Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2](CCN)C=O.C(OC(=O)C)(=O)C.[C:15]([O:18][CH:19]([CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH:20]=[O:21])(=[O:17])[CH3:16].[H-].[Na+].CI>N1C=CC=CC=1>[C:15]([O:18][CH:19]([CH2:22][CH2:23][N:24]([CH3:2])[C:25](=[O:27])[CH3:26])[CH:20]=[O:21])(=[O:17])[CH3:16]
Reactant: CC(=O)NCCC(C=O)OC(C)=O
Reactant: NCCC(O)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C=O)CCN(C)C(C)=O

Procedure:
Treat the diethylacetal of 2-hydroxy-4-aminobutanal with acetic anhydride in pyridine followed by treatment of the resulting diethylacetal of 2-acetoxy-4-acetamidobutanal with sodium hydride and methyl iodide to obtain the diethylacetal of 2-acetoxy-4-(N-methylacetamido)butanal. Remove the acetal protecting group by means of acid to obtain 2-acetoxy-4-(N-methylacetamido)butanal.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]3[NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[C:25]=2[F:32])[CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)(=[O:3])[NH2:2].ClC1C(F)=C(NC2C3C(=CC(O)=C(OC4CN(C(OCCCC)=O)C4)C=3)N=CN=2)C=CC=1F>>[Cl:31][C:26]1[C:25]([F:32])=[C:24]([NH:23][C:14]2[C:13]3[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][C@H:8]4[CH2:7][CH2:6][NH:5][C@H:4]([C:1]([NH2:2])=[O:3])[CH2:9]4)[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C1
Agent: CCCCOC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2O)C1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Yield: 71 %

Procedure:
The procedure of step 2) of Example 115 was repeated except for using the compound obtained in step 3) instead of tent-butyl 3-(4-(3-chloro-2,4-difluorophenylamino)-7-hydroxyquinazolin-6-yloxy)azetidin-1-carboxylate to obtain the title compound (580 mg, 71%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[C:15]([O:18][CH3:19])[CH:14]=2)[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(OC)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(OC)ccc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid (27.5 g, 0.105 mol) and POCl3 (60 ml) is refluxed overnight. The reaction mixture is poured into ice waterl, basified with NH4OH and the solid which forms is collected by filtration to afford 20 g of 4-chloro-1-ethyl-6-methoxy-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)(Cl)Cl)=[CH:4][N:3]=1.[Cl-].[NH4+:13]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:13])=[CH:4][N:3]=1
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cn1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(Cl)nc1
Yield: 73.3 %

Procedure:
In a 200-ml reaction flask equipped with a thermometer, a Dimroth condenser and a stirrer were fed 46 g (0.2 mole) of 2-chloro-5-trichloromehtylpyridine, 16 g (0.3 mole) of ammonium chloride and 0.23 g (0.5% by weight) of cupric oxide. The mixture was reacted at 200° C. for 12 hours. The reaction mixture was cooled. At 130° C., 100 ml of xylene was added into the reaction flask. The mixture was cooled further. At 60° C., the mixture was filtered to remove a copper salt and excessive ammonium chloride. The filtrate (xylene layer) was concentrated. The resulting concentrate was subjected to distillation to obtain 20.3 g of 2-chloro-5-cyanopyridine as a fraction having a boiling point of 146°-150° C./15 mmHg. [Yield: 73.3%, colorless crystals having a melting point of 117°-118° C. (crystallization took place after distillation)]
Reaction SMILES: Cl[O-].[Na+].[OH-].[NH4+:5].[Cl-].[NH4+].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.[OH-].[Na+]>C1COCC1.O>[NH:5]=[C:9]1[CH2:10][CH:11]([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13][NH:8]1
Reactant: OCCC1CCNCC1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: O
Product: N=C1CC(CCO)CCN1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 61.8 %

