Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]1([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:26][OH:27]>C(O)C.O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]1([CH2:17][CH2:16][C:15](=[N:26][OH:27])[CH2:14][CH2:13]1)[CH2:5]2
Reactant: NO
Reactant: O=C1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ncc(Br)cc2CC12CCC(=NO)CC2
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
To a stirred solution of 6′-bromo-1′H-spiro[cyclohexane-1,3′-[1,8]naphthyridine]-2′,4(4′H)-dione (P) (0.35 g, 1.13 mmol) in ethanol/water (18 mL/2 mL) were added Na2CO3 (0.6 g, 5.68 mmol) and hydroxylamine hydrochloride (0.39 g, 5.68 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 4 h. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get the desired compound as an off-white solid (200 mg, 95%); 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.28 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 2.99 (s, 2H), 2.30-2.16 (m, 4H), 1.84-1.66 (m, 2H), 1.50-1.38 (m, 2H).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.[C:19](Cl)(=[O:27])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.C(N(CC)CC)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)[C:19](=[O:27])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)CCN1CCSc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a stirred solution of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (100 mg, 0.374 mmol) in dichloromethane (5 mL) under argon was added phenyl carbonochloridate (0.094 mL, 0.748 mmol). The resulting mixture was stirred at room temperature. A precipitate was observed, and triethylamine (3 drops) was added to aid dissolution (reaction turned clear). The mixture was then stirred over the weekend. The clear yellow mixture was then diluted with water and sodium carbonate and then extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in ethyl acetate, giving the desired product (139 mg, 100%). 1H NMR (DMSO-d6) δ 7.84-7.74 (m, 2H), 7.39-7.31 (m, 2H), 7.23-7.16 (m, 1H), 7.03-6.93 (m, 3H), 3.85-3.78 (m, 3H), 3.73-3.65 (m, 2H), 3.55-3.50 (m, 1H), 3.09, 2.97 (2s, 3H), 3.09-3.05 (m, 2H); MS-EI: (m/z, %) 373 (M+, 4), 209 (31), 179 (100), 151 (28).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(Cl)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:42][NH2:43]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:8]([C:18]([NH:43][CH2:42][C:41]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:39]([O:38][CH3:37])[CH:40]=2)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN)cc1OC
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)NCc2ccc(OC)c(OC)c2)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=528.4.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[CH2:5][CH2:6][CH2:7][Cl:8].O[Li].O.Cl>C1COCC1.CO>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:4]([CH2:5][CH2:6][CH2:7][Cl:8])[C:3]([OH:16])=[O:2])=[N:10][CH:11]=1
Reactant: COC(=O)C(CCCCl)c1ccc(Br)cn1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(5-Bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (2.0 g, 6.5 mmol) in THF/MeOH (5/1) 30 mL, LiOH.H2O (1.092 g, 26 mmol.) was added. After the solution was stirred at room temperature for 16 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (50 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain of an oil product without further purification. MS: calc'd 291 (MH+), exp 291 (MH+).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:15][CH3:16])[C:6]=1[F:17].C(OCC)(=O)C.N>CN(C)C=O>[CH2:15]([O:14][C:7]1[C:6]([F:17])=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH3:13])[C:2]#[N:3])[CH3:16]
Reactant: N#C[Cu]
Reactant: CCOc1ccc(Br)c(F)c1OCC
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C#N)c(F)c1OCC
Temperature: 155 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Copper(I)cyanide (6.8 g, 68.3 mmol) was added to a solution of 1-bromo-3,4-diethoxy-2-fluorobenzene (12.0 g, 45.6 mmol) in N,N-dimethylformamide (DMF) (60 mL) at room temperature, and this was then stirred at 155° C. for 3 hours. The reaction solution was cooled on ice. Following addition of ethyl acetate and 28% aqueous ammonia, the organic layer was separated and washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed after filtration, and the residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 9.0 g of the subject compound (yield: 94.3%).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14]=[C:15]([CH3:16])[C:10]3=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>CO.O.C(O)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH:15]([CH3:16])[C:10]3=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NCCn2c1cc(-c1ccccc1)c2-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC1NCCn2c1cc(-c1ccccc1)c2-c1ccccc1
Yield: 86 %

