Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[N:29]1[CH:30]=[CH:31][N:32]=[CH:33][C:28]=1[NH:27][C:11](=[O:13])[C@@H:10]([N:8]1[CH2:9][C:5]([O:4][C:3]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])[C:2]=2[F:1])=[CH:6][C:7]1=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: Nc1cnccn1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Yield: 52.6 %

Procedure:
A solution of (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (prepared as in Example 143, 400 mg, 1.10 mmol), 2-aminopyrazine (208 mg, 2.18 mmol) and carbonyldiimidazole (186 mg, 1.15 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 12 h. At this time the mixture was transferred to an Emrys Optimizer microwave tube and microwaved at 120° C. for 5 h. The mixture was concentrated in vacuo and the residue partioned between ethyl acetate and 0.1N aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, aqueous sodium bicarbonate solution, and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by ISCO flash chromatography (RediSep silica 40 g, 70% to 100% ethyl acetate/hexanes) to afford (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (256 mg, 53%) as an off-white fluffy powder: HR-ES-MS (m/z) calculated for C23H27FN4O4 [M+H]+ 443.2089, observed 443.2088. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=6.8 Hz, 6H), 1.41-1.54 (m, 1H), 1.49 (s, 6H), 1.56-1.73 (m, 1H), 1.73-1.91 (m, 1H), 4.25 (d, J=18.4 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.04 (dd, J=11.0, 4.4 Hz, 1H), 5.42 (br. s., 1H), 7.24 (t, J=7.7 Hz, 1H), 7.32-7.40 (td, J=7.7, 1.5 Hz, 1H), 7.56 (td, J=7.7, 1.5 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.42 (s, 1H), 9.28 (s, 1H), 11.19 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:22](=[O:25])[CH:23]=[CH2:24])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)([O-:3])=[O:2]
Reactant: C=CC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
Dissolve 3-nitro-5-(trifluoromethyl)aniline (150 mg, 0.73 mmol), triethylamine (220 mg, 2.18 mmol) in DCM (8 mL), cool to 0° C. at ice bath, add slowly acryloyl chloride (198 mg, 2.18 mmol). After addition, stir the reaction at room temperature for 2 hrs. Pour the mixture into water (30 mL), extract with EtOAc (10 mL×3), combine the organic layers; wash with brine (50 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product (190 mg) which is used without further purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[C:19]2[NH:18][C:17](=[O:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.[ClH:29].CCO.C(OCC)C>O1CCCC1>[ClH:29].[CH2:21]([N:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:10][CH2:9][NH:7][CH3:6])[C:19]=2[NH:18][C:17]1=[O:20])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN(CCc1cccc2c1[nH]c(=O)n2Cc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: CNCCc1cccc2c1[nH]c(=O)n2Cc1ccccc1

Procedure:
[2-(1-Benzyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-ethyl]-methyl-carbamic acid tert-butyl ester (31 mg) was dissolved in 2.0 ml of tetrahydrofuran and 100 uL of 2.0 N HCl/EtOH was added. The solution was heated on a steam bath for 30 minutes and then after cooling diethyl ether was slowly added to produce 10 mg of 1-benzyl-4-(2-methylamino-ethyl)-1,3-dihydro-benzoimidazol-2-one hydrochloride salt as a colorless powder. MS: 282 (M+H)−.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[N:14][OH:15])[NH2:13])=[CH:4]1)[CH3:2].[H-].[Na+].C(O[CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)(=O)CCC.[CH2:31]1[CH2:35]OC[CH2:32]1>>[N:27]1([CH2:30][CH2:32][CH2:31][C:35]2[O:15][N:14]=[C:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:3]([CH2:1][CH3:2])[CH:4]=3)[N:13]=2)[CH2:26][CH2:25][CH2:24][CH2:29][CH2:28]1
Reactant: CCn1cc(C(N)=NO)c2ccccc21
Reactant: C1CCOC1
Reactant: CCCC(=O)OC1CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Product: CCn1cc(-c2noc(CCCN3CCCCC3)n2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1-Ethylindole-3-ylcarboxamide oxime (200 mg, 0.98 mmol, prepared by the general method of EP-A-328200) was dissolved in anhydrous THF (4 ml) containing 4-A° powdered molecular sieves (300 mg). The mixture was stirred for 30 mins., sodium hydride (80% dispersion in oil) (40 mg, 1.3 mmol) was added and the mixture was heated at 60° C. for 20 min. It was then cooled to RT and a solution of methyl-4-piperidinyl butyrate (364 mg, 1.98 mmol) in THF (2 mol) was added. The resulting mixture was heated at reflux for 1 hr., cooled, filtered and the filtrate concentrated under vacuum. The residue was purified by column chromatography to give the product (210 mg).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCC1.[C:68]([O:72][C:73](=[O:83])[N:74](C1C=CC=C(N)C=1)[CH3:75])([CH3:71])([CH3:70])[CH3:69].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:68]([O:72][C:73](=[O:83])[N:74]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:75])([CH3:71])([CH3:70])[CH3:69]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCC2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 9, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. The product was characterised as the hydrochloride salt. 1H NMR (DMSO-d6) 9.89 (1H, br s), 7.84-7.40 (6H, m), 7.20 (1H, m), 6.66 (1H, m), 4.78 (2H, m), 3.98 (1H, m), 3.68 (1H, m), 3.35 (1H, m), 2.73 (3H, s), 1.85-1.33 (8H, m), 1.13 (9H, s).
Reaction SMILES: [C:1]1(N)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1N.[N+]([NH:12][C:13]1[CH:18]=CC=CC=1)([O-])=O.S(=O)(=O)(O)O.[As](=O)(O)(O)O.[N+]([C:32]1C=C(S(O)(=O)=O)C=CC=1)([O-])=O>OCC(CO)O>[CH:32]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:13][N:12]=1
Reactant: Nc1ccccc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: O=[N+]([O-])Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Solvent: OCC(O)CO
Product: c1ccc2cnccc2c1