Procedure:
A 50 mL four-necked flask was charged with sodium hypochlorite solution (8.44 g, 7.00 mL, 15.5 mmol, Eq: 4) and the solution was cooled to −10° C. Maintaining this temperature, ammonium hydroxide 25% NH3 (949 mg, 1.05 ml, 13.9 mmol, Eq: 3.6) and ammonium chloride 1M (11.6 mL, 11.6 mmol, Eq: 3) were added simultaneously. After 5 min, 2-(piperidin-4-yl)ethanol (500 mg, 3.87 mmol, Eq: 1.00, CAN 622-26-4) in 2 mL THF and sodium hydroxide (2.58 g, 1.94 mL, 19.3 mmol, Eq: 5) were added simultaneously at the same temperature as before, and the reaction allowed to proceed for another 2 hours at rt. The mixture was diluted with H2O and extracted with EtOAc (2×10 mL). The aqueous layer was concentrated in vacuo and the residue taken up in CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Thereby, 340 mg of 2-(1-mino-piperidin-4-yl)-ethanol were obtained as white semi-solid; MS (EI) 145.2 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>O1CCCC1>[OH:26][C@@H:27]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][N:32]=1)=[O:29]
Reactant: CSc1ccc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (10.04 mL, 10.04 mmol) was added in one portion to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxy-N-(5-(methylthio)pyridin-2-yl)propanamide (Intermediate AI1) in tetrahydrofuran (50 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The majority of the THF was evaporated in vacuo. The residue was diluted with EtOAc (100 mL), washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in isohexane to afford the product (2.38 g, 88%). 1H NMR (400 MHz, DMSO) δ 1.03-1.07 (6H, m), 3.28 (3H, s), 3.53-3.64 (3H, m), 4.19-4.22 (1H, m), 5.95 (1H, d), 7.77-7.80 (1H, d), 8.04-8.06 (1H, d), 8.24-8.25 (1H, s), 9.60 (1H, s); m/z (ES+) (M+H)+=271; HPLC tR=1.74 min.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:13](OCC)=O)=[C:6]([CH3:12])[C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2].C=O>>[CH2:1]([C:3]1[NH:4][C:5]([CH3:13])=[C:6]([CH3:12])[C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(CC)c(CC(C)C)c1C
Agent: C=O
Product: CCc1[nH]c(C)c(C)c1CC(C)C

Procedure:
2-Ethyl-3-isobutyl-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehye to yield 2-ethyl-3-isobutyl-4,5-dimethylpyrrole ##STR108##
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[N:15]=[C:14]([N:16]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]2[N:31]=[C:32]([CH3:34])[NH:33][C:12]=2[C:11]=1[CH3:35].[CH2:36]([O:38][CH2:39][CH2:40]Br)[CH3:37]>CC(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([N:16]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]2[N:31]=[C:32]([CH3:34])[N:33]([CH2:37][CH2:36][O:38][CH2:39][CH3:40])[C:12]=2[C:11]=1[CH3:35]
Reactant: Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c2[nH]1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c21
Yield: 57.7 %

Procedure:
Sodium iodide (1.5 g) and potassium carbonate (1 g) were added to a solution of 6-chloro-2,7-dimethyl-N4,N4 -bis(phenylmethyl)-1H-imidazo[4,5-c]pyridin-4-amine (1.0 g, 2.7 mmole) in acetone (250 mL). 2-Bromoethyl ethyl ether (0.5 mL, 4.4 mmole) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between methylene chloride and water. The methylene chloride phase was separated, dried with magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 10-30% ethyl acetate in hexane to provide 0.7 g of the desired product.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].CC(C)CC=O.Cl.[OH:12][C@H:13]1[CH2:30][C@@:29]2([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[C@H:27]([NH:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:38]([OH:40])=[O:39])[CH2:15][C@@H:14]1[OH:41]>C(O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[OH:12][C@H:13]1[CH2:30][C@@:29]2([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[C@H:27]([NH:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:38]([O:40][CH3:1])=[O:39])[CH2:15][C@@H:14]1[OH:41]
Reactant: [BH3-]C#N
Reactant: CC(C)CCN[C@@H]1C[C@]2(C)[C@@H](C(=O)O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](O)C[C@]3(C)[C@H]21
Agent: CC(C)CC=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
Sodium cyanoborohydride (2.0 g) and 3-methylbutanal (2.8 ml) were added to a solution of Intermediate 2 (2.0 g) in ethanol (30 ml) and the mixture stirred for 18 h. The mixture was diluted with NaHCO3 solution and extracted with ethyl acetate (3×). The extract was washed with water (1×), dried and evaporated to give a foam. This was dissolved in ethyl acetate and extracted with dilute hydrochloric acid (3×) and water (1×). These aqueous extracts were brought to pH 10 by the addition of 0.88 NH3 solution and then extracted with ethyl acetate (3×). This extract was washed with water, dried, filtered and evaporated to give a foam. This was purified by column chromatography eluted with chloroform/methanol (9:1) to give a foam which was crystallised from ethyl acetate to give the title compound (565 mg), m.p. 159°-161°, [α]D +24.2°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (100 mg, 0.36 mmol) and pyridine (0.12 mL, 1.44 mmol) in anhydrous dichloromethane was added methanesulfonyl chloride (41.3 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by prepared HPLC to give N-[2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide as white solid. LC/MS m/e obsd. (ESI+) [(M+H)+] 356.20.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15](Cl)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>>[NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][N:34]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2[nH]c1=O
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
The reaction of 3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (433 mg, 1.0 mmol, Example 106(a)) with tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (428 mg, 2 mmol, Fluorochem) under the conditions of Example 34 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 612 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)=[O:13])=[CH:6][CH:5]=1.CO.[CH2:25](Cl)Cl>CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:25][C@H:11]2[C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:19]2)=[O:13])=[CH:6][CH:5]=1
Reactant: ClCCl
Reactant: CC(C)N1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccc(F)cc2)CC1
Reaction time: 0.05 h
Yield: 57 %

