Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[H-].[Na+].[H-].[CH3:24][N:25](C)[CH2:26]CO>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH2:20][N:25]([CH3:26])[CH3:24])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
To a mixture of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate in 2-dimethylamino ethanol is added sodium hydride. After the hydride is reacted the mixture is heated on a steam bath for 6 hours. The solvent is removed and the residue acidified with dilute acetic acid to give the product of the example.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2]C(C)=O.[OH-].[Ca+2].[OH-].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].N>C(Cl)Cl.C(C(C)=O)C>[C:12]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)C(=O)Cl
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COC(=O)CC(=O)C(C)C
Yield: 94.3 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 122.6 g (1.15 mol) of isobutyryl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.2. This gave 136 g (GC purity 79.8%) of methyl isobutyrylacetate (yield 75.4%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:13]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:8][CH:7]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:31](=[O:34])[CH2:32][CH3:33])[CH:15]=2)[CH2:10][CH2:11][CH:12]1[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(OCCNC(=O)CC)cc2C1Cc1ccc(Cl)c(Cl)c1
Yield: 86.7 %

Procedure:
Ethyl 7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate hydrochloride (example 2.1, 100 mg, 0.229 mmol) and N,N-dimethyl amino pyridine (30.7 mg, 0.252 mmol) were dissolved in CH2Cl2 (20 ml) and propionyl chloride (30.7 mg, 0.252 mmol) was added at RT. After stirring at RT for 14 h 0.5 N HCl was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 and NaCl solution, dried over Na2SO4, and concentrated to afford a residue. White solid ethyl 1-(3,4-dichlorobenzyl)-7-(2-propionamidoethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (98 mg, 87%) was obtained from precipitation in ethyl acetate. Further transformation in analogy to example 2 and 97 finally gave N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-propionamide hydrochloride.
Reaction SMILES: C1(P([C:14]2[CH:19]=[CH:18]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(C)C.[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[NH:39][N:38]=1>C1COCC1>[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[N:39]([CH:19]([CH3:18])[CH3:14])[N:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CSc1ncc2c(Cl)n[nH]c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CSc1ncc2c(Cl)nn(C(C)C)c2n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Triphenylphosphine (387 mg, 1.5 mmol) was dissolved in THF (15 mL) and the solution was cooled to −78° C. Diethyl azodicarboxylate (225 uL, 1.5 mmol) was added slowly to the reaction mixture. The reaction was stirred for 5 min and then isopropanol was added (115 uL, 1.5 mmol) dropwise. After stirring an additional 5 min. the 3-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (305 mg, 1.6 mmol) was added as a solid. The resulting suspension was kept at −78° C. for 5 min then the cooling bath was removed. The reaction was stirred for 3 hours at room temperature. After concentration the desired 3-Chloro-1-isopropyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine was obtained by column chromotography (0–5% MeOH/methylene chloride); 1H-NMR (CDCl3): • 1.46 (d, 1H), 2.66 (s, 3H), 4.53 (q, 6H), 8.87 (s, 1H); LC/MS (m/e)=243.0 (MH+), Rt=2.25 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.ClC1[N:12]=[C:13]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:14]2[S:19][C:18]([CH2:20][N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)=[CH:17][C:15]=2[N:16]=1.NC1C=CC=CC=1N>>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][C:18]1[S:19][C:14]2[C:13]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[N:12][C:2]([NH:3][C:4]3[C:5]([NH2:1])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCc4ccccc4C3)cc2n1
Reactant: c1ccc2[nH]cnc2c1
Agent: Nc1ccccc1N
Product: Nc1ccccc1Nc1nc(N2CCOCC2)c2sc(CN3CCc4ccccc4C3)cc2n1

Procedure:
Following General Procedure J for Multi-Step Benzimidazole Formation by Buchwald coupling, 4-(2-chloro-6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 1,2-diaminobenzene were reacted to give N1-(6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzene-1,2-diamine which was cyclized with acetic acid to give 204. LCMS m/z: 497.6 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Solvent: O
Product: CC(=O)Oc1ccc([N+](=O)[O-])c(CO)c1

