Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][C@H:24]([C:29]([NH:31][C@H:32]([C:39]([NH:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)=[O:30])[C@H:25]([CH2:27][CH3:28])[CH3:26].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:39]([NH:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)=[O:30])[C@H:25]([CH2:27][CH3:28])[CH3:26])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 20 h

Procedure:
900 mg of Z-Sta-OH (for manufacture see stage 1.12), 1.24 g of H-Ile-His-Lys(Boc)-OMe and 560 mg of HOBt×H2O are dissolved in 13 ml of DMF. After the addition of 600 mg of DCCI, the whole is left to stand at room temperature for 20 hours, then the DCH which has crystallised out is filtered off and the filtrate is concentrated to dryness. The greasy residue is triturated at 0° with 30 ml of diisopropyl ether, the solvent is decanted and the residue is dried. Purification is carried out by Craig partitioning in the system methanol/buffer/ethylene chloride/chloroform (10:3:8:4; buffer=14.3 ml of glacial acetic acid and 9.6 g of ammonium acetate in 1000 ml of H2O) over 700 stages. The thin layer chromatographically pure fractions (K=0.5) are combined, strongly concentrated and lyophilised. To remove acetic acid, the product is dissolved and reprecipitated from 5% strength methanolic NaHCO3 solution, yielding Z-Sta-Ile-His-Lys(Boc)-OMe in the form of amorphous powder; Rf (B)=0.8; Rf (I)=0.56.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([Mg]Br)=CC>>[CH2:1]([O:8][CH2:9][C@H:10]([OH:14])[CH2:11][CH:12]=[CH:13][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@@H](O)COCc1ccccc1
Reactant: CC=C[Mg]Br
Product: CC=CC[C@@H](O)COCc1ccccc1

Procedure:
The product was obtained according to the method used for synthesis of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1) in Preparation P1, except that 1-propenylmagnesium bromide was used in place of vinylmagnesium bromide. The product was obtained as a brown oil, which was used without further purification; by 1H NMR, this material consisted of a 1:1 mixture of geometric isomers. Yield: 140 g, 0.679 mol, 100%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.42 (m, 5H), 5.39-5.67 (m, 2H), 4.57 (s, 2H), 3.80-3.92 (m, 1H), 3.48-3.57 (m, 1H), 3.35-3.43 (m, 1H), 2.36-2.50 (br m, 1H), 2.24-2.33 (m, 1H), 2.17-2.24 (m, 1H), [1.68 (br d, J=6 Hz) and 1.64 (br d, J=7 Hz), total 3H].
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15]C)([O:13]C)[O:11]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15][Si:18]([CH3:21])([CH3:20])[CH3:19])([O:13][Si:18]([CH3:21])([CH3:20])[CH3:19])[O:11][Si:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Reactant: C[Si](C)(C)Cl
Product: C=C(C)C(=O)OCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
γ-Methacryloxypropyl-tris (trimethylsiloxy)silane (TRIS) was prepared by hydrolysis of 0.1 mole of γ-methacryloxypropyl-trimethoxysilane (MEMO) and 0.35 mole of chlorotrimethylsilane and subsequent distillation following the same procedure as in Example (a).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH:24]=[CH:25][CH:26]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[NH2:40][CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>C(#N)C>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:40][CH2:41][C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:22]=1
Reactant: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)c1
Reactant: NCc1cccnc1
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)c1
Yield: 77.1 %