Procedure:
To a vigorously stirring mixture of NaH (300 mg, 12.5 mmol) in DMSO (30 mL) at ambient temperature under an argon (g) atmosphere was added (CH3)3S(I)O (2.50 g, 11.4 mmol) in small portions over 1 min. Following complete addition, the reaction was stirred for 50 min before the rapid dropwise addition of DMSO (10 mL) solution of 10A (1.57 g, 5.68 mmol). After ca. 50 h the reaction was quenched with H2O (80 mL) and extracted into EtOAc (75 mL). The phases were separated and the aq. phase was further extracted with EtOAc (2×70 mL). The combined organics were washed with H2O (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting gum was subjected to flash chromatography (SiO2-40 g; gradient elution: 1% MeOH/DCM for 3 min then 1%-5% MeOH/DCM over 20 min at 40 mL/min) to afford 947 mg 10B (57% yield). m/z (ES+) M+1=291.3; HPLC tR=1.52 min. 1H NMR (500 MHz, CDCl3) δ 7.07 (dd, J=8.7, 5.3 Hz, 2H), 6.96 (t, J=8.7 Hz, 2H), 3.63 (dd, J=14.5, 5.0 Hz, 4H), 2.71 (ddd, J=13.0, 6.7, 6.6 Hz, 1H), 2.57-2.44 (m, 4H), 1.90 (ddd, J=8.3, 5.4, 4.3 Hz, 1H), 1.68-1.56 (m, 2H), 1.21 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 1.04 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@:25]2([CH3:49])[C:26](=[O:27])[C:15]3[C:16]([O:24]2)=[C:17]([CH3:23])[C:18]([OH:22])=[C:19]2[C:20](=[O:21])[C:10](=[C:11](Br)[C:12]([C:14]=32)=[O:13])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1.C[N:53](C)C=O>>[CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@:25]2([CH3:49])[C:26](=[O:27])[C:15]3[C:16]([O:24]2)=[C:17]([CH3:23])[C:18]([OH:22])=[C:19]2[C:20](=[O:21])[C:10](=[C:11]([NH2:53])[C:12]([C:14]=32)=[O:13])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1
Reactant: CN(C)C=O
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(Br)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(Br)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Temperature: 20 °C
Reaction time: 5 h

