Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[CH2:15]([O:22][CH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH:35]=[CH:34]3)[CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([O:22][CH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH2:35][CH2:34]3)[CH:25]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: c1ccc(COCc2cc(Oc3ccc4c(c3)CCN4)ncn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylsilane (4 mL, 24.7 mmol) and TFA (6 mL) are added to 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole (0.22 g, 0.682 mmol) in 6 mL of acetonitrile and stirred at rt overnight. The reaction is concentrated to an oil that is dissolved in EtOAc and washed with a saturated aqueous sodium bicarbonate. The organic layer is removed, dried, and concentrated to an to obtain crude 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-1H-indole. MS (ESI) m/z 334.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(N([CH:39]([CH3:41])[CH3:40])CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:5]([C:40]3[CH:39]=[CH:41][CH:8]=[CH:7][CH:6]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(c3ccccc3)c3ccccc3)C2)c1
Yield: 97.8 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (58 mg, 0.13 mmol) in CH3CN (5 ml) was added α-Bromodiphenyl methane (48.0 mg, 0.19 mmol), and diisopropylethylamine (45 μl, 0.26 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (39 mg, 49%). Calcd for C39H42F3NO2 (M+H) 613.75, Found 614.4
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:27])[C@H:8]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:26])[O:22][CH:23]([CH3:25])[CH3:24])[NH:9]C(OC(C)(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:1].[ClH:1].[NH:26]=[C:21]([O:22][CH:23]([CH3:25])[CH3:24])[NH:20][CH2:19][CH2:18][CH2:17][C@@H:8]([C:7]([OH:27])=[O:6])[NH2:9]
Reactant: CC(C)OC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=N)NCCC[C@H](N)C(=O)O
Reaction time: 14 h
Yield: 271.5 %

Procedure:
To a 0° C. stirred solution of 0.54 g (1.32 mmol)N2-(tert-butoxycarbonyl)-N5-(iminoisopropoxymethyl)-L-ornithine tert-butyl ester hydrochloride in 2 ml dioxane was added 10 mL of 4N hydrochloric acid in dioxane solution. The solution was stirred 14 h leaving a pale yellow precipitate. The dioxane was removed under reduced pressure and the residue suspended in ether. After stirring for 3 h, the ether was decanted and the solids dried under vacuum to give 0.52 g N5-(iminoisopropoxymethyl)-L-ornithine dihydrochloride. TLC (silica gel, ammonium hydroxide:methanol/1:25) Rf=0.27.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)COc1ccccc1Cl
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1ccccc1Cl)NCCO[N+](=O)[O-]
Yield: 31.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.79 g of 2-chlorophenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.31 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]#[N:6])[CH2:2][CH3:3].S(=O)(=O)(O)[OH:11]>>[CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]([NH2:6])=[O:11])[CH2:2][CH3:3]
Reactant: CCCC(C#N)CCC
Reactant: O=S(=O)(O)O
Product: CCCC(CCC)C(N)=O

Procedure:
Process according to claim 1, whereby the di-n-propyl acetonitrile is hydrolysed by means of 80% aqueous sulphuric acid, in the proportion of 3 to 5 g of dilute acid/g of nitrile, at a temperature of 80°-85° C., and then the crude di-n-propyl acetamide thus obtained is hydrolysed in the same aqueous sulphuric acid medium in the presence of 1.4 mol of sodium nitrite/mol of nitrile, at a temperature of 40°-50° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(N)(=O)C1C=CC=CC=1.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([NH:32][C:33]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:34]=2[C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=2)=[O:36])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:49][C:47]1[CH:46]=[CH:45][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=2)=[O:36])=[C:33]([NH:32][C:30]([CH:27]2[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]2)=[O:31])[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Cl)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)cc1NC(=O)C1CCNCC1