Procedure:
3,4-Dihydro-6,7-diphenyl-1-methylpyrrolo[1,2-a]pyrazine (2.0 g) was dissolved in a mixture of 100 ml of methanol and 10 ml of water under argon. The solution was treated portionwise with 0.8 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 150 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 60 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude produce, 2.0 g of yellow resin, was dissolved in a 20-fold amount of ethanol and boiled briefly with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.1 g (86%) of 6,7-diphenyl-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (2:1); m.pt.: 187°-190° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([OH:11])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[C:21]([Cl:27])[CH:20]=1>C(Cl)Cl.CN(C)C=O.COCCOC.[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:11])=[C:21]([Cl:27])[CH:20]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: Cn1cc(C(=O)O)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: COCCOC
Product: Cn1cc(C(=O)Cc2ccc(Br)cc2Cl)ccc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (606 mg) in CH2Cl2 (5 ml) were added one drop of N,N-dimethylformamide and oxalylchloride (803 mg). The mixture was stirred at room temperature for 1.5 h and was then concentrated to dryness. 1,2-Dimethoxyethane was added and the solvent was evaporated again to give the crude acid chloride. To a suspension of zinc powder (517 mg) in 1,2-dimethoxyethane (5 ml) was added tetrakis(triphenylphosphine)palladium(0) (55 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (5 ml) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-chloro-benzene (1.125 g) in 1,2-dimethoxyethane (5 ml) was slowly added over 30 min. The mixture was stirred for 30 min at 0° C. and for 1.5 h at room temperature. The mixture was filtered and the filtrate was concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 7:3=>0:1) to give the title compound (603 mg, not completely pure) as a colorless solid. MS (m/e, ISP neg. ion)=338.0 [M−H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1>C(O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: COc1ccccc1OCC1CO1
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCC(N2CCCNC2=O)CC1

Procedure:
A solution of 9 g of 1-(o-methoxy-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95°C and then evaporated in vacuo. The residue is recrystallised from ethyl acetate/petroleum ether to yield the 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 130°-133°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH2:20][CH2:21][CH3:22]
Reactant: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Reactant: CCCCBr
Product: CCCCN1CCN(c2cc(F)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and 1-bromobutane, the title compound was recovered by the procedure described in Example 2; MS m/z (rel. intensity, 70 eV) 304 (M+, 22), 261 (bp), 218 (22), 190 (21), 70 (46).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Br:6].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Br-:6].[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cccc(CBr)c1OC
Solvent: Cc1ccccc1C
Product: COc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1OC
Product: [Br-]

Procedure:
The nonadecylcatechol acetate (NDC-AC) used in the tests was prepared as follows: 2, 3 dimethoxybenzaldehyde was reduced in the presence of sodium borohydride and the reduction product reacted with phosphorus tribromide to form 2, 3 dimethoxybenzylbromide. The benzylbromide reaction product was refluxed with triphenyl phosphine in xylene to form 2, 3 dimethoxybenzyl-triphenyl phosphonium bromide which was then reacted with octadecanal in the presence of butyl lithium to form 2, 3 dimethoxy-nonadecenylbenzene. Subsequent steps of reduction and reaction with boron tribromide produced 3-nonadecylcatechol which was purified by chromatography. The catechol was acetylated with acetic anhydride in pyridine to form the acetate (NDC-AC).
Reaction SMILES: C(OC(=O)NC1([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])CCC(OC2C=C3C(=CC=2Cl)C(OCC2C=CC=CC=2)=NC=C3)CC1)(C)(C)C.C(O[C:45](=[O:78])[NH:46][C:47]1(CC=C)[CH2:54][CH2:53][CH2:52][CH:51]([O:55][C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][C:65]=2[Cl:66])[C:62]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[N:61][CH:60]=[CH:59]3)[CH2:50][CH2:49][CH2:48]1)(C)(C)C.O.C[N+]1([O-])CCOCC1.[C:88]([OH:92])([CH3:91])([CH3:90])[CH3:89]>[Os](=O)(=O)(=O)=O>[C:88]([O:92][C:45](=[O:78])[NH:46][C:47]1([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[CH2:54][CH2:53][CH2:52][CH:51]([O:55][C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][C:65]=2[Cl:66])[C:62]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[N:61][CH:60]=[CH:59]3)[CH2:50][CH2:49][CH2:48]1)([CH3:91])([CH3:90])[CH3:89]
Reactant: CC(C)(C)O
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Reactant: CC(C)(C)OC(=O)NC1(CC(O)CO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CC(O)CO)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1