Procedure:
540 g of 3-bromo-rifamycin S are dissolved in 1500 ml of N,N-dimethyl formamide at 20° C. A steam of N2 is bubbled through the solution for 20', then 60 g of sodium nitrite are added portionwise allowing the temperature to rise to 39° C. while stirring under nitrogen atmosphere. The temperature is kept at 40° C. with a water bath for 30', then cooled at 20° C.; 10 g of urea are added and 70 ml of acetic acid are added dropwise. The steam of N2 is stopped and 130 g of zinc powder are added portionwise with vigorous stirring and cooling with an ice bath to keep the temperature below 60° C. The reaction mixture is stirred allowing the temperature to decrease to room temperature, and stirring is continued for 5 hours. The reaction mixture is filtered and the solution is diluted with 3000 ml of dichloromethane and washed with water several times. The dichloromethane solution is treated with manganese dioxide in order to oxidize 3-amino-rifamycin SV to 3-amino-rifamycin S. After filtration and evaporation to dryness, raw material such obtained is crystallized from 600 ml of 2-methoxy-ethanol to give 440 g of TLC pure 3-amino-rifamycin S in black crystals. U.V.; I.R. and PMR are identical to an authenic sample prepared according to W. Kump, H. Bickel, Helv. Chem. Acta, 56(7), 2348 (1973).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH:32]=O)[CH3:27].C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:32][N:8]1[CH2:9][CH2:10][C:5]2([NH:1][C:2](=[O:12])[NH:3][C:4]2=[O:11])[CH2:6][CH2:7]1)[CH3:27]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC3(CC2)NC(=O)NC3=O)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of 1,3,8-triaza-spiro[4.5]decane-2,4-dione (25.4 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in ethanol (1 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate B10, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.6 mg (17%) of the title compound. MS (ISP): 338.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:16]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20](=[O:28])[C:19]4=[C:29]([CH3:32])[CH:30]=[CH:31][N:18]4[N:17]=3)[CH2:13][CH2:14][OH:15])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:3]=1.[OH:41][C:42]1[CH:43]=[C:44]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:41][C:42]1[CH:43]=[C:44]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:45]=[C:46]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:16]4[N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:20](=[O:28])[C:19]5=[C:29]([CH3:32])[CH:30]=[CH:31][N:18]5[N:17]=4)[CH2:13][CH2:14][OH:15])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:3]=2)[CH:47]=1
Reactant: Cc1ccn2nc([C@H](CCO)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(NS(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](CCO)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 39 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-hydroxypropyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (85 mg, 0.21 mmol), sodium carbonate (23 mg, 0.22 mmols) and 1,11-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (21 mg, 0.03 mmol) in 1,2-dimethoxyethane (1.6 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 35 mg (39% yield, 65% purity) of the title compound.
Reaction SMILES: C1CO[CH:8]2[CH:3]([CH2:4][C:5](=[O:24])[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18]C(N=[N+]=[N-])=O)([CH3:11])[CH2:7]2)[O:2]1.C(O)(=O)C.C[N:30](C)C=O>>[O:24]=[C:5]1[CH2:4][C:3](=[O:2])[CH2:8][CH2:7][C:6]1([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:30])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC1(c2ccccc2CC(=O)N=[N+]=[N-])CC2OCCOC2CC1=O
Solvent: CC(=O)O
Product: CC1(c2ccccc2CN)CCC(=O)CC1=O
Temperature: 100 °C

Procedure:
The acyl azide 5 is dissolved in dimethylformamide and heated to 100° C. until nitrogen evolution ceases. The solution is cooled and treated with aqueous acetic acid to form 2-(2', 4'-dioxo-1'-methyl-cyclohexyl)-benzyl amine 6. Diethyl ether is added and the solution is washed successively with saturated sodium bicarbonate solution, water, and saturated salt solution and dried over anhydrous sodium sulfate. The solvent is removed by rotoevaporation to yield 1,2,3,4,4a,5,6,10b-octahydro- 10b-methyl-3-phenanthridinone 7.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10](O)=[O:11])=[CH:7][C:6]=1[S:13](=[O:16])(=[O:15])[NH2:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1.CCCCCC>[C:1]([C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=1[S:13]([NH2:14])(=[O:16])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1oc(C(=O)O)cc1S(N)(=O)=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1oc(CO)cc1S(N)(=O)=O
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Under cooling with ice, a solution of methyl ester of 5-tert-butyl-4-sulfamoyl-furan-2-carboxylic acid (1.90 g) in THF (20 ml) was added dropwise to a suspension of lithium aluminum hydride (0.55 g) in THF (10 ml) over 35 min., followed by stirring for 2 hours. The reaction mixture was diluted with n-hexane, mixed with saturated aqueous ammonium chloride (5 ml) and filtered on Celite, being washed with ethyl acetate. The filtrate was dried over magnesium sulfate and evaporated to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (1.66 g, 98%).