Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH:4]=1.Cl.[CH3:21]O>>[CH3:21][O:1][CH2:2][C:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH:4]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C=C(CO)C1(CCC1)O2
Reactant: CO
Agent: Cl
Product: COCC1=Cc2c(C)c(O)c(C)c(C)c2OC12CCC2

Procedure:
3-(Methoxymethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol was prepared by treating 3-(hydroxymethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol with methanol in the presence of conc. hydrochloric acid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]#[N:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[O:30]1C[CH2:33][CH2:32][CH2:31]1.OCC(=O)C.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][NH:27][C:28]3[O:30][CH:31]=[C:32]([CH3:33])[N:29]=3)[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: N#CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: C1CCOC1
Agent: CC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1coc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)n1
Reaction time: 2 h
Yield: 6 %

Procedure:
To a stirred mixture of 1.95 parts of [2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-cyanamide, 45 parts of tetrahydrofuran and 50 parts of water was added a solution of 3.7 parts of 1-hydroxy-2-propanone in water (=50%). 5 Parts of a sodium hydroxide solution 2N were added dropwise. Upon completion, stirring was continued for 2 hours at room temperature. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.3 parts (6%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(4-methyl-2-oxazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 178.1° C. (compound 84).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[N:12]([O-])=O.[Na+].S(=O)(=O)(O)O>CC(O)=O>[NH:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=[N:12]1
Reactant: O=N[O-]
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nn[nH]c2c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
3,4-diaminobenzoic acid (5 g, 32.8 mmol) was dissolved in AcOH (30 ml) and this mixture cooled to 5° C. To this mixture NaNO2 solution (2.7 g in 8 ml water) was added followed by 2 ml sulphuric acid. Reaction mixture was allowed to stir for 90 mins. After that, reaction mixture quenched with ice and solid that obtained was filtered and washed with water to obtain the title compound (4.5 g) as a brown solid.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:31]1[CH2:34][CH:33]([C:35]([N:37]2[CH2:43][CH2:42][CH2:41][N:40]([CH:44]3[CH2:47][CH2:46][CH2:45]3)[CH2:39][CH2:38]2)=[O:36])[CH2:32]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH:44]1([N:40]2[CH2:41][CH2:42][CH2:43][N:37]([C:35]([CH:33]3[CH2:32][N:31]([C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:9])[CH2:34]3)=[O:36])[CH2:38][CH2:39]2)[CH2:47][CH2:46][CH2:45]1
Reactant: O=C(O)C1CCCCC1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CN(C(=O)C2CCCCC2)C1)N1CCCN(C2CCC2)CC1
Yield: 82.2 %

Procedure:
To a stirred solution of cyclohexanecarboxylic acid (10.8 mg, 0.084 mmol) in DCM/DMF (1.1 ml) was added HOBt (11.4 mg, 0.084 mmol) and EDCI (16.1 mg, 0.084 mmol). After 10 mins a solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (20 mg, 0.084 mmol) in DCM (1 ml) and DIPEA (0.01 ml, 0.084 mmol) was added dropwise. After 15 h the solvent was evaporated at reduced pressure and purified by silica FCC (eluting with 99:1 to 95:5 gradient of DCM/2M NH3 in MeOH) to give the title compound (24 mg, 82% yield) as brown oil.
Reaction SMILES: [N+]([O-])([O-])=O.[O-2].[Bi+3:6].[C:7]([OH:19])(=[O:18])[CH2:8][C:9]([CH2:14][C:15]([OH:17])=[O:16])([C:11]([OH:13])=[O:12])[OH:10].N>O>[C:7]([O-:19])(=[O:18])[CH2:8][C:9]([CH2:14][C:15]([O-:17])=[O:16])([C:11]([O-:13])=[O:12])[OH:10].[Bi+3:6]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Yield: 101 %

