Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([O-:10])=O.C1COCC1.[CH3:16][NH2:17]>C(OCC)(=O)C>[CH3:16][NH:17][C:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH3:2])=[O:10]
Reactant: Cc1sccc1C(=O)[O-]
Reactant: CN
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccsc1C
Yield: 71.8 %

Procedure:
2-Methyl-3-thiophenecarboxylate chloride (60.5 g)/THF (300 ml) solution was added dropwise to a 40% aqueous solution of methylamine (400 ml) at 0° C. Ethyl acetate (2 l) was added thereto, and then the organic layer was washed sequentially with water, a 5N aqueous solution of hydrochloric acid, an aqueous solution of saturated sodium bicarbonate, water and brine, dried and evaporated. The resulting residue was crystallized from n-hexane, to give the title compound as a white powder (43.5 g, yield; 71.8%).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:24][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:24]([CH3:25])[C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2ccccc2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution of 0.30 g (0.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.19 g (1.31 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt with ethanolic HCl to yield 0.41 g (89%) of the title compound as a white solid; mp=222-224° C.; MS (+) ESI m/z=456 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([CH2:43][CH2:44][C:45](=O)[CH3:46])=[CH:42][C:37]=2[O:36][CH2:35]1>>[CH3:46][C:45](=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:44][CH2:43][C:41]1[CH:40]=[CH:39][C:38]2[O:34][CH2:35][O:36][C:37]=2[CH:42]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)CCc1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)CCc1ccc2c(c1)OCO2
Yield: 30.7 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (1.82 g, 4.07 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 2.6 mL, 4.07 mmol, 1.0 equiv.) and 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one (1.17 g, 6.10 mmol, 1.5 equiv.), 0.35 g (30%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([N:5]1[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:13]=[CH:14][O:15][C:7]=2[CH2:6]1)=O.B.O>C1COCC1>[F:17][C:2]([F:1])([F:16])[CH2:3][N:5]1[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:13]=[CH:14][O:15][C:7]=2[CH2:6]1
Reactant: O=C(N1CCC(O)c2ccoc2C1)C(F)(F)F
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OC1CCN(CC(F)(F)F)Cc2occc21

Procedure:
7-Trifluoroacetyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]-azepin-4-ol prepared in the step 1 was dissolved in 1 mL of THF, a three molar equivalent of a solution of borane in THF was dropped thereinto under ice-cooling with stirring and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured over 1 mL of water followed by extracting with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The resulting residue was purified by silica gel column chromatography to give 23 mg of the objective compound.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[N:16]([CH:20]([CH3:22])C)[CH:17]([CH3:19])C.N1CCCC1>C(#N)C>[C:8]1([CH:2]([N:16]2[CH2:17][CH2:19][CH2:22][CH2:20]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.8 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml). DIPEA (0.26 ml, 1.48 mmol) and pyrrolidine (0.12 ml, 1.48 mmol) were sequentially added and the solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=9/1) to obtain ethyl 2-phenyl-2-(pyrrolidin-1-yl)acetate (315 mg, quantitative yield) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24].[H-].[Na+]>C1COCC1.CN(C=O)C>[C:23]([C:22]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])[CH2:13][CH2:12][N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1)#[N:24]
Reactant: Cc1ccccc1CC#N
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (1.438 g, 5.94 mmol) and 2-methylphenyl acetonitrile (600 mg, 3.96 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (357.9 mg, 8.7 mmol) at 60° C. (3 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H2O (2×50 ml), and saturated aqueous NaCl (50 ml), dried (Na2SO4) and concentrated in vacuo. PCTLC (SiO2, 6 mm, 100% hexane) afforded 4-cyano-N-(1,1-dimethylethoxy)carbonyl-4-(2-methylphenyl) piperidine as a yellow/orange oil.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[C@@H:4]([CH3:7])[CH2:5][CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@@H:3]([C@H:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:21]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC[C@H](C)[C@H](N)CO
Product: CC[C@H](C)[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1

Procedure:
(1S,2S)-1-(Hydroxymethyl)-2-methylbutylamine was converted to (1S,2S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S,2S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-((2S)-2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-((2S)-2-butyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH2:17])[CH:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC([OH:30])=C(C(C)(C)C)C=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCCl>[CH3:1][O:2][C:3]([C:4]1([CH:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][O:30]1)=[O:18]
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Reactant: C=C(C(=O)OC)C(O)CCCCc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: COC(=O)C1(C(O)CCCCc2ccccc2)CO1

Procedure:
A solution of 11.2 g (45 mmol) of β-hydroxy-α-methylenebenzeneheptanoic acid methyl ester in 300 ml of 1,2-dichloroethane is treated with 200 mg of 4,4'-thiobis(6-t-butyl-m-cresol) and 24.5 g (138 mmol) of m-chloroperoxybenzoic acid. The mixture is heated to reflux under nitrogen for 26 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH2:15][OH:16]>C1COCC1.C(Cl)(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: CC(C)(C)c1cc2ncc(CO)c(N)n2n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ncc(C=O)c(N)n2n1

