Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N(C(=O)C(C)C)C(N)[C:6](O)=[O:7])C.[NH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18].C(OC(=O)C)(=O)C>C(O)=O>[CH:6]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[O:7]
Reactant: CC(C)(N)C(=O)O
Reactant: CCN(C(=O)C(C)C)C(N)C(=O)O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)(NC=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation of ethyl-α -aminoisobutyrylglycinate hydrochloride: To a solution of 10.3 g (0.10 mol) of α-aminoisobutyric acid in 210 ml of 98% formic acid at 0° C, there was added dropwise with stirring 70 ml of acetic anhydride. After stirring at room temperature for 2 hr., 85 ml of ice water was added and the solution evaporated under reduced pressure to give an off-white solid. Recrystallization from absolute ethanol gave 11.2 g (0.085 mol), 85%, N-formyl-α-aminoisobutyric acid, mp 129.5° -131° C; pmr (D2O) δ 1.50 (s, 6H), 4.06 (s, 2H) and 8.16 (s, 1H) ppm.
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].C1CCN2C(=NCCC2)CC1.[CH2:41]([O:48][C:49]1[C:54]2[CH:55]=[CH:56][O:57][C:53]=2[C:52]([CH:58]=O)=[CH:51][CH:50]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[O:4][CH2:2][CH3:3])=[CH:58]/[C:52]1[C:53]2[O:57][CH:56]=[CH:55][C:54]=2[C:49]([O:48][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:50][CH:51]=1)[CH3:10]
Reactant: O=Cc1ccc(OCc2ccccc2)c2ccoc12
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c2ccoc12)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A suspension of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride (2.04 g, 4.8 mmol) and DBU (0.8 g, 5.2 mmol) in THF (40 ml) was stirred for 10 min at ambient temperature under an argon atmosphere [for the preparation of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride see: K. K. Bach, H. R. El-Seedi, H. M. Jensen, H. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetrahedron 1994, 50, 7543-7556]. 4-Benzyloxy-benzofuran-7-carbaldehyde (0.8 g, 3.2 mmol) was added and the mixture was heated under reflux for 12 h. The solvent was concentrated at reduced pressure, the residue taken up with ethyl acetate, washed with saturated aqueous NH4Cl solution and two times with brine. The organic layer was dried over sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 0.8 g (2.2 mmol, 69%) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[CH:3]=1)=[N+:13]=[N-:14]
Reactant: OCCOc1cc(Cl)ncn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(OCCO)ncn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 28.9 %

Procedure:
To a solution of 2-(6-chloropyrimidin-4-yloxy)ethanol (5.61 g) in dimethylformamide (60 ml) is added sodium azide (4.18 g), and the mixture is stirred at 70° C. for 20 hours. After cooling, the reaction solution is treated with water, and extracted with ethyl acetate. The ethyl acetate layer is dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate=1:1) to give 2-(6-azidopyrimidin-4-yloxy)ethanol (1.68 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH3:19])[CH2:17][OH:18].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.C(O)(=O)C>[CH2:20]([NH:15][C@@H:16]([CH3:19])[CH2:17][OH:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (36.7 g) was added portion wisely to a mixture of (2S)-2-amino-1-propanol (10.0 g) and benzaldehyde (13.53 ml) in a mixture of dichloromethane (140 ml) and acetic acid (8.38 ml) at 0° C. and the whole was stirred at room temperature overnight. The mixture was washed successively with 2N sodium hydroxide and brine, and dried over sodium sulfate. The solution was evaporated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (30:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-benzylamino-1-propanol (15.96 g).
Reaction SMILES: [CH:1]1[C:6]([S:7]([OH:10])(=[O:9])=[O:8])=[C:5]([NH2:11])[CH:4]=[C:3]([S:12]([OH:15])(=[O:14])=[O:13])[C:2]=1N.[C:17](=[O:20])(O)[O-].[Na+].[N:22]([O-])=O.[Na+].Cl>CN1CCCC1=O>[NH2:22][C:3]1[CH:4]=[CH:5][C:6]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:1][CH:2]=1.[NH2:11][C:5]1[C:6]2[C:1](=[CH:5][C:6]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:1][C:17]=2[OH:20])[CH:2]=[C:3]([S:12]([OH:15])(=[O:13])=[O:14])[CH:4]=1
Reactant: Nc1cc(S(=O)(=O)O)c(N)cc1S(=O)(=O)O
Reactant: O=N[O-]
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Product: Nc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C