Procedure:
A mixture of 5-hydroxy-2-nitrobenzaldehyde (4 g.) and acetic anhydride (10 ml.) was heated on a steam bath for 1 hour, then poured into water (100 ml.) and extracted with diethyl ether (3×50 ml.). The extracts were combined and dried, and the solvent was evaporated. The residue of 5-acetoxy-2-nitrobenzaldehyde was dissolved in absolute ethanol (100 ml.), and stirred and ice-cooled while sodium borohydride (1.5 g.) was added in portions. The reaction mixture was stirred at room temperature for 1 hour, then water (100 ml.) was added, and the mixture was extracted with ether (3×70 ml.). The extracts were combined and dried, and the solvent was evaporated to give 5-acetoxy-2-nitrobenzyl alcohol, which was hydrogenated by the general process described in the latter part of Example 13(a) to give the required starting material.
Reaction SMILES: Br[Zn]C[Zn]C[Zn]Br.[CH2:8]1OCCC1.[C:13]([Si:17]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:18][CH:19]1[CH2:23][CH:22]([OH:24])[C:21](=O)[CH:20]1[CH2:26][O:27][C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1.Cl[Ti](Cl)(Cl)Cl>[C:13]([Si:17]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[O:18][CH:19]1[CH2:23][CH:22]([OH:24])[C:21](=[CH2:8])[CH:20]1[CH2:26][O:27][C:28]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OC1CC(O)C(=O)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Br[Zn]C[Zn]C[Zn]Br
Product: C=C1C(O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 50 %

Procedure:
2.4 ml (1.26 mmol) of 20% suspension Nysted reagent and 6.4 ml of tetrahydrofuran were added dropwise to a reactor successively and cooled to 0° C. 0.14 ml (1.26 mmol) of TiCl4 was added thereto dropwise, and the resulting mixture was stirred. The reaction mixture was cooled to −40° C., and a solution which had been prepared by dissolving 0.527 g (0.842 mmol) of 3-(tert-butyl-diphenyl-silanyloxy)-5-hydroxy-2-trityloxymethyl-cyclopentanone (a compound of formula (2)) obtained in Example 2 in 2.4 ml of tetrahydrofuran was added thereto. The reaction mixture was stirred at room temperature for 3.5 hrs. After completion of the reaction, the reaction mixture was cooled to −20° C., quenched by adding 25 ml of 1N hydrochloric acid, and extracted with 25 ml of dichloromethane to separate an organic layer. The organic layer was washed with 20 ml of 4% sodium bicarbonate solution and 20 ml of brine successively, dried over anhydrous sodium sulfate, filtered, and condensed. The residue thus obtained was isolated by HPLC to obtain 0.184 g of the title compound (yield: 50%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[CH2:23]([N:25]([CH2:26][CH3:27])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20])[CH3:24]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CCNCC
Product: CCN(CC)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and diethylamine to give 253. MS: (ESI+)=369.1
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][C:11]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5].[H+].[B-:14]([F:18])([F:17])([F:16])[F:15].[N:19]([O-])=O.[Na+]>C(O)C.O>[F:15][B-:14]([F:18])([F:17])[F:16].[C:4]([C:3]1[CH:6]=[C:7]([S:10][C:11]#[N:12])[CH:8]=[CH:9][C:2]=1[N+:1]#[N:19])#[N:5]
Reactant: N#CSc1ccc(N)c(C#N)c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CSc1ccc([N+]#N)c(C#N)c1
Yield: 95.4 %

Procedure:
To a solution of 2-amino-5-(thiocyanato)benzonitrile (2.00 g (11.4 mmol)) and 42% borofluoric acid (7.16 g (34.2 mmol)) in ethanol (10.0 ml), a solution of sodium nitrite (0.87 g (12.6 mmol)) in water (1.2 ml), was added dropwise under cooling with ice. The mixture was stirred under cooling with ice for 2 hours and crystals separated were filtered. The solid was washed with water, methanol and then ether, successively, and dried under reduced pressure to give 2.98 g (95%) of 2-cyano-4-(thiocyanato)benzenediazonium fluoroborate as white crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[BH4-].[Na+].O>CO>[OH:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCCCCCCCCC(=O)OCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCCCCCCCCCC(O)CCCO1
Yield: 97.9 %