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(2′-methyl-1,1′-biphenyl-3-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step C (0.600 g, 1.1 mmol) and dimethyl sulfoxide (0.41 mL, 5.8 mmol) in dry acetonitrile (5.5 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.23 mL, 2.2 mmol) and the reaction mixture heated to reflux for 45 hours. The cooled reaction mixture was concentrated in vacuo, the oily residue redissolved in ethyl acetate (25 mL), washed with 1 M sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale orange foam. Purification by flash chromatography using ethyl acetate as solvent afforded a pale yellow foam that was recrystallized from ethyl acetate/diethyl ether/hexane to give the title compound (0.435 g, 74%) as an off-white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:39])[C:31]=1[C:32](=O)[C:33]([O:35]CC)=O.CC(O)=O>COCCO>[Cl:39][C:30]1[CH:29]=[N:28][CH:27]=[C:26]([Cl:25])[C:31]=1[C:32]1[C:33](=[O:35])[N:23]([CH3:24])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Reactant: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1
Solvent: COCCO
Solvent: CC(=O)O
Product: CCN(CC)CCOc1ccc(Nc2ncc3nc(-c4c(Cl)cncc4Cl)c(=O)n(C)c3n2)cc1
Yield: 15.3 %

Procedure:
A mixture of 0.465 g (1.4 mmol) of 5-amino-2-[[4-[2-(diethylamino)-ethoxy]-phenyl]amino]-4-(methylamino)pyrimidine, 0.69 g (2.8 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.5 mL of HOAc in 15 mL of 2-methoxyethanol is heated under reflux for 18 hours, and the reaction is worked up as above in 6 to give 0.11 g (15%) of the title compound (Compound 20): mp (MeOH) 179–180.5° C.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][C@H:3]([C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8])[NH:2]2.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:2]2[C@@H:3]([C:7]([NH:9][C@H:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[CH3:11])=[O:8])[CH2:4][CH:5]3[CH:1]2[CH2:6]3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compounds (D149) (14 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-((3R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (D106) (11 mg) and 4-(trifluoromethyl)-benzylbromide (0.007 ml). (Na2CO3: 3 eq; Reaction time: 18 hrs; 68° C.)
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22]Cl)=[CH:15][CH:14]=2)[C:11](=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:15][CH:14]=2)[C:11](=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2-ethyl-3-[4-(3-chloropropoxy)phenyl]-4(3H)-quinazolinone (19 g, 55.6 mmol), piperidine (23.7 g, 278 mmol), potassium carbonate (11.5 g, 83.4 mmol) and potassium iodide (13.8 g, 83.4 mmol) were mixed in dimethylformamide (400 mL) and stirred at 80° C. for 24 hours.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH:9]1[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=1[OH:45]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:45][C:39]2[C:40]([CH3:44])=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:37])=[O:15])[CH2:10][CH:9]1[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC1CN(C(=O)c2c(Cl)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C
Reactant: Cc1cccc(C)c1O
Product: COC(=O)CC1CN(C(=O)c2c(Oc3c(C)cccc3C)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C

Procedure:
The compound of step 1 (254 mg, 507 μmol) and 2,6-dimethylphenol were reacted analogously as described in example 1, step 6. 340 mg of crude title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O.S(=O)(=O)(O)O>C(O)=O.O>[CH3:19][NH:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8]([OH:11])(=[O:9])=[O:10])[NH2:1]
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CNc1cc(N)ccc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
97 g of 1,3-diaminobenzene-4-sulfonic acid were stirred with 250 ml of water and, after the addition of 38 ml of 98% w/w formic acid, boiled at 95°-100° C. The mixture was then colled to 30° C., and 65 g of ice were added, the pH being adjusted to 6.5 to 7.0 with 60.5 ml of 50% w/w caustic soda solution. There were then added 45 ml of 50% w/w caustic soda solution and 70 ml of dimethyl sulfate, and stirring was continued for 30 minutes. The mixture was then acidified with 43 ml of 96% w/w sulfuric acid and stirred at 100° C. for 3 hours. The mixture was then cooled, and the precipitated 3-(N-methylamino)aniline-4-sulfonic acid was isolated by filtration.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Na+].[I-].C[Si](C)(C)[C:22]([F:25])(F)[F:23].C1COCC1>C(Cl)Cl>[F:23][C:22]1([F:25])[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate 11B (280 mg, 1.16 mmol), NaI (112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF (10 mL), The tube was sealed, and then the mixture was stirred at 80° C. overnight. The resulting mixture was diluted with DCM, filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which was used for next step without further purification. LC-MS: m/z 292.3 (M+H)+
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([Mg]Br)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([C:7]2([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][CH:2]2[CH3:1])[CH:27]=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Product: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1cccc(OCc2ccccc2)c1
Yield: 44 %