Procedure:
32.3 parts of 4,5-dichloro-1-(N'-difluorotriazin-2'-ylaminoethyl)-pyridaz-6-one are dissolved in 150 parts by volume of N-methylpyrrolidone, and the solution is added dropwise at 40° C. to a neutral aqueous solution of 26.8 g of 1,4-phenylenediamine-2,5-disulfonic acid. The pH is then kept at 6 for 4 hours with a little sodium bicarbonate. The mixture is then cooled to 0° C. with ice and diazotized with sodium nitrite in the presence of hydrochloric acid, and the resulting diazo suspension is added to a suspension of the red monoazo dye obtained from 17.3 parts of aniline-4-sulfonic acid and 31.3 parts of 1-amino-8-hydroxynaphthalene-3,6-disulfonic acid by a method similar to that described in Example 1. Coupling is completed overnight at pH 5.5-6, and the product is precipitated with 250 parts of sodium chloride, filtered off and dried under mild conditions to give the dye of the formula ##STR55## in the form of a black powder, which dyes cotton in navy hues possessing generally good fastness properties.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[CH:17]=[O:18]>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)[CH:17]=[O:18]
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(F)c1

Procedure:
Prepared from the product of Example 4 and 3,4-difluorobenzaldehyde.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[C:13](=[O:29])[N:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.O>C(O)(=O)C>[CH2:1]([C:8]1[C:12]2[C:13](=[O:29])[N:14]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1ccc(O)cc1
Yield: 86.1 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (200 mg, 0.52 mmol, prepared in Example 51) in acetic acid (2 ml) was added 47% hydrogen bromide (1 ml), and the mixture was heated under reflux overnight. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-benzyl-5-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (165 mg, 86%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[Na+].[I-].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:41]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[O:33][CH2:32][CH2:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1)([CH3:42])[CH3:43]
Reactant: CC(C)[Si](OCCN1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of Intermediate A (102 mg, 0.63 mmol) in DMF (1.5 mL) was added NaI (60% dispersion in oil, 68 mg, 1.71 mmol). The mixture was stirred at RT for 5 min, then a solution of Intermediate 94b (240 mg, 0.57 mmol) in DMF (1.5 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound as a pale brown gum (219 mg, 68%). LCMS (Method 3): Rt 2.65 min, m/z 565 [MH+].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:23]([SH:25])[CH3:24]>B(F)(F)F.CCOCC>[CH2:23]([S:25][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1)[CH3:24]
Reactant: C(=Cc1ccc(OCc2ccccc2)cc1)Cn1cccn1
Reactant: CCS
Agent: FB(F)F
Solvent: CCOCC
Product: CCSC(CCn1cccn1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
4.51 g of 1-benzyloxy-4-[3-(1-pyrazoly)prop-1-enyl]benzene were dissolved in a mixture of 25 ml of ethanethiol and 25 ml of boron trifluoride diethyl etherate, and the resulting mixture was stirred at 25° C. for 0.75 hour. The excess thiol was removed by evaporation, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate, and filtered. The filtrate was evaporated, and the residue was chromatographed on silica gel using chloroform for the elution. The eluate was evaporated, whereby 3.5 g (86%) of 4-[1-ethylthio-3-(1-pyrazolyl)propyl]phenol in the form of an oil was obtained.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](I)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C(N(CC)CC)C.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(=O)n2nc(SCc3ccccc3)sc2n1
Reaction time: 4 h

Procedure:
In a mixture of 30 ml of triethylamine and 60 ml of tetrahydrofurane, 7.0 g of the thus obtained 55% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved, and 0.68 g of bis(triphenylphosphine)palladium (II) chloride and 0.18 g of cuprous iodide were added to the solution. A solution of 3.8 g of ethynyltrimethylsilane in 20 ml of triethylamine was added dropwise to the above solution, the resulting solution was heated to 68°-70° C. and stirred for 4 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using an ethyl acetate/hexane mixture as an eluent, and thus 4.2 g of 2-benzylthio-7-trimethylsilylethynyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][O:11][CH2:12][CH:13]=O.CN(C)C>C1C=CC=CC=1.CO>[CH3:10][O:11][CH2:12][CH:13]=[N:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1N
Reactant: COCC=O
Agent: CN(C)C
Solvent: CO
Solvent: c1ccccc1
Product: COCC=Nc1c(C)cccc1C