Procedure:
A solution of (7-amino-2-tert-butylpyrazolo[1,5-a]pyrimidin-6-yl)methanol (380 mg, 1.73 mmol, 1 eq.) and MnO2 (1.5 g, 17.25 mmol, 10 eq.) in THF (6 mL) and CHCl3 (12 ml) was stirred for about 36 h at 25° C. under nitrogen. MnO2 was filtered and washed with 15% MeOH in CHCl3 (˜100 mL) and 30% MeOH in CHCl3 (˜100 mL) until no additional product was observed through analysis of the filtrates by TLC. The filtrates were combined and concentrated under vacuum to give Compound [CCXXXVII] as a yellow solid: LCMS (m/e) 219 (M+H); 1H NMR (300 MHz, DMSO, δ, ppm) 9.87 (s, 1H), 8.99-8.82 (s, 2H), 8.50 (s, 1H), 6.52 (s, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].CC(N(C)C)=O.C([O-])(=O)C.S(Cl)([Cl:32])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:32])=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 8-Nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10 g, 38.14 mmol) in 100 ml of thionyl chloride in a 250 ml round bottom flask was added a catalytic amount of 200 ul of dimethyl acetamide. The mixture was heated and refluxed for 2 hrs with stirring. The reaction was monitered by TLC (n-hexanelethyl acetate=3/1). After completing and cooling to room temperature, thiony chloride was removed under vacuum and 100 ml of water was added. The residue was extracted three times with 100 ml of ethyl acetate each time and the organic layer was dried over magnesium sulfate and filtrated. The residue was purified by column chromatography (hexan/ethyl acetate=3/1) to give 8-nitro-4-chloro-quinoline-3-carboxylic acid ethyl ester (9.5 g, 33.85 mmol, 89%)
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].O>CN(C)C(=O)C>[CH3:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH2:25][CH3:26])=[O:23])[N:7]2[CH:8]=1
Reactant: Cc1cn2c(Br)cccc2n1
Reactant: C=CC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C/c1cccc2nc(C)cn12
Temperature: 100 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 5-bromo-2-methylimidazo[1,2-a]pyridine (5.00 g, 23.7 mmol) in N,N-dimethylacetamide (60 mL) were added sodium acetate trihydrate (3.89 g, 47.4 mmol), ethyl acrylate (3.10 mL, 28.4 mmol) and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (1.73 g, 2.37 mmol) at room temperature, and the mixture was stirred under nitrogen stream at 100° C. for 24 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (3.00 g, yield 55%).
Reaction SMILES: [C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[H][H]>C(O)C.[Pd].[C]>[C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc(N)cc1
Yield: 96.9 %

Procedure:
Nα -Boc-4-Nitrophenyl-D-alanine (209 grams, 0.68 mole) was dissolved in 500 mL of ethyl alcohol and acidified with acetic acid (10 mL). To this was added 0.65 g of 10% Pd/carbon, and the mixture was hydrogenated at about room temperature using H2 at about 40 psi until the uptake of hydrogen had ceased (6 hours). The catalyst was removed by filtration, and the reaction products were concentrated under vacuum to yield a viscous oil that solidified upon trituration with petroleum ether. The amino acid was collected by filtration, washed with petroleum ether and dried to give 184 g of Nα -Boc-4-aminophenyl-D-alanine (0.659 mole, 97%) having [α]D =-40.2° (c=1.0 in EtOAc) and -23.4° (c=1.0 in MeOH); mp=128°-133° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].[Br:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:8][C:9]1[C:10]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CCCCO
Reactant: Cc1cnc(Cl)c(Br)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ncc(C)cc1Br
Reaction time: 4 h
Yield: 71.7 %