Procedure:
This compound was prepared from tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate and 3-benzyloxyphenylmagnesium bromide as described in Step 1 of Example 6 in 44% yield.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: NCCO
Product: CC(C)(CO)NCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}benzofuran and 2-amino-2-methyl-1-propanol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:24]2[CH:25]=[CH:26][C:27]([S:29]([O-:32])(=[O:31])=[O:30])=[CH:28][C:23]=2[S:22]/[C:4]/1=[N:5]\[N:6]=[C:7]1/[S:8][C:9]2[CH:17]=[C:16]([S:18]([O-:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:10]=2[N:11]/1[CH2:12][CH3:13].[NH4+].[NH4+].P([O-])([O-])([O-])=O.OO>>[N:5](=[C:4]1[N:3]([CH2:2][CH3:1])[C:24]2[CH:25]=[CH:26][C:27]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:28][C:23]=2[S:22]1)[N:6]=[C:7]1[N:11]([CH2:12][CH3:13])[C:10]2[CH:14]=[CH:15][C:16]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:17][C:9]=2[S:8]1
Reactant: CCn1/c(=N/N=c2\sc3cc(S(=O)(=O)[O-])ccc3n2CC)sc2cc(S(=O)(=O)[O-])ccc21
Agent: O=P([O-])([O-])[O-]
Agent: OO
Agent: [NH4+]
Product: CCn1c(=NN=c2sc3cc(S(=O)(=O)O)ccc3n2CC)sc2cc(S(=O)(=O)O)ccc21

Procedure:
The reaction mixture (0.2 ml) contained 1.0 mM ABTS, buffer (50 mM phosphate buffer pH 7 or 50 mM Britton-Robinson buffer pH 4), 20 μl peroxygenase fermentation supernatant (see Example 1) and 0.5 mM hydrogen peroxide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:23])[N:13]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:23])[N:13]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:29]=[O:30]
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.37 %

Procedure:
N,N-dimethylformamide (1.5 ml) was added slowly with phosphorus oxychloride (115 μl, 3.2 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (719 mg, 2.91 mmol) in 3 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (20 ml) and stirred for another 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with triethylamine: methanol:dichloromethane (1:20:500) as eluents to give 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (411 mg, 51.37%) as a brown oil which was used as such.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5][CH2:4][NH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:23][NH:24][O:25][CH3:26].Cl.O1CCOCC1>C(Cl)Cl>[CH3:26][O:25][N:24]([CH3:23])[C:8]([CH:6]1[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]1)=[O:10]
Reactant: CNOC
Reactant: O=C1CC(C(=O)O)CCN1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CON(C)C(=O)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2-oxopiperidine-4-carboxylic acid (CAS #24537-50-6) (1.4 g, 9.78 mmol) in DCM (20 ml) was added portion wise CDI (1.665 g, 10.27 mmol). The suspension was stirred at room temperature for 5 hrs and N,O-dimethylhydroxylamine (1.002 g, 10.27 mmol) was added to the suspension and the reaction mixture was stirred overnight at room temperature. HCl (4M) in 1,4-dioxane (2.445 ml, 9.78 mmol) was added to the cloudy brown-orange solution and the reaction was stirred for 30 min (pH 7). The white precipitate was filtered off and the filtrate was washed with aqueous NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as brown liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]([NH:26][CH2:27][C:28]23[CH2:37][CH:32]4[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]4)[CH2:29]2)[CH2:35]3)=[O:25])[CH:18]=1)[CH2:5][CH2:6][N:7](C)[C:8](=O)OC(C)(C)C.Cl.N>CO.O1CCOCC1>[OH:1][CH2:2][CH2:3][N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH:18]=1)[C:24]([NH:26][CH2:27][C:28]12[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2)=[O:25])[CH2:5][CH2:6][NH:7][CH3:8]
Reactant: Cc1ccc(CN(CCO)CCN(C)C(=O)OC(C)(C)C)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CNCCN(CCO)Cc1ccc(C)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
[2-[(2-Hydroxyethyl)[[4-methyl-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]ethyl]methyl-carbamic acid, 1,1-dimethylethyl ester (Example 72a, 0.285 g) was dissolved in methanol (10 ml), 4 N HCl in dioxane (10 ml) was added and the mixture stirred for 14 h at room temperature. The solution was poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by chromatography over silica gel (eluting with 8:2:0.2/dichloromethane:methanol:ammonia) to afford the title compound as an oil (0.167 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33]C)=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F)c1cc(F)ccc1O
Reaction time: 20 h