Procedure:
A mixture of bismuth oxynitrate (22.96 g) and citric acid (33.60 g) in water (80 ml) was heated on a steam bath with frequent stirring for 30 min, by which time one drop of the suspension added to weak aqueous ammonia gave a clear solution. The mixture was diluted with water, filtered, and the residue washed well with water until free of nitrate and excess citric acid. The residue was dried under vacuum to give the title compound (32.18 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[N:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][O:9][C:8]1[C:3]([CH2:2][N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:4][CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: c1c[nH]c(-c2nccs2)n1
Reactant: COc1nc(-c2ccccc2)cnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2)cnc1Cn1ccnc1-c1nccs1
Temperature: 45 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
A mixture of 2-chloromethyl-3-methoxy-5-phenyl-pyrazine (90 mg, 0.38 mmol; prepared as described above), 2-(1H-imidazol-2-yl)-thiazole (55 mg, 0.363 mmol) and K2CO3 (159 mg, 1.15 mmol) in DMF (7 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (3 mL) and extracted with DCM (3×15 mL). The combined organic layers are dried and solvent removed. PTLC separation (silica gel; 10% MeOH in DCM) gives 78 mg of 3-methoxy-5-phenyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-pyrazine as an oil. 1H NMR (CDCl3) 8.47 (s, 1H), 7.97–8.01 (m, 2H), 7.76 (d, 1H), 7.42–7.49 (m, 3H), 7.28 (d, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 6.03 (s, 2H), 4.05 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1>>[Cl:1][C:2]1[C:21]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 56 using 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide and 3-fluoropyridine-5-boronic acid pinacol ester to afford the title product as a beige solid. UPLC-MS (Condition 2) tR=1.13 min, m/z=412 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.39 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 8.02-8.12 (m, 1H) 8.49 (d, J=2.35 Hz, 1H) 8.64-8.76 (m, 2H) 8.99 (dd, J=2.35, 0.78 Hz, 1H) 10.65 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6](=[C:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1>C(O)C.[Pd]>[CH3:18][C:2]1([CH3:1])[CH2:7][CH:6]([CH:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1
Reactant: CCOC(=O)C(C#N)=C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C#N)C1CC(C)(C)NC(C)(C)C1

Procedure:
This ester is hydrogenated over Pd/C in ethanol and gives ethyl 2-(2,2,6,6-tetramethyl-4-piperidinyl)-cyanoacetate which has a melting point of 116°-117° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:21][C@@H:22]([CH3:39])[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:36]=[C:35]([F:37])[C:32]([C:33]#[N:34])=[C:31]([Cl:38])[CH:30]=2)=[N:25]1>>[Cl:38][C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][N:24]([CH2:23][C@@H:22]([NH:21][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=3)=[O:12])[CH3:39])[N:25]=2)[CH:36]=[C:35]([F:37])[C:32]=1[C:33]#[N:34]
Reactant: CC(C)(O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)(C)O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.33 mmol) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (370 mg, 1.33 mmol). The product was purified with flash-chromatography. Yield 305 mg. LC-MS: [M+1]=561.17.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CN(C)P(=O)(N(C)C)N(C)C.C1(C)C=CC=CC=1.[C:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=2)[CH:26]=1)(=[O:24])[CH3:23]>O.C(OCC)(=O)C>[C:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=2)[CH:26]=1)(=[O:24])[CH3:23].[C:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([N:2]([CH3:3])[CH3:1])[CH:31]=2)[CH:26]=1)(=[O:24])[CH3:23]
Reactant: CNC
Agent: COc1ccc2cc(C(C)=O)ccc2c1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2cc(N(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 123.8 %