Procedure:
Using methods substantially equivalent to those described in Example 9-B, 4-chloro-N-(5-chloropyridin-2-yl)-2-1(4-piperidinylcarbonyl)amino]benzamide trifluoroacetate (3.66 g, 93%) was prepared from 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([SH:22])=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:26]>C(O)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([S:22][CH3:26])=[N:7][C:8]([C:12]([F:20])([F:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(F)(F)c2nc(S)c3ccc(Br)cc3n2)nc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-4-thiol (500 mg, 1.29 mmol) in isopropanol (10 mL) were added 1N NaOH (1.94 mL, 1.94 mmol) and iodomethane (0.097 mL, 1.55 mmol) and the mixture was stirred at rt for 30 min. A brown solid formed, which was collected by filtration and washed with MeOH to afford 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (0.373 g, 72%). 1H NMR (300 MHz, CDCl3) δ 8.45-8.51 (m, 1H), 8.26-8.32 (m, 1H), 7.93-8.03 (m, 2H), 7.74 (dd, J=1.9, 8.9 Hz, 1H), 7.54-7.65 (m, 1H), 2.61 (s, 3H); LC-MS (ESI) m/z 400/402 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=1)=[O:12].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:18]=[CH:17][C:16](=[O:19])[NH:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(C(=O)/C=C/c2cc(Cl)ccc2Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(/C=C/c1cc(Cl)ccc1Cl)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, (E)-3-(2,5-dichlorophenyl)-1-(6-methoxypyridin-3-yl)prop-2-en-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a light yellow solid, MS (ESI+): m/z=294.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1N.N([O-])=O.[Na+]>Cl.O.CCO.O>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:11]=1[C:10]([OH:19])=[N:9][N:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Nc1cccc(F)c1C(=O)NNc1ccccc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1nn(-c2ccccc2F)c2cccc(F)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Intermediate 44 (2.182 g, 8.289 mmol) was suspended in 1M HCl (20 ml), cooled to 0° C. and treated dropwise with a solution of sodium nitrite (1.144 g, 16.58 mmol) in water (7 ml). The mixture was stirred for 10 minutes at 0° C., diluted with 1:1 EtOH/H2O (30 ml) and heated to reflux for 3 hours, then stirred at room temperature for 18 hours. The solid was filtered, rinsed with water and dried to afford 1.939 g (95%) of 4-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-ol (Intermediate 45) as a tan solid. MS (APCI): (M+1)=247.1, (M−1)=245.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:30][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@H](CCCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Product: C[C@H](CCCNS(C)(=O)=O)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 89 %

Procedure:
4-chloro-N-(5-chloro-2-fluorophenyl)-N-[4-[(methylsulfonyl)amino]-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[4 (methylsulfonyl)methyl]-1-piperidinyl]-1(R)-methylbutyl]benzenesulfonamide by reacting 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[4-bromo-1(R)-methylbutyl]benzenesulfonamide with methanesulfonamide. Yield=89%; MS (ESI+), 483 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:23].Cl.CO.N>O1CCOCC1>[NH3:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2)=[O:23]
Reactant: CN(CCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CNCCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 112 %

Procedure:
[3-[[4-Chloro-3-[[(tricyclo[3.3. 1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methoxy]propyl]methyl-carbamic acid, 1,1-dimethylethyl ester (0.236 g, Example 23b), 4M hydrogen chloride in 1,4-dioxane (5 ml and methanol (5 ml) were stirred together under nitrogen for 3 h, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica gel, eluting with 19:1:0.1/dichloromethane:methanol: ammonia to afford the title compound as an oil (0.106 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCOCC>[OH:8][C:6]1[C:5]([CH3:9])=[C:4]2[C:3](=[C:2]([CH3:1])[CH:7]=1)[O:10][C:6](=[O:8])[CH2:7][C:2]2([CH3:3])[CH3:1]
Reactant: CC1=CC(=O)C(C)=CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(O)c(C)c2c1OC(=O)CC2(C)C
Yield: 197.6 %

Procedure:
2,5-Dimethylbenzoquinone (10 g, 73.5 mmol) was dissolved in 300 mL of ether, which was mixed with an aqueous solution of sodium hydrosulfite (178 g in 150 mL of water, 85% pure, 870 mmol). The mixture was shaken until the ether layer became nearly colorless. The ether layer was separated, and the aqueous layer was extracted with ethyl ether (3×200 mL). The combined ether layers were washed with brine (2×150 mL) and dried over MgSO4. Filtration and solvent evaporation gave 10.03 g (72.6 mmol) of the hydroquinone as a white solid.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][NH:17][CH3:18].[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38](I)[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38]([N:17]([CH2:16][C:15]4[CH:19]=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=4)[CH3:18])[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1
Reactant: CNCc1cccc(OC)c1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: CNCc1ccc(F)cc1
Product: COc1cccc(CN(C)c2cncc(-c3nc(C)c(C(=O)NCc4ccc(F)cc4)s3)n2)c1
Yield: 75 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with (3-methoxy-benzyl)-methyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro benzylamide, the title compound was obtained in 75% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.55 (s, 1H), 8.07 (s, 7.27-7.37 (M, 2H), 7.18-7.26 (m, 1H), 6.90-7.08 (m, 2H), 6.70-6.88 (m, 3H), 6.21 (bs, 1H), 4.79 (s, 2H), 4.53 (d, J=4.0 Hz, 2H), 3.72 (s, 3H), 3.15 (s, 3H), 2.69 (s, 3H); MS (ES+) m/z 478.2 (M+1), Rt=1.58 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4](=[N+]=[N-])[C:5](=[O:18])[CH2:6][CH:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH2:9]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]12[CH2:9][CH:8]1[CH:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:18])=[O:21]
Reactant: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)OCc1ccccc1
Solvent: Cc1ccccc1C
Product: COC(=O)C12CC1C(OCc1ccccc1)CC2=O
Yield: 23.8 %

