Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][CH2:11][OH:12])[C:3]=1[Cl:13].[C:14](Cl)(=[O:16])[CH3:15].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][CH2:11][O:12][C:14](=[O:16])[CH3:15])[C:3]=1[Cl:13]
Reactant: Nc1c(Cl)cnc(OCCO)c1Cl
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCOc1ncc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22.3 grams (0.1 mole) of 4-amino-3,5-dichloro-2-(2-hydroxyethoxy)pyridine (prepared by the method of Example I) dissolved in 150 milliliters of pyridine was added dropwise, with agitation, 8.7 grams (0.11 mole) of acetylchloride. The mixture was brought to reflux (~100° C.) and held at this temperature for 1 hour. The mixture was cooled to room temperature and poured into water. The oil which separated was extracted with methylene chloride, washed with 200 milliliters of water and dried over potassium carbonate. The solvent was evaporated under reduced pressure and the 4-amino-3,5-dichloro-2-(2-acetoxyethoxy)pyridine product was recovered by recrystallization from hexane. The product was recovered in a yield of 13.7 grams which melts at 76°-77° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH3:16])[N:12]=[CH:11][C:10]=1[C:17]([NH2:19])=[O:18])=O)[CH3:2].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]1[NH:19][C:17](=[O:18])[C:10]2[CH:11]=[N:12][N:13]([CH2:14][CH2:15][CH3:16])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCCn1ncc(C(N)=O)c1NC(=O)c1ccccc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Yield: 88.7 %

Procedure:
A solution of 5-(2-ethoxybenzamido)-1-n-propyl-pyrazole-4-carboxamide (Preparation 2; 0.541 g, 0.0017 mol) and sodium hydroxide (0.10 g, g, 0.0026 mol) in a mixture of water (5 ml) and ethanol 1 ml) was heated under reflux for 20 hours. The cool reaction solution was extracted with dichloromethane (5×30 ml), then the combined extracts dried (Na2SO4) and evaporated under vacuum to give the crude product. Purification by column chromatography (SiO2, 5% MeOH in CH2Cl2) afforded the title compound as a white solid (0.45 g, 89%). Crystallisation of a sample from ethyl acetate-hexane gave colourless needles, m.p. 154-155° C. Found: C,64.45; H,5.97; N,18.89. C16H18N4O2 requires C,64.41; H,6.08; N,18.78%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[NH2:26]/[C:27](/[CH3:34])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(O)C>[C:15]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([CH3:34])[NH:26][C:23]=1[CH3:24])(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccccc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
353 mg (1.06 mmol) of 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-1-phenylbutane-1,3-dione are dissolved with 137 mg (1.06 mmol) of ethyl 3-aminocrotonate in 5 ml of ethanol and heated under reflux under argon for 24 h. The reaction solution is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 245 mg (52% of theory) of the title compound as a yellow solid.
Reaction SMILES: C(O[C:4](=[O:21])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[CH:18]([F:20])[F:19])C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C[Al](C)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:4](=[O:21])[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:7][C:6]=2[CH:18]([F:19])[F:20])=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C(F)F
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc(C(F)F)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 110 °C
Yield: 13 %