Procedure:
A solution of 480 g (1.89 mol) of 12-oxo-15-pentadecanolide (VI) in 735 ml of methanol is cooled to 10°-15° C. 26.2 g of sodium borohydride are added in portions at this temperature. The mixture is allowed to after-react at 15° C. for a further 2 hours. After addition of water, excess methanol is distilled off. The organic content of the reaction mixture is extracted with toluene, the toluene phase is washed neutral and dried, the toluene is stripped off and the residue is subjected to fractional distillation. 470 g (1.85 mol) of 12-hydroxy-15-pentadecanolide are obtained;
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.C(O)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:ethanol (60:40 v/v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:ethanol (60:40 v/v, 106 ml) at room temperature. The reaction mixture was stirred at room temperature for an additional 16 hours to obtain a pH of 4.11. The white solid was filtered, washed with ethanol (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 5.1 g of ibandronate sodium crystal form R.
Reaction SMILES: [Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.CCOC(C)=O>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:35][C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CN(c1cccnc1Br)S(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN(c1cccnc1Br)S(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 130 °C

Procedure:
To a solution of N-(2-bromo-pyridin-3-yl)-4-fluoro-N-methyl-benzenesulfonamide (0.1 g, 0.28 mmol) from Step B in dimethylacetamide (2 ml) was added K2CO3 (0.08 g, 1.0 mmol) and 4-trifluoromethoxyphenol (0.051 g, 0.28 mmol). The mixture was microwaved/heated at 130° C. (PMAX 130 on CEM Reactor) for 15 minutes. The reaction mixture was diluted EtOAc and washed with saturated NaCl and water. The organic phase was dried over sodiumsulfate and concentrated. The crude was purified through chromatography (20-50% EtOAc in hexanes) MS 502.6 (M+H)+
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([NH:9][NH2:10])=[O:8].[C:15](=S)=[S:16]>O.C(O)C>[SH:16][C:15]1[O:8][C:7]([C:6]2[CH:11]=[CH:12][C:13]([OH:14])=[C:4]([OH:3])[CH:5]=2)=[N:9][N:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1ccc(-c2nnc(S)o2)cc1O
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
19.8 g (0.353 mol) of potassium hydroxide was dissolved in 5.1 ml of water and 830 ml of ethanol, and 39.6 g (0.236 mol) of 3,4-dihydroxybenzohydrazide and 99 ml (1.65 mol) of carbon disulfide was added thereto. The mixture was heated for 24 hours under reflux. The reaction solution was stirred for 1.5 hours under cooling with ice. The precipitated crystals were collected by filtration and washed with 200 ml of ethanol. The crystals were dissolved in 3 liter of water and adjusted to pH1.5 with 6N hydrochloric acid under cooling with ice. The solution was extracted with 1 liter of ethyl acetate and 400 ml of ethyl acetate. The organic layers were put together, washed twice with 300 ml of a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 42.8 g (yield: 86.5%) of 2-mercapto-5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazole.
Reaction SMILES: [N:1]1([C:10]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[N:1]1([C:10]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(n2ccc3cccnc32)CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(n2ccc3cccnc32)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarboxylic acid (394) (1.2 g, 5.21 mmol) in dichloromethane (80 mL) was dropwise added oxalyl chloride (1 mL, 11.47 mmol) at 0° C., followed by dimethyl formamide (0.1 mL). The reaction mixture was stirred for 1 h at room temperature. After completion, the reaction mixture is concentrated under argon atmosphere tog et 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarbonyl chloride (395) (1.3 g, 100%, crude) as a yellow solid which was directly used for the next step without analysis.