Procedure:
In accordance with the process of Preparation 22, 5-benzyloxy-2-diazo-3-oxo-6-heptenoic acid methyl ester (1.16 g; 4 mmol) and copper acetylacetone complex (100 mg) were dissolved in 30 ml of anhydrous xylene. The reaction product was purified by silica gel column chromatography to obtain two types of isomers of 4-benzyloxy-2-oxo-bicyclo[3.1.0] hexane-1-carboxylic acid methyl ester (248mg) as an oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH2:13])=[O:5])[CH3:2].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>CCOCC>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH:13][C:14](=[O:20])[CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: O=C1C=CC(=O)O1
Solvent: CCOCC
Product: CCOC(=O)c1c(NC(=O)C=CC(=O)O)sc(C)c1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 72.1 %

Procedure:
A solution of 2-Amino-4,5-dimethyl-thiophene-3-carboxylic acid ethyl ester (5.53 g, 27.8 mmol) in 25 mL of anhydrous ether was added dropwise to a solution of maleic anhydride (2.72 g, 27.8 mmol) in 25 mL of anhydrous ether. The reaction mixture was stirred at room temperature for 10 h. A yellow precipitate was formed. 2-(3-Carboxy-acryloylamino)-4,5-dimethyl-thiophene-3-carboxylic acid ethyl ester (5.96 g, 72% yield) was obtained as a yellow solid by filtration.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7](=[CH2:12])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2].S(Br)([Br:20])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12][Br:20])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(COCC)C(O)C(NC=O)C(=O)OCC
Solvent: O
Solvent: ClCCCl
Product: CCOCC(=CC(NC=O)C(=O)OCC)CBr
Reaction time: 1 h

Procedure:
3.70 g (15.1 mmol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane, and 1.8 ml (22.8 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with 1N potassium hydrogen carbonate solution and with brine, dried over sodium sulfate, filtered and concentrated by evaporation. 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish-brown oil which is reacted further in the crude state.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].CCN(CC)CC>C(Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
2,2-dimethylpropanoyl chloride (28 g, 232.2 mmol) was added to a stirred solution of 4-bromo-3-nitro-aniline (42 g, 193.5 mmol) and Et3N (51 mL, 366 mmol) in anhydrous DCM (200 mL) at 0° C. under an atmosphere of N2. The cooling bath was removed and the stirring was continued at room temperature for 2 h. The reaction mixture was poured into ice (500 g) and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to afford crude product N-(4-bromo-3-nitrophenyl)pivalamide (55 g, 94%) which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ: 8.18-8.17 (m, 1H), 7.64-7.63 (m, 2H), 7.50 (br s, 1H), 1.32 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4](=[O:18])[CH:3]=1.CN.FC1C=C(I)C=C[C:23]=1[N:29]1C(=O)C=C(NC)N(C)C1=O>CO>[F:15][C:9]1[CH:10]=[C:11]([I:14])[CH:12]=[CH:13][C:8]=1[N:7]1[C:2]([NH:29][CH3:23])=[CH:3][C:4](=[O:18])[N:5]([CH3:17])[C:6]1=[O:16]
Reactant: CNc1cc(=O)n(-c2ccc(I)cc2F)c(=O)n1C
Reactant: Cn1c(=O)cc(Cl)n(-c2ccc(I)cc2F)c1=O
Agent: CN
Solvent: CO
Product: CNc1cc(=O)n(C)c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.9 %