Procedure:
A mixture of 2-(difluoro-methyl)-6-methyl-4-morpholin-4-yl-benzoic acid ethyl ester (0.30 g, 1.00 mmol), 4-chlorobenzylamine (1.42 g, 10.0 mmol) and trimethylaluminium (2M in toluene) (3.50 ml, 7.00 mmol) in toluene (10 ml) is heated at 110° C. for 18 h. After completion of the reaction (monitored by TLC), a 2M aqueous solution of sodium hydroxide is carefully added and the mixture is extracted with ethyl acetate (2×15 ml). The combined organic layers are washed with 2M aqueous solution of sodium hydroxide (10 ml), brine (10 ml) and dried over sodium sulfate. The solvent is evaporated to get the crude product, which is purified by column chromatography (silica gel, 30% ethyl acetate/cyclohexane) to afford N-[(4-chlorophenyl)-methyl]-2-(difluoro-methyl)-6-methyl-4-morpholin-4-yl-benzamide (example 20) (0.05 g, 0.13 mmol, 13%). [M+H]+ 395.1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][CH2:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH:15](O)[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH:15]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(NCC(C)(C)CC(O)c2cccnc2)ccc(C#N)c1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(N2CC(C)(C)CC2c2cccnc2)ccc(C#N)c1Cl
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-4-(4-hydroxy-2,2-dimethyl-4-pyridin-3-yl-butylamino)-3-methyl-benzonitrile (570 mg, 1.66 mmol) in pyridine (2.3 mL) add tosyl chloride (950 mg, 4.98 mmol) in pyridine (1.2 mL) at room temperature. Heat the reaction mixture at 100° C. for 24 h, add additional tosyl chloride (950 mg), and heat for 24 h at 100° C. Cool to room temperature and concentrate under vacuum. Dissolve the residue in ethyl acetate and wash with water. Dry the organic layer over anhydrous sodium sulfate and concentrate to obtain a brown oil. Purify the oil by silica gel chromatography and preparative HPLC to obtain the title compound. Mass spectrum (m/e): 326 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([CH3:18])C(O)=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[O:20]1CCC[CH2:21]1>>[Cl:1][C:2]1[C:3]([CH2:14][CH2:18][CH2:21][OH:20])=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1c(Cl)cccc1-c1ccccc1
Reactant: C1CCOC1
Solvent: O
Product: OCCCc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry argon atmosphere, borane-tetrahydrofuran complex (230 ml of a 1.5 M solution in tetrahydrofuran) was added dropwise to a stirred solution of (3-chloro[1,1'-biphenyl]-2-ylpropanoic acid (40.0 g, 0.15 mole) in tetrahydrofuran (250 ml). The reaction mixture was stirred at room temperature for approximately 18 hours. Water (30 ml) was then added to the reaction mixture during a 0.5 hour period. The solvent was removed from the mixture under reduced pressure to yield an oil. The oil was partitioned betwen methylene chloride and dilute aqueous sodium hydroxide. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield 3-(3-chloro[1,1'-biphenyl]-2-yl)-1-propanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([NH:53][NH2:54])(=[O:52])[CH3:51].CCN(C(C)C)C(C)C>ClCCl>[C:50]([NH:53][NH:54][C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:24])([F:23])[F:25])=[CH:16][N:15]=2)=[CH:4][C:5]=1[O:11][CH3:12])(=[O:52])[CH3:51]
Reactant: CNc1nc(Nc2cc(OC)c(C(=O)O)cc2Cl)ncc1C(F)(F)F
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nc(Nc2cc(OC)c(C(=O)NNC(C)=O)cc2Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A suspension of 5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoic acid (144 mg, 50% pure material, 0.19 mmol), HATU (85 mg, 0.22 mmol), acetic hydrazide (16 mg, 0.22 mmol) and DIPEA (81 uL, 0.46 mmol) in dichloromethane (4 mL) was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). A solid persisted in the aqueous layer; this was filtered, washed with water and then suspended in methanol. The solid was collected by filtration and dried in a vacuum oven to afford N′-acetoyl-5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzohydrazide as a white solid (68 mg, 85%). This was taken through to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.CN(C)[CH:18]=[O:19]>>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[CH:18]=[O:19]
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: O=Cc1cc(Br)c(F)cc1F

Procedure:
As a raw material, 17.7 g of 1,5-dibromo-2,4-difluorobenzene obtained in Production Example II-5-a was subjected to lithiation with n-butyllithium by the procedure of Production Example II-5-b, was subjected to formylation with N,N-dimethylformamide, to give 10.7 g of 5-bromo-2,4-difluorobenzaldehyde. This compound was allowed to react with benzothiophene by the procedure of Production Example II-12-a to yield an alcohol, and then the alcohol was oxidized by the procedure of Production Example II-10-b, to give 9.7 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][O:22][CH3:23])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:35]=[O:36])C>C1COCC1>[Cl:1][C:2]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:35]([OH:36])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: COCOc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 98.1 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-chloro-4-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (2.83 g, 8.48 mmol) was dissolved in THF (110 mL), and the solution was treated with TMEDA (4.10 mL, 27.2 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 27.0 mL, 27.2 mmol) and DMF (1.40 mL, 18.1 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0 to 97/3) to obtain 4-chloro-5-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.01 g, yield 98%).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:16][NH:17][O:18][CH3:19].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:17]([O:18][CH3:19])[CH3:16])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Yield: 99.5 %

Procedure:
Prepared according to Method A step A from 2-fluoro-3-trifluoromethylbenzoic acid (5.0 g, 24 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35 mmol), oxalyl chloride (2.18 mL, 25 mmol) and 6 mL of pyridine to give the title compound (6.0 g) as an oil. Used as is in the next prep
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:17]=[CH:16][C:9]([CH:10]=[CH:11][S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][S:12]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(=N)N
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Product: CC(=N)NS(=O)(=O)C=Cc1ccc(Cl)cc1