Procedure:
A solution of 24.2 (0.2 mole) of 2,6-dimethylaniline and 17.8 g (0.24 mole) of methoxy-acetaldehyde in 150 ml of benzene is treated with 1 ml of 25% trimethylamine solution in methanol and the mixture is refluxed for 5 hours using a steam trap. The reaction mixture is evaporated in vacuo and vacuum distillation of the residue yields the 1-(2'-methoxy-ethylidene-amino)-2,6-dimethylbenzene with a boiling point of 58°-61° C. at 0.1 Torr.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[C@@H:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.[CH:34]([N-]C(C)C)(C)C.[Li+].CI>CN(C)C=O.C(#N)C>[CH3:34][N:3]1[C@H:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:31])=[O:32])[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C:2]1=[O:1]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
A solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 50 mg, 0.11 mmol) in N,N-dimethylformamide (1.0 mL) is treated with lithium diisopropylamide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 63 μL, 0.12 mmol) and methyl iodide (9 μL, 0.14 mmol). After 20 min the mixture is diluted with acetonitrile and purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 15 mg; ESI mass spectrum [M+H]+=490; Retention time HPLC: 1.00 min (Z017_S04).
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C([N:20]([CH:24]([CH3:26])[CH3:25])C(C)C)C>CN(C=O)C.CCOC(C)=O.C1COCC1>[CH:14]1([NH:17][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=2[NH:20][CH:24]2[CH2:26][CH2:25]2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-3-nitrobenzoic acid (500 mg, 2.03 mmol) in DMF (3 mL) was added cyclopropylamine (0.14 mL, 2.03 mmol), N-ethyl-N-isopropyl-propan-2-amine (0.34 mL, 2.03 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)-tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (1.27 g, 2.44 mmol). The resulting mixture was stirred at rt for 24 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to flash chromatography on a silica gel column using 0 to 100% gradient of EtOAC:DCM (1:1) in DCM as eluent to give a crude product mixture. To the crude mixture in THF (10 mL) was added cyclopropylamine (0.141 mL, 2.03 mmol) and the resulting mixture was heated under N2 at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water, brine and dried over magnesium sulfate. After being concentrated in vacuo, the residue was purified by flash chromatography on silica gel using 0 to 100% gradient of EtOAC:DCM (1:1) in DCM as eluent to give N-cyclopropyl-2-(cyclopropylamino)-3-nitrobenzamide: 1H NMR (400 MHz, CDCl3) δ 8.27 (1H, s), 8.01 (1H, d, J=8.0 Hz), 7.45 (1H, d, J=8.0 Hz), 6.62 (1H, t, J=8.0 Hz), 5.98 (1H, s), 2.90-2.65 (2H, m), 0.90-0.78 (2H, m), 0.75-0.65 (2H, m), 0.58-0.50 (2H, m), 0.48-0.40 (2H, m); LC-MS (ESI) m/z 262.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]([OH:7])=[O:6])[NH2:4].O.[OH-].[Li+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12].Cl>O.C(OCC)(=O)C.CC(C)=O>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N@:4]1[CH2:2][CH:3]1[C:5]([OH:7])=[O:6])(=[O:22])=[O:21])([O-:13])=[O:12]
Reactant: N[C@H](CCl)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)C1C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
200 mg (1.62 mmol) of (S)-3-chloroalanine was dissolved in 4.0 mL of water. After adding 136 mg (3.24 mmol) of lithium hydroxide monohydrate, the resulting mixture was slowly heated to 50° C. and then stirred for 3 hours. The reaction container was ice-cooled and 6.4 mL of acetone, 431 mg (1.94 mmol) of 2-nitrobenzenesulfonyl chloride and 68 mg (1.62 mmol) of lithium hydroxide monohydrate were successively added thereto at an internal temperature of 5° C. After 1 hour, 30 mL of ethyl acetate was added. Further, 6 N hydrochloric acid was added to adjust to pH 2.0. Then the reaction mixture was divided into layers and the organic layer was collected. The aqueous layer was extracted with 50 mL portions of ethyl acetate twice to give an organic layer. The organic layers thus obtained were combined, washed successively with 50 mL of water and 50 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. After distilling off the solvent under reduced pressure, 265 mg of (S)-N-2-nitrobenzenesulfonyl-aziridine-2-carboxylic acid was obtained. Yield: 60%.
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12]([CH:14]1[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1)=O)[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC(F)(F)C([O-])=O.[NH4+:34]>>[CH3:1][C:2]1[N:11]=[C:12]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15]2)[NH:34][C:3]=1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: CC(NC(=O)C1CN(Cc2ccccc2)CCO1)C(=O)c1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: Cc1nc(C2CN(Cc3ccccc3)CCO2)[nH]c1-c1ccccc1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 97.5 %