Procedure:
To a 6:5 mixture (75.7 g) of 6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione 65 and 6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyrimidine-2,4-dione 66 obtained in Step 3 were added methanol (227 ml) and 40% solution (152 ml) of methylamine in methanol, and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was concentrated under reduced pressure, and toluene(150 ml) and water (150 ml) were added to the residue, and the mixture was stirred under heating at reflux for 30 min. After allowing to return to room temperature, the crystals were collected by filtration and dried to give a 6:5 mixture (59.6 g, yield 79.9%) of 1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione 67 and 3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione 68 as pale-yellow crystals.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.C(#N)CCCCCCCCCC.N[CH:27]([OH:29])[CH3:28]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:1]([C:12]1[O:29][CH2:27][CH2:28][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCC#N
Reactant: CC(N)O
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCC#N
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCC1=NCCO1
Yield: 64.3 %

Procedure:
Undecyl cyanide in Example 1 was substituted with 18.13 g (108.4 mmoles) of undecanenitrile and allowed to react with 7.5 ml (121.3) mmoles of aminoethanol in presence of cadmium acetate dihydrate (667 mg; 2.5 mmoles) in 1-butanol under identical reaction conditions. The reaction mixture was worked up following Example 1 and the residue was distilled at 118°-120° C./1.2 mm to give 14.72 g (64.3%) of 2-decyl-2-oxazoline.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of N-benzyloxycarbonyl-ethanolamine (12.03 g, 61.6 mmol) in dry dichloromethane (50 ml) was added diisopropylethylamine (32.2 ml, 184.9 mmol) and 2-methoxyethoxymethyl chloride (16.9 ml, 147.9 mmol) with stirring. The mixture was allowed to warm to room temperature then stirred for a further 3 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed successively with 1M hydrochloric acid, sat. aq. sodiumhydrogen carbonate and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to porvide the title compound as a orange/yellow oil which was used without further purification. 1H--NMR; δ(CDCI3), 7.35 (5H, m), 5.45 (1H, m), 5.11 (2H, s), 4.72 (2H, s), 3.67 (4H, m), 3.55 (2H, m) and 3.38 (5H, m).
Reaction SMILES: [NH2:1][C:2]([O:9][CH2:10][CH2:11][CH3:12])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO.C>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([O:9][CH2:10][CH2:11][CH3:12])[C:3]=1[C:7]#[N:8]
Reactant: CCCOC(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Product: CCCOc1nsc(N)c1C#N
Yield: 95.2 %

Procedure:
A mixture of 111 g of 3-amino-2-cyano-3-propoxypropene-thioamide in 250 ml of ethanol was heated to reflux. To this stirred mixture was added 20.4 g of 30% hydrogen peroxide, at such a rate as to maintain a uniform rate of reflux. After complete addition, the reaction mixture was heated under reflux for 20 minutes. A quantity of activated charcoal was added to the reaction mixture. The reaction mixture was filtered hot and allowed to cool. The filtrate was poured into 1500 ml of water, and the solid precipitate was collected by filtration. The dried solid was recrystallized from toluene, to give 104.5 g of 5-amino-4-cyano-3-propoxyisothiazole, m.p. 122°-125°.
Reaction SMILES: [N:1](/[C:4](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:12][CH:11]=1)/[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([NH:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[NH:1]2)=[CH:11][CH:12]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)/C(=C\c1ccc(NC(=O)OC(C)(C)C)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
851 mg (2.67 mmol) of methyl (2E)-2-azido-3-{4-[(tert-butoxycarbonyl)amino]phenyl}prop-2-enoate was dissolved in 40 mL toluene. The mixture was heated to 80° C. for 2 h, cooled, and concentrated. Purification by column chromatography, eluting with 25% ethyl acetate/hexane provided 551 mg of methyl 6-[(tert-butoxycarbonyl)amino]-1H-indole-2-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[BrH:22]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][Br:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCC1CCCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCC1CCCN(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
55.1 g (0.268 mol) of N-benzyl-3-(hydroxymethyl)-piperidine are added to 400 ml of 48% hydrobromic acid with vigorous stirring and the mixture is refluxed for 1 hour. Then hydrogen bromide is introduced to saturation point (about 1 hour), the mixture is refluxed for another hour and left to stand overnight. It is then neutralized with solid potassium carbonate whilst cooling with ice and then extracted with methylene chloride. The organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 52.0 g (72.2% of theory), Rf value: 0.85 (aluminium oxide neutral, eluant: methylene chloride).