Reaction SMILES: [OH:1][CH:2]([CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:25]I.[H-].[Na+].O>CN(C)C=O>[CH3:25][O:1][CH:2]([CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CI
Reactant: CCOC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To 2 g of ethyl 2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionate dissolved in 30 ml of anhydrous dimethylformamide, CH3I (0.78 ml) was added at 3° C., then, in two additions, at the same temperature, NaH 50% (0.3 g) was added too. The whole was stirred at 3° C. for one hour and at room temperature for one hour, after which it was poured into 300 ml of water, extracted with ethyl ether which, after washing with NaCl saturated water and dehydration with sodium sulphate, was evaporated to dryness under reduced pressure. There was obtained 2 g (96%) of ethyl 2-methoxy-3-phenyl-3-(2-nitro-phenoxy)-propionate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-])=[O:24])[CH:19]=2)[C:14]1=[O:26].O.O.[Sn](Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH:40]2[CH2:41][CH2:42]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:23][OH:24])[CH:19]=2)[C:14]1=[O:26]
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1C(=O)c2ccc(NO)cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (60 mg, 0.092 mmol) was dissolved in THF (5 ml), and added with tin(II) chloride dihydrate (25.0 mg, 0.111 mmol). The reaction was stirred at RT for 18 hours. THF was evaporated under vacuum at RT, and the residue quenched by addition of K2CO3/H2O (15% w/w; 50 ml) and extracted with EtOAc (50 ml). The organic phase was extracted with K2CO3/H2O (15% w/w) (×3), dried over Na2SO4 and the solvent removed under reduced pressure to yield the title compound (35.0 mg, 0.055 mmol, 60% yield). 1H NMR (400 MHz, acetone) ppm 8.80 (bs, 1H), 8.32 (bs, 1H), 8.18 (s, 2H), 7.70 (d, J=8.38 Hz, 1H), 7.36 (d, J=1.76 Hz, 1H), 7.28 (dd, J=8.16, 1.98 Hz, 1H), 7.15-7.23 (m, 2H), 7.03 (dd, J=8.38, 1.76 Hz, 1H), 6.93 (t, 1H, CHF2), 6.13 (dd, J=9.48, 4.63 Hz, 1H), 4.39 (s, 2H), 4.00 (dd, J=7.06, 3.09 Hz, 2H), 3.51 (dd, J=14.33, 9.48 Hz, 1H), 3.31 (dd, J=14.11, 4.41 Hz, 1H), 1.24-1.36 (m, 1H), 0.53-0.71 (m, 2H), 0.31-0.49 (m, 2H). MS/ESI+ [MH]+=637.9
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.NC(N)=[O:36].OO.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N+:26]([O-:36])[C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cn1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a suspension of N-cyclopropyl-1-[3-(6-methylsulfonylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 51 in methylene chloride (30 ml/mmol) was added urea-hydrogen peroxide (8 eq) and the resulting mixture was cooled to 0° C. Trifluoroacetic acid (4.7 eq) was added and the mixture was warmed to room temperature as a solution was obtained. After 18 hours, more urea-hydrogen peroxide (2.6 eq) and trifluoroacetic acid (2 eq) were added and stirring was continued for 2 hours. The mixture was quenched with saturated aqueous sodium metabisulfite, diluted with methylene chloride and the organic phase was washed with 1N aqueous HCl, then brine and water, dried and evaporated. The crude product was chromatographed on silica gel eluting with 40% toluene in acetone to afford the title compound as a solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:26]([O-])([N+]([O-])=O)=[O:27]>>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 68.5 %

Procedure:
3.8 g of 1-(2-chloroethyl)-3-cyclohexylmethyl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-cyclohexylmethyl-3-(D-galactopyranosyl)urea are thereby obtained as pale yellow poder.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(Cl)Cl.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
1-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) was added to a cold (5° C.) solution of 2-chloro-5-nitropyridine (1 g, 6.3 mmol,) in DCM (5 mL). The reaction mixture was allowed to warm to rt, stirred for 16 h, diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to provide 1.58 g of the title compound as a yellow solid: ESI-MS: 251.2 [M+H]+; tR=2.20 min.