Procedure:
A mixture of N-(1-methyl-2-oxo-2-phenylethyl)-4-(phenylmethyl)-2-morpholinecarboxamide (1.3 g, 3.69 mmol) and ammonium trifluoroacetate (2.417 g, 18.44 mmol) was stirred for 0.75 hours at 150° C. The LCMS indicated that the starting material was consumed. The desired product was contained in the residue. Water (150 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (3×100 mL). The organics were dried (Na2SO4), filtered, and evaporated to afford the title compound (1.2 g) as a brown oil. LC-MS (ES) m/z=334 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]([CH3:17])([CH3:16])[C:14]#[CH:15].N12CCCN=C1CCCCC2.O>C(#N)C.[Cu](Cl)Cl>[CH3:16][C:13]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:17])[C:14]#[CH:15]
Reactant: C#CC(C)(C)Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: Cl[Cu]Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: C#CC(C)(C)Oc1cccc(C(=O)OC)c1
Reaction time: 0.25 h
Yield: 27.9 %

Procedure:
To a solution of methyl 3-hydroxybenzoate (10.0 g, 65.7 mmol) in acetonitrile (200 mL) were added 3-chloro-3-methylbut-1-yne (20.0 g, 195 mmol) and copper (II) chloride (88 mg, 0.654 mmol) under ice-cooling, and the mixture was stirred for 15 min under ice-cooling. 1,8-Diazabicyclo[5.4.0]undec-7-ene (10 mL, 70.0 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (300 mL), and the mixture was extracted with ethyl acetate (400 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→0/100) to give the title compound (4.0 g, 28%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:8])[CH:5]([CH3:7])[CH3:6])[CH3:2].[CH2:9]=O>>[CH3:9][N:3]([CH:4]([CH3:8])[CH:5]([CH3:7])[CH3:6])[CH2:1][CH3:2]
Reactant: C=O
Reactant: CCNC(C)C(C)C
Product: CCN(C)C(C)C(C)C
Yield: 97.4 %

Procedure:
In a similar manner to Example 1, 230.4 g (2.0 mol) of N-ethyl-1,2-dimethylpropylamine and 330.2 g (3.2 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.3 MPa is established at a temperature of 120° C. After the crude amine (aqueous and organic phase) has been degassed at a maximum temperature of 94° C., the water is removed on a water separator. The remaining organic phase is subsequently fractionally distilled. 251.7 g of N-methyl-N-ethyl-1,2-dimethylpropylamine having a purity of 98.6% are isolated, corresponding to a yield of 96.0% of theory.
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1Br>O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1[O:6][CH3:5]
Reactant: Brc1cncc(Br)c1Br
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(Br)cncc1Br
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of MeOH (0.115 mL, 2.85 mmol) and THF (0.5 mL) at 0° C. was added sodium hydride (60% dispersion, 114 mg, 2.85 mmol). After stirring for 15 min, Intermediate 31B (600 mg, 1.900 mmol) was added, and the resulting mixture was stirred at room temperature for 19 hours, diluted with water (3 mL) and extracted with EtOAc (2×10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield Intermediate 31 (0.480 g, 1.798 mmol, 95% yield) as a beige color solid. MS (ES): m/z=267.9 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 8.68 (2 H, s), 3.99 (3 H, s). Intermediate 31 was used in the synthesis of Example 185.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[N:7][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=[O:40].[O:41]1[CH2:45]CCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:12][O:11][C:5]1[C:6]2[N:7]=[CH:8][O:9][C:10]=2[C:2]([C:45]([OH:41])=[O:40])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)c2ocnc12
Reactant: [C]=O
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)O)c2ocnc12
Temperature: 25 °C

Procedure:
7-Bromo-4-methoxybenzoxazole (630 mg), triethylamine (3.85 ml), triphenylphosphine (290 mg), bis(triphenylphosphine)palladium chloride (88 mg), water (20 ml) and tetrahydrofuran (40 ml) were combined and heated to 90° C. in a Parr apparatus under 1035 kPa (150 psi) of carbon monoxide for 3 days. After cooling to room temperature, the tetrahydrofuran was evaporated. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous phase was acidified to pH4 with acetic acid, and the layers separated. The aqueous phase was extracted with ethyl acetate (2×30 ml) followed by dichloromethane (2×30 ml). The combined organic phases were dried over magnesium sulphate and evaporated in vacuo. Purification of the residue by flash chromatography eluting with ethyl acetate and trituration with diethyl ether afforded the title compound as a white solid (125 mg). On standing, a white solid precipitated in the water layer which was removed by filtration and dried in vacuo at 45° C. for 1 hour to give a further portion of the title compound as a white solid (49 mg).