Procedure:
Reaction of acetamidine with 4-chlorostyrylsulfonyl chloride according to the above procedure affords N-[(4-CHLOROSTYRYL)-SULFONYL]ACETAMIDINE, m.p. 161°-163° C., crystallized from ethyl acetate.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:18]O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[S:7])(C)(C)C.[ClH:20]>>[ClH:20].[OH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]2[CH2:18][S:7][C:6]([NH2:5])=[N:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccc(O)cc1
Agent: Cl
Product: NC1=N[C@H](Cc2ccc(O)cc2)CS1

Procedure:
A solution of 0.2 g of N-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]-thiourea in 2.6 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 110° C. for 18 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 55° C. and is then taken up successively in 10 cm3 of isopropyl ether, 10 cm3 of diethyl ether, 10 cm3 of pentane, 10 cm3 of petroleum ether and 10 cm3 of isopropyl ether, concentrating under the same conditions as above between each wash. The solid obtained is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. to give 0.098 g of (+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-2-thiazolylamine hydrochloride in the form of an orange-coloured solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2.78 (dd, J=13.5 and 7.5 Hz: 1H); 2.88 (dd, J=13.5 and 5.5 Hz: 1H); 3.26 (dd, J=11.5 and 6 Hz: 1H); 3.55 (dd, J=11.5 and 7.5 Hz: 1H); 4.45 (mt: 1H); 6.74 (d, J=8.5 Hz: 2H); 7.07 (d, J=8.5 Hz: 2H); 9.09 (unresolved complex: 1H); 9.41 (s: 1H); 9.56 (unresolved complex: 1H); 9.97 (broad s: 1H); (αD20=+9.5+/−0.5 at a concentration of 0.5% in methanol)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][C:11]([NH2:13])=[O:12]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][C:11]([NH2:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)CBr
Reactant: Nc1cccc(F)c1
Solvent: CCO
Product: NC(=O)CNc1cccc(F)c1
Temperature: 25 °C

Procedure:
An ethanol solution (50 ml) of 1.45 ml of 3-fluoroaniline and 1.37 g of 2-bromoacetamide was heated under reflux for 24 hours. The reaction liquid was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in chloroform and washed with 1N aqueous sodium hydroxide solution. The aqueous solution used for the washing was extracted with chloroform and combined with the earlier obtained chloroform extract, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (chloroform/methanol=100/3) to provide 1.03 g of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:14][C:12]([CH3:15])([CH3:13])[CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cccc(Br)c1F
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1c(Br)cccc1C#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-bromo-2-fluoro-benzonitrile (40.0 g, 0.200 mol) and tetrahydrofuran (200 mL) was chilled to 0° C. and stirred for 5 min. A solution of potassium tert-butoxide (130 mL, 0.210 mol) was added dropwise at 0° C. and the reaction was allowed to warm to RT with stirring over 90 min. The reaction was quenched with water (200 mL) and 2 M Na2CO3 (100 mL) and extracted with EtOAc (3×200 mL). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to provide the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH:16]=[CH2:17])[O:13][N:12]=2)=[CH:3]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.ClCCl>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:13][N:12]=2)=[CH:3]1
Reactant: C1CCNCC1
Reactant: C=Cc1nc(-c2cn(C)c3ccccc23)no1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: Cn1cc(-c2noc(CCN3CCCCC3)n2)c2ccccc21
Reaction time: 0.17 h