Procedure:
To a solution of 5.26 g (117 mmol) of dimethylamine in 29 mL of freshly distilled hexamethylphosphoric triamide (HMPT) were added 31 mL of dry toluene and 780 mg (112 mmol) of Li in small pieces. The mixture was stirred under argon at room temperature for 1.5 hours. 2-Acetyl-6-methoxynaphthalene was prepared as described in Arsenijevic et al., Org. Synth. Coll. 1988, 6:34-36, the disclosure of which is incorporated herein by reference. 2-Acetyl-6-methoxynaphthalene (5.57 g, 27.8 mmol) was added in one portion, and stirring was continued for 20 hours. The mixture was cooled in an ice-water bath and poured into a cold water/ethyl acetate mixture (300 mL each). After thorough mixing, the layers were separated, and the water layer was extracted twice with 225 mL of ethyl acetate. Organic extracts were combined, dried, and evaporated to give a yellow solid. Recrystallization from ethanol afforded 3.67 g (64%) of 2-acetyl-6-(dimethylamino)naphthalene (ADMAN) as a yellow solid, melting at 153.5-155° C.: 1H NMR (CDCl3, TMS) δ 2.67 (s, 3H, COCH3), 3.15 (s, 6H, N(CH3)2), 6.87 (d, 1H, H-5), 7.17 (dd, 1H, H-7), 7.63 (d, 1H, H-4), 7.80 (d, 1H, H-8), 7.92 (dd, 1H, H-3), 8.32 (bs, 1H, H-1). J1,3=2.3 Hz, J3,4=8.7 Hz, J5,7=2.4 Hz, J7,8=9.3 Hz. MS (M+) 213: found: 213. Anal. Calcd for C14H15NO: C, 78.84: H, 7.09; N, 6.57. Found C, 78.96; H, 7.10; N, 6.45.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([O:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O)=O.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C.O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]1[O:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:32]=1
Reactant: CCOC(=O)C(OC(=O)c1c(F)cccc1F)C(=O)c1ccc(OC)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1oc(-c2c(F)cccc2F)nc1-c1ccc(OC)cc1
Yield: 50 %

Procedure:
To a stirred solution of 3-ethoxy-1-(4-methoxyphenyl)-1,3-dioxopropan-2-yl 2,6-difluorobenzoate (0.082 g, 0.22 mmol) in acetic acid (3 mL) was added ammonium acetate (0.125 g, 1.62 mmol) and the reaction mixture heated to reflux for 3 hours. A further portion of ammonium acetate (0.017 g, 0.22 mmol) was added the reaction mixture heated to reflux for 1 hour. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 15% EtOAc in hexanes as eluent to afford ethyl 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylate (0.041 g, 0.11 mmol, 53%) as a white crystalline solid. 1H NMR (CDCl3) δ 1.41 (3H, t), 3.87 (3H, s), 4.43 (2H, q), 6.99 (2H, d), 7.07 (2H, t), 7.49 (1H, m), 8.15 (2H, d). LCMS (1) Rt: 2.46 min; m/z (ES+) 360.
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:46][N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.4 %

Procedure:
Compound 1 (4.00 g, 6.67 mmol) obtained in Example 1 was dissolved in 1,2-dichloroethane (50 mL) and methanol (50 mL), and stirred at room temperature for 1 hour after adding formaldehyde (4.96 mL, 66.7 mmol) and sodium triacetoxyborohydride (Acros Organics; 7.06 g, 33.3 mmol). The reaction mixture was further stirred at room temperature for 2.5 hours after adding sodium triacetoxyborohydride (Acros Organics; 7.06 g, 33.3 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction solution. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 10 (3.99 g, 97.4%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:45]=[N+:46]=[N-:47].[Na+].[N-]=[N+]=[N-]>CN(C=O)C.O>[N:45]([C@@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@H:11]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N+:46]=[N-:47]
Reactant: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](I)[C@@H]1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](N=[N+]=[N-])[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound 87 (30 mg) was dissolved in DMF/water 1:1 (2 ml) and followed by sodium azide (26 mg, 10 equiv.). The reaction mixture stirred at 80° C. overnight. LCMS confirms conversion of starting material to product substituted with azide.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH:39]([OH:41])[CH3:40])[CH:37]=2)[CH:32]=[C:31]1[C:42]1[CH:47]=[C:46]([C:48]2[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=2)[N:45]=[N:44][C:43]=1[O:54][CH3:55])=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:27][C:28]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39](=[O:41])[CH3:40])[CH:37]=2)[CH:32]=[C:31]1[C:42]1[CH:47]=[C:46]([C:48]2[CH:49]=[CH:50][N:51]=[CH:52][CH:53]=2)[N:45]=[N:44][C:43]=1[O:54][CH3:55])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C(C)O)cc2n1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C(C)=O)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
200 mg Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) is added to a solution of 210 mg 6-(1-hydroxy-ethyl)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butylester (145a) in 4 ml dichloromethane and the mixture stirred for 2.5 hours at room temperature. Than the solution is extracted with a 5% Na2SO3 solution and water, dried using a silicagel cartridge and the solvent removed in vacuo. The crude product is purified by chromatography on silica gel (heptane/ethylacetate)
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2
Reactant: Cc1ccc2[nH]ncc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2[nH]ncc2c1N
Yield: 93 %