Procedure:
Sodium hydride dispersion in oil (55-65%, 1.16 g) was added in portions to a well stirred solution of 1-butanol (2.4 mL, 27 mmol) in DMF (50 mL). After stirring the mixture for 1 h at room temperature 3-bromo-2-chloro-5-methyl-pyridine (5.0 g, 24 mmol) was added and stirring continued for 18 h at room temperature and for 4 h at 70° C. The cooled mixture was poured into saturated sodium bicarbonate solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 4.2 g of the title compound as a light red oil, MS (EI) 243.1, 245.1 (M)+.
Reaction SMILES: [BH4-].[Na+].CC([N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:13]=1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([CH:28]([OH:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (20.52 mg, 0.543 mmol) was added to a stirring solution of 1,1-dimethylethyl({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate (for a preparation see Intermediate 75) (260 mg, 0.452 mmol) in MeOH (5 mL) at 25° C. under N2. The reaction mixture was stirred at room temp for 2 h. About ˜⅔ of the methanol was evaporated in vacuo and the residue was treated slowly with 1M HCl (5 mL). The product was extracted with EtOAc (2×40 mL) and the combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford a yellow oil. 4N HCl in Dioxane (2 mL, 8.00 mmol) was added to the residue at 25° C. and the reaction mixture was stirred for 30 min. The crude sample was loaded straight on to a pre-washed (MeOH) SPE sulphonic acid (SCX-2) cartridge (20 g). The SCX cartridge was washed with 2 column volumes of MeOH and the product was collected by washing with 3 column volumes of 2N Ammonia in MeOH. The appropriate fractions were combined and evaporated in vacuo to give the title compound (235 mg, 91)%. LCMS (System A) RT=0.77 min, ES+ve m/z 477/479 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][O:9][C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1CCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (240 mg, 1.33 mmol) in DMF (10 mL) was treated with NaH (170 mg, 4.26 mmol, 60% wt in mineral oil) at 0° C., resulting in an orange mixture. The mixture was then treated with 2-chloro-N,N-dimethylethanamine hydrochloride (384 mg, 2.66 mmol), resulting in a dark red mixture. The reaction was stirred at room temperature for 1 hour. At this time, the reaction was then heated to 90° C. and stirred for another 45 minutes. The reaction was cooled to room temperature, water (15 mL) was added, and the reaction was extracted into EtOAc (2×12 mL). The combined organic layers were washed with brine (3×5 mL), dried (Na2SO4), filtered, and concentrated. The residue was subjected to flash chromatography on silica gel: CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a yellow/orange solid (210 mg, 63%). 1H-NMR (DMSO-d6) δ 7.75 (dd, J=2.7, 9.0 Hz, 1H), 7.48 (d, J=2.7 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 4.18 (t, J=4.5 Hz, 2H), 3.57-3.53 (m, 4H), 2.54-2.45 (m, 2H), 2.23 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH:15]([NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:37][CH3:38])[CH:11]=1
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C(CN)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile B was then dissolved in ethanol (60 ml) and hydrazine hydrate (2 g) was added. The solution was heated to 60-70 degrees C. for 1.5 hours. TLC showed reaction was complete. The suspension was filtered to remove by-product and the ethanol removed in vacuo. The residue was submitted to flash chromatography on silica gel (ethyl acetate: 2N NH3 in methanol, 9:1) to yield 372 mg of 4-[2-Amino-1-(4-benzyloxy-3methoxy-phenyl)-ethylamino]-benzonitrile D (100%). 1HNMR(CDCl3): 7.3-7.45 (m, 7H), 6.32 (m, 3H), 6.5 (d, 2H), 5.52 (d, 1H), 4.3 (q, 1H), 3.83 (s, 3H), 3.08 (m, 2H), 1.95 (s,
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1.Cl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: COc1ccc(C=O)c(Cl)c1O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(/C=C/C(=O)O)c(Cl)c1O
Temperature: 100 °C
Yield: 91.9 %

Procedure:
2-Chloro-3-hydroxy-4-methoxybenzaldehyde (1.86 g, 10 mmol) was dissolved in pyridine (7 ml), malonic acid (1.25 g, 10 mmol) and piperidine (0.1 ml) were added and the mixture was heated at 100° C. for 2 hrs, then it was poured in 100 ml HCl 1N and extracted with AcOEt. This was dried and evaporated, and the residue was triturated with diethyl ether and filtered, giving 2.10 g of (E)-3-(2-chloro-3-hydroxy-4-methoxy-phenyl)-acrylic acid as a white solid, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:24][C:25]1([CH3:36])[O:29][CH:28]([CH2:30]OS(C)(=O)=O)[CH2:27][O:26]1>CN(C)C=O.CCOCC>[CH3:24][C:25]1([CH3:36])[O:29][CH:28]([CH2:30][O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=2)[CH2:27][O:26]1
Reactant: CCCCCCCCCCCCCCc1ccc(O)cc1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)cc1
Temperature: 25 °C

Procedure:
To a prewashed suspension of about 10.8 g of sodium hydride in about 800 ml of dimethylformamide was added about 43.5 g of 4-tetradecylphenol. The reaction was then refluxed about 2 hours, cooled to room temperature and about 37.8 g of freshly prepared 2,2-dimethyl-4-[[(methylsulfonyl)oxy]methyl]-1,3-dioxolane was added. The reaction was then refluxed for about 24 hours, cooled, diluted with ether, washed with water and dried, giving about 58.7 g of the desired title compound, mp 52°-53° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=[O:3])[CH3:2].[CH2:8]([O:10][SiH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH3:9]>C(#N)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][Si:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: C=CCOC(C)=O
Reactant: CCO[SiH](OCC)OCC
Solvent: N#Cc1ccccc1
Product: CCO[Si](CCCOC(C)=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Into a 200-ml four-necked glass flask equipped with a thermometer, condenser, stirrer, and dropping funnel were introduced 46.0 g (0.46 mol) of allyl acetate and 184 μl of a 0.05M benzonitrile solution of H2PtCl6.6H2O. The contents were heated to 60° C., followed by dropwise addition of 75.6 g (0.46 mol) of triethoxysilane thereto over a period of 30 minutes. Thereafter, the mixture was reacted at 60° C. for 3 hours. The reaction product was purified by vacuum distillation (88° to 85° C./2 mmHg). Thus, triethoxysilylpropyl acetate as the objective compound was obtained in a yield of 89.2% (purity determined by gas chromatography, 99.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[O:31]1[C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:36]([C:35]4[O:31][N:32]=[CH:33][CH:34]=4)=[O:37])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Reactant: O=C(O)c1ccno1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3ccno3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 522.1 (MH+, 1Cl).