Procedure:
58 mg of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(2,3-dihydroxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (63) were synthesized using the procedure described for the synthesis of [4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(2,3-dihydroxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (56) starting from 90.0 mg (0.16 mmol) of [1-allyl-5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclooctyl]-carbamic acid tert-butyl ester (58), 30.9 mg (0.23 mmol) N-methylmorpholine oxide monohydrate and 16.6 μL (1.63 μmol) of a 2.5% solution of osmium tetroxide in tert-butanol. Rt=1.58 min (Method I). Detected mass: 585.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=2)[CH:14]=1.[CH3:34][NH:35][CH3:36].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:35]([CH3:36])[CH3:34])=[CH:27][CH:26]=2)[CH:14]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)nc(N3CCCCC3)c2)c(=O)[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)nc(N3CCCCC3)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-formylphenyl)-6-(piperidin-1-yl)isonicotinamide (0.2 g, 0.45 mmol) in methanol (12 mL), dimethyl amine (2.6 mL, 4.5 mmol, 2M solution in THF) and acetic acid (0.02 g, 0.45 mmol) were added and reaction mass stirred at rt for 90 min. Then reaction mass was cooled to 0° C. and sodium cyanoborohydride (0.056 g, 0.9 mmol) was added. Reaction stirred at 0° C. for 2 h and then stirred at rt for overnight. On completion, solvent was removed under reduced pressure, residue treated with water and extracted with ethyl acetate. Combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel obtaining N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((dimethylamino)methyl)phenyl)-6-(piperidin-1-yl)isonicotinamide as light green solid (0.173 g, 79%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:47]2[C:42]([CH3:41])=[N:43][CH:44]=[CH:45][CH:46]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1ncccc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Yield: 86.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (226 mg), 15-crown-5 (185 mg) and a solution of 2-methylpyridine-3-sulfonyl chloride (174 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a yellow oil (yield 288 mg, 86%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].Cl.[CH3:14][O:15][CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].CC([O-])=O.[Na+]>O.CO>[F:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH:8][N:1]=[C:18]([C:17](=[O:23])[CH2:16][O:15][CH3:14])[C:19]([O:21][CH3:22])=[O:20]
Reactant: Nc1ccccc1F
Reactant: COCC(=O)CC(=O)OC
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=O)C(=NNc1ccccc1F)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
A solution of NaNO2 (1.66 g, 24 mmol) in H2O (5 mL) was added dropwise at 0° C. to a mixture of 2-fluoroaniline (1.93 mL, 20 mmol) and 6 M HCl aqueous solution (20 mL, 120 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (2.59 mL, 20 mmol) and NaOAc (9.84 g, 120 mmol) in MeOH (40 mL) pre-cooled at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (5.03 g, 94% yield) as pale yellow crystals: mp 121-126° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H, s), 3.94 (3H, s), 4.68 (2H, s), 7.08-7.25 (3H, m), 7.63 (1H, dt, J=1.5, 7.9 Hz), 13.06 (1H, br s). Anal. Calcd for C12H13FN2O4: C, 53.73; H, 4.88; N, 10.44. Found: C, 53.69; H, 4.96; N, 10.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of 4-aminophenol (30.00 g, 275 mmol) in DMF (120 ml) at 0° C. under an atmosphere of nitrogen was added triethylamine (42.5 ml, 302 mmol, 1.2 eq). The reaction mixture was stirred for 10 minutes before dropwise addition of benzoyl chloride (31.9 ml, 275 mmol, 1.0 eq) over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was poured in ice cold water (800 ml) with vigorous stirring. A precipitate was collected by filtration and washed with water (2×500 ml). The precipitate was slurried in diethyl ether (1.5 L) and vigorously stirred for 30 minutes. The precipitate was collected by filtration and allowed to dry under reduced pressure to afford the title compound as an off-white solid (41.56 g, 71% yield).
Reaction SMILES: [C:1]([CH2:4][N:5]([S:15]([CH3:18])(=[O:17])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([OH:3])=O.Cl.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:1]([CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16])=[O:3]
Reactant: CN
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC(=O)CN(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O

Procedure:
Prepared from N-carboxymethyl-N-methylsulphonyl-4-nitroaniline and methylamine hydrochloride
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
In 33 ml of tetrahydrofuran is dissolved 3.3 g of benzyl (2S,4R)-2-{[methoxy(methyl)amino]carbonyl}-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidine-carboxylate. After adding 0.64 g of lithium aluminum hydride at −70° C., the mixture thus obtained is stirred at −70° C. for one hour. After dropwise adding 33 ml of ethyl acetate to the reaction mixture over a period of 30 minutes and then 66 ml of tetrahydrofuran containing 20% of water over a period of 30 minutes, the mixture thus obtained is stirred at ambient temperature for 30 minutes. The mixture is filtered with Celite, and the organic layer is separated from the filtrate. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1) to obtain 1.25 g of benzyl (2S,4R)-2-formyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidinecarboxylate as a light yellow oily product.