Procedure:
2[3-(1-Methylindol-3-yl)-1,2,4-oxadiazol-5-yl]ethene (0.4 g) was partially dissolved in ethanol. Piperidine (2 ml) was added to the mixture and this was stirred for 10 minutes. Ethanol was evaporated under reduced pressure and excess piperidine was removed by heating under high vacuum. The residual oil crystallised upon refrigeration. The crude oil was converted to the monooxalate salt by treatment with 1 equivalent of oxalic acid in dichloromethane which afforded a white amorphous powder. This was recrystallised from ethanol yielding the title compound, m.p. 186°-188° C. Found: C, 59.85; H, 6.10; N, 13.95; C18H22N4O. (COOH)2 requires C, 59.99; H, 6.04; N, 13.99%; δH (360 MHz, D2O) 1.48-2.06 (8H, m, CH2 pip: NCH2CH2 ×2+NCH2CH2CH2), 3.00-3.08 (2H, m, NCH2) 3.50 (2H, t, J=9 Hz, CH2CH2N), 3.58-3.70 (4H, m, CH2CH2N+NCH2CH2 pip, overlapping), 3.87 (3H, s, NCH3), 7.36 (dt, 1H, J=7.2, 1.1 Hz, H-5 or H-6), 7.42 (1H, d, J=7.2, 1.1 Hz, H-5 or H-6) 7.58 (1H, d, J=8.2 Hz, H-7), 7.89 (s, 1H, H-2), 8.00 (1H, d, J=7.5 Hz, H-4); m/z (CI+) 311 (M+ +1, 100%), 226 (30), 157 (70), 98 (90).
Reaction SMILES: ClC1C=C2NC(=O)C3(C(CC(C)(C)C)[CH2:14][C:13](=[O:21])[NH:12][CH:11]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)C2=CC=1.C(OC([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([Cl:44])[CH:42]=2)/[C:37](=[CH:45]/[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)/[C:36]1=[O:52])=O)C.CO.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:44][C:41]1[CH:42]=[C:43]2[NH:35][C:36](=[O:52])[C:37]3([CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:14][C:13](=[O:21])[NH:12][CH:11]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:38]2=[CH:39][CH:40]=1
Reactant: CC(C)(C)CC1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOC(=O)N1C(=O)/C(=C\c2ccccc2)c2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1CC(c2ccccc2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1c in toluene (30 mL) was added E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in Example 12b (0.4 g, 1.22 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 1 h. After the solution was cooled to room temperature, methanol (40 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in methanol (30 mL) and 1N of NaOH solution (5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h, then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:4) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow oil (Yield 0.5 g, 100%).
Reaction SMILES: [C:1]([C:3]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(OCCCCN)cccc1[N+](=O)[O-]
Yield: 148.4 %

Procedure:
A solution of tert-butyl 4-(2-cyano-3-nitrophenoxy)butylcarbamate (Example 210e) (671 mg, 2 mmol) in DCM/TFA (1:1, 20 mL) was stirred at room temperature for 2 hrs. The solvent was removed under vacuum to give the title compound (698 mg, 100%). MS 236 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.[OH-].[Na+]>C(O)C.[Pd]>[CH3:18][C:3]1[CH:2]=[N:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[N:8]2
Reactant: Cc1c(Cl)ncc2ncc(-c3ccccc3)cc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cncc2ncc(-c3ccccc3)cc12
Reaction time: 0.5 h

Procedure:
33.7 g (132 mmol) of the compound from Example II are dissolved in 600 ml of ethanol, the solution is treated with 293 ml of 1N NaOH and 10 g of 5% Pd/C and the mixture is immediately hydrogenated in the Parr apparatus at 3 bar for 30 min. It is filtered through kieselguhr and the ethanol content is evaporated in vacuo. The product precipitated in this way is filtered off with suction, washed with plenty of water and then with ether and dried. Yield: 23.6 g (81.2%) M.p.: 135°-138° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH3:36])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1.[C:38](=[O:40])=[O:39]>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH2:36][C:38]([OH:40])=[O:39])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Reactant: O=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)c1cc(F)cc(F)c1)N1COC(CC(=O)O)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.5 ml of 1.0M solution) was added to a solution of 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (0.5 g) in tetrahydrofuran, under inert atmosphere at -5° C. After stirring for 0.5 hours, the solution was poured onto solid carbon dioxide (excess), allowed to warm to ambient temperature and poured onto water. The aqueous phase was acidified, extracted (ethyl acetate), dried (magnesium sulphate) and evaporated, to give 1-(3,5-difluorophenyl)-2-(6-carboxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (Compound 704, 0.065 g), NMR 1.5 (s,6H), 3.2 (s,2H), 5.4 (s,2H), 6.8 (m,1H), 7.0 (m,2H), 7.2 (m,3H), 7.5 (d,2H), 9.0 (bs,1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1.[Na+].[I-:18]>CC(=O)CC.CCCCCCC>[I:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)C1(CCCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)C1(CCCCCI)CC1
Yield: 97.7 %

Procedure:
To a solution of tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g, 128 mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166 mmol). The reaction mixture was stirred under reflux for 24 h, diluted with heptane (220 mL) and filtered through a layer of silica 2 cm) in a glassfilter. The residue was eluted with a mixture of heptane and EtOAc (3:1, 5×100 mL). The combined filtrate and elutes were evaporated in vacuo to give tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (42.3 g, 99%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=3.18 (t, J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=174.0, 79.9, 34.1, 33.6, 30.8, 28.2 (3×), 26.8, 24.3, 15.4 (2×), 7.4. HRMS calcd for C13H2IO2 (M+): 338.0743. found: 338.0743.