Procedure:
220 mg (0.46 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylic acid amide is dissolved in 5.0 ml of dichloromethane and mixed with 9.2 ml of a 1N boron tribromide solution in dichloromethane. After 20 hours at room temperature, the reaction is halted by adding methanol. The solvent is removed in a vacuum, the residue is taken up in saturated sodium bicarbonate solution and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0-100%), 60 mg (28% of theory) of the product is obtained.
Reaction SMILES: [NH2:1]N.ClC1C=C(Cl)C=C[C:5]=1[O:6][C:7]1[C:8](=[O:30])[C:9]2[C:14]([C:15](=[O:26])[C:16]=1[O:17][C:18]1C=CC(Cl)=CC=1Cl)=[CH:13][C:12]([N+]([O-])=O)=[CH:11][CH:10]=2>[Pd].C(O)C>[CH3:5][O:6][C:7]1[C:8](=[O:30])[C:9]2[C:14]([C:15](=[O:26])[C:16]=1[O:17][CH3:18])=[C:13]([NH2:1])[CH:12]=[CH:11][CH:10]=2
Reactant: O=C1C(Oc2ccc(Cl)cc2Cl)=C(Oc2ccc(Cl)cc2Cl)C(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NN
Agent: [Pd]
Solvent: CCO
Product: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Yield: 82.8 %

Procedure:
Hydrazine (4.0 ml, 125 mmol of 97%) was added dropwise, over a 2 hour period, to a stirred mixture of the captioned compound of Preparation 2 (19.9 g, 75.6 mmol), 5% palladium on carbon (10 g) and ethanol (750 ml) in a nitrogen atmosphere. The catalyst was filtered off through a celite pad that was washed with hot ethanol (2×300 ml). The combined filtrate and washings were concentrated to dryness in vacuo and the residue recrystallized from water:ethanol (1.5:1) giving 14.6 g of 2,3-dimethoxy-5-amino-1,4-naphthoquinone, mp 116°-117°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.O1CCCC1.[Br:29]N1C(=O)CCC1=O>>[Br:29][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[N:19]2[C:14]=1[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Into a 30 mL vial, 7-(4-Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.205 g, 0.000642 mol), Methanol (4 mL, 0.1 mol) and Tetrahydrofuran (9 mL, 0.1 mol) were added. N-Bromosuccinimide (0.137 g, 0.000770 mol) was added portion wise over 5 minutes. The reaction was stirred at room temperature over night. The solvent was removed under vacuum. The solid was partitioned with water and filtered to give a yellow solid. The solid was washed with cold methanol to give 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (140 mg, 55%). NMR 1H (DSMO-d6)-9.01 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.07 (d, 2H, J=8.53 Hz), 7.79 (s, 1H), 3.28 (s, 3H), 2.62 (s, 3H)