (m, 1H), 2.33-2.56 (m, 2H), 2.04-2.14 (m, 2H), 1.88-2.03 (m, 2H), 1.74-1.87 (m, 1H).
Reaction SMILES: [N:1]([C:4]1[C:9](Cl)=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=[O:12])=[N+:2]=[N-:3].[Br:13]C1C(Cl)=C(C=O)C=NC=1.[N-]=[N+]=[N-].[Na+]>>[N:1]([C:4]1[C:9]([Br:13])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=[O:12])=[N+:2]=[N-:3]
Reactant: O=Cc1cncc(Br)c1Cl
Reactant: [N-]=[N+]=Nc1c(Cl)cncc1C=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1c(Br)cncc1C=O
Yield: 83 %

Procedure:
Following the procedure described for 4-azido-5-chloro-pyridine-3-carbaldehyde, 5-bromo-4-chloropyridine-3-carbaldehyde and sodium azide were reacted to afford the title compound as a pale yellow solid (3.18 g, 83% yield). 1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 8.85 (s, 1H), 8.79 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:19])[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(Cl)Cl.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:19][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21)c1ccccc1
Reaction time: 1 h

Procedure:
To a 0° C. solution of 8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroquinolin-8-amine (62 mg, 0.136 mmol) and DCM (1 mL) was added DIEA (0.035 mL, 0.201 mmol) and then benzoyl chloride (0.0175 mL, 0.151 mmol) dropwise. After 1 h, the reaction was poured into water and the aqueous layer back extracted with DCM (5 mL). The combined DCM layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0-30% EtOAc in hexane, to provide the title compound as a white solid. MS (ESI, positive ion) m/z: 397.0 (MH+). 1H NMR (300MHz, CDCl3) δ: 8.46-8.63 (m, 2H), 7.74-7.88 (m, 2H), 7.33-7.66 (m, 8H), 7.24-7.28 (m, 1H), 3.55 (dt, J=14.0, 4.2 Hz, 1H), 2.89 (dd, J=9.6, 6.8 Hz, 1H), 2.54-2.82 (m, 2H), 1.86-2.01 (m, 1H), 1.65-1.83 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:6](OCC)=[O:7])[CH3:2].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH:6]=[O:7])([CH3:16])[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH3:2]
Reactant: CCOC(=O)C(C)(CCC(C)C)C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C=O)CCC(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 36.5 %

Procedure:
A solution of 2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (500 mg, 2.05 mmol) in anhydrous dichloromethane (4 mL) was stirred at −78° C. under a blanket of nitrogen and treated dropwise via syringe with a 1.0 M solution of DIBAL in toluene (4.1 mL, 4.1 mmol) over a period of 15 min. The reaction was stirred for 4 h at −78° C. and quenched sequentially with a saturated aqueous ammonium chloride solution (3 mL) and a 4% aqueous hydrochloric acid solution (3 mL). The resulting gelatinous suspension was allowed to warm to 25° C. and was filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (ISCO RediSep column, 0 to 20% ethyl acetate in hexanes) to give 2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (150 mg, 36%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (d, 6H, J=6.9 Hz), 1.07-1.15 (m, 2H), 1.23-1.26 (m, 3H), 1.28 (s, 3H), 1.52 (septet, 1H, J=6.6 Hz), 1.83-1.92 (m, 2H), 4.21 (q, 2H, J=6.9 Hz), 9.69 (s, 1H).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8])(=[O:5])=[O:4])[CH3:2]>[Pd].O.C(O)C>[CH2:1]([S:3]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)=[O:8])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)NC(=O)c1cccc(N)c1
Yield: 73.6 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(ethylsulphonylaminocarbonyl )-3-nitrobenzene (3 g, 11.6 mmol), 10% palladium on carbon (0.3 g, 10% (w/w)) in water (3 ml) and ethanol (100 ml), the title compound (1.95 g, 74%) was afforded as a pale beige solid after recrystallisation from ethanol. mp 129°-132° C. 1H NMR (360 MHz, D6 -DMSO) δ 1.24 (3H, t, J=7.4 Hz), 3.47 (2H, q, J=7.4 Hz), 5.40 (2H, brs), 6.77-6.83 (1H, m), 7.02-7.08 (2H, m), 7.13 (1H, dd, J=7.8 and 7.7 Hz).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:47]([CH3:49])[CH3:48])[C:10]([O:12][CH2:13][N:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([C:21]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=3)[C:24]([O:40][CH3:41])=[C:23]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:22]=2)[C:15]1=[O:46])=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:42]([C:23]1[CH:22]=[C:21]([C:16]2[C:15](=[O:46])[N:14]([CH2:13][O:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH:47]([CH3:48])[CH3:49])[CH:19]=[C:18]([F:20])[CH:17]=2)[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=2)[C:24]=1[O:40][CH3:41])([CH3:43])([CH3:45])[CH3:44]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cc(F)cn(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c2=O)cc1C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cc(F)cn(COC(=O)[C@@H](N)C(C)C)c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
step 3—To a solution of 342 (0.886 g, 1.266 mmol and DCM (10 mL) at RT was added a HCl/dioxane solution (1.899 mL, 7.60 mmol, 4M solution) and the resulting solution stirred at RT for 3 h. The resulting solution was poured into DCM (150 mL) which produced a gummy oil. When the mixture was sonicated a white powder formed which was filtered, washed with DCM and air-dried. The solid was dried under high vacuum to remove all traces of solvent which afforded 698 g of II-7 as a white powder: MS (M+H)=600.