Procedure:
m.p. 197°-200° C. (yield 93% of theory) by hydrogenating 4-nitro-5-methylindazole in methanol in the presence of palladium-charcoal;
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.C=O.[CH2:14]([Cl:16])Cl>>[Cl:16][CH2:14][C:11]1[C:3]([CH3:2])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: ClCCl
Reactant: Cc1ccc2c(c1)OCO2
Agent: C=O
Agent: [Br-]
Product: Cc1cc2c(cc1CCl)OCO2
Reaction time: 8 h

Procedure:
To a mixture of methylene chloride (130L), concentrated HCl (130L), and tetrabulylammonium bromide (1.61 Kg) was added 5-methylbenzo[d][1,3]dioxole (10 Kg) followed by the slow addition of formaldehyde (14L, 37 wt% in water). The mixture was stirred overnight. The organic layer was separated, dried with magnesium sulfate and concentrated to an oil. Hexane (180L) was added and the mixture heated to boiling. The hot hexane solution was decanted from a heavy oily residue and evaporated to give almost pure 5-chloromethyl-6-methylbenzo[d][1,3]dioxole as a white solid. Recrystallization from hexane (50L) gave 5-chloromethyl-6-methylbenzo[d][1,3]dioxole (80% recovery after recrystallization).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:17]([Br:36])=[C:16]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=3)[N:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cc(Oc3cc(C(F)(F)F)nn3C)ncn2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ncnc(Oc3cc(C(F)(F)F)nn3C)c2Br)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester (150 mg, 0.37 mmol) and NBS (65 mg, 0.37 mmol) in DMF (3 ml) was stirred at 60° C. for 2 days. The mixture was quenched with sodium thiosulfate, and extracted with ethyl acetate. The combined organic layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (hexanes:ethyl acetate=3:1) provided compound A19 as a white solid (100 mg, 57%). 1HNMR (CDCl3, 400 MHz) δ 1.28 (t, 3H), 1.78-1.88 (m, 2H), 1.95-2.05 (m, 2H), 2.57-2.62 (m, 1H), 3.17 (t, 2H), 3.81 (s, 3H), 4.18 (q, 2H), 4.22-4.33 (m, 2H), 6.41 (s, 1H), 8.22 (s, 1H). Exact mass calculated for C17H19BrF3N5O3 477.06, found 478.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=[CH:14][CH:13]=1>CCCCO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1ccnc2cccnc12
Solvent: CCCCO
Product: COc1ccc(CNc2ccnc3cccnc23)cc1
Temperature: 150 °C
Yield: 88.5 %

Procedure:
p-Methoxybenzylamine (1.45 g, 10.6 mmol) was added to a solution of 4-chloro-[1,5]naphthyridine 484 (0.35 g, 2.13 mmol) in n-BuOH (9 ml) and the mixture was heated at 150° C. for 18 h. The solvent was removed in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (80:20) as the eluent to give the title compound (0.5 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C.O1CCCC1>C(O)C.O.[Fe]>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2cc(NC(=O)N3CCOCC3)ncn2)c(F)c1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
Morpholine-4-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (107 mg) was dissolved in ethanol (5 ml)-water (1 ml), and then electrolytic iron powder (110 mg) and ammonium chloride (220 mg) were added thereto, followed by heating under reflux for 30 min. The reaction mixture was cooled down to room temperature, and ethyl acetate-tetrahydrofuran (1:1) was then added thereto, followed by stirring. The reaction mixture was filtered through celite to remove an insoluble portion, which was washed with ethyl acetate and water. The organic layer of the filtrate was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1). Fractions containing the target compound were concentrated under a reduced pressure, and dried in vacuum to provide the titled compound (82.4 mg, 85.2%) as a yellow solid.