Procedure:
In a Skraup synthesis, a phenylene diamine (148) or a nitroaniline is reacted with glycerine (149) and sulfuric acid or arsenic acid and an oxidizing agent, such as m-nitrobenzene sulfonic acid (Scheme 66). ##STR86## An intermediate amino- or nitro-quinoline or isoquinoline is produced. In the case of the amino-quinoline, it is not isolated, as it reacts immediately with excess reagents to yield the phenanthroline. If a nitro-aniline has been used to produce a nitroquinoline, it is isolated and purified if necessary. This often removes large amounts of tars produced by the Skraup synthesis. The nitro group is then reduced by standard conditions to yield an aminoquinoline. The aminoquinoline is then subjected to another Skraup reaction (sulfuric or arsenic acid, or both, glycerine and m-nitrobenzenesulfonic acid) to yield the phenanthroline.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H-].[Na+].[H][H].[CH2:13]([O:15][C:16](=[O:25])[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)Br)[CH3:14]>CN(C)C=O.O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:25])=[CH:1][CH:2]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: [H][H]
Reactant: Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccccc1Oc1ccc(C)cc1
Reaction time: 20 h
Yield: 60.3 %

Procedure:
p-Cresol (4.45 g) was added portionwise over 30 minutes to a stirred suspension of sodium hydride (60% dispersion in mineral oil; 1.81 g) in N,N-dimethylformamide (DMF) (80 ml). When evolution of hydrogen ceased, ethyl-α-bromophenylacetate (10.0 g) was added and the mixture was left to stand for 20 hours. Water (500 ml) was added and the mixture was extracted with ethyl acetate (2×250 ml). The extracts were washed with water (250 ml), followed by saturated sodium chloride solution (250 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:19 v/v), to give ethyl 2-(4-methylphenoxy)phenylacetate (B) (6.7 g), as an oil; NMR (d6 -DMSO): 1.2(t, 3H), 2.15(s, 3H), 4.1(q, 2H), 5.9(s, 1H), 7.2-7.6(m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.II.C(N(CC)CC)C.[F:21]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1ccnc2ccccc12
Reactant: FF
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1cc(Cl)c2ccccc2n1
Yield: 69.8 %

Procedure:
A solution containing 4-chloroquinoline (1.0 g, 6 mmol), iodine (l.55 g, 6 mmol) and triethylamine (0.60 g, 6 mmol) in CF2ClCFl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution at room temperature using narrow bore PTFE tubing at 20 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (1.01 g). GC/MS analysis showed a 76% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2 fluoro-4-chloroquinoline (0.76 g, 90%); m.p 60°-61° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles; RF 0.78 (CH2CI2); (Found C, 59.7;H, 2.9; N, 7.6. C9H5NClF requires: C, 59.5; H, 2.75; N, 7.7%); δH (400 MHZ, CDCl3, Me4Si) 7.20 ppm (1H, d, JH,3,F 2.4, H-3), 7.62 (1H, d d d, JH5,H6 =JH6,H7 7.4, JH6,H8 1.2, H-6), 7.78 (1H, d d d, JH6,H7 =JH7,H8 7.8, JH5,H7 1.2, H-7), 7.96 (1H, d, JH7,H8 8.4, H-8), 8.19 (1H, d, HH5,H6 8.4, H-5); δF (235 MHz, CDCl3, CFCl3) -61.5 pm (s); δC (100 MHz, CDCl3, Me4Si) 110.2 ppm (d, 2J 45.8, C-3), 124.2 (d, 5J 0.8, C-5), 125.1 (d,4J 2.6, C-4a), 127.0 (d 6J 2.7, C-6), 128.5 (d, 4J 1.5, C-8), 131.6 (s, C-7), 145.9 (d, 3J 18, C-8a), 146.6 (d, 3J 12.5, C-4), 160.2 (d, 1J 242.3, C-2); m/z (E1+) 183 (M+, 26%), 181 (M+, 100%), 146 (35), 126 (15), 75 (12), 50 (11).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13]([NH2:15])=O)[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13](=[S:39])[NH2:15])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(C(N)=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: Cc1ccccc1
Product: Cc1c(C(N)=S)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 100 °C
Yield: 25 %

Procedure:
A mixture of 3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid amide (Example 9) (23 mg, 0.06 mmol) and Lawessons Reagent (48.5 mg, 0.12 mmol) in toluene (2 ml) was heated at 100° C. for 5 min. After regular workup, the residue was purified by prep. TLC to give impure 423A (6 mg, 25%) (5% MeOH—CHCl3). It has a retention time of 6.19 min (standard LC1 method, 8 min run). LCMS Found: (M+H)+=400.2
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: ClCc1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccc2ccccc2c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 2-chloromethyl naphthalene, in 81% overall yield. the crude product was crystallized from ether/hexane to afford a white solid, mp 81°-87° C.; IR (KBr) 3459, 2940, 1665, 1500, 1403, 1277, 1242, 1066, 746 cm-1 ; 1H NMR (CDCl3) δ 2.23-2.40 (m, 3H), 3.95 (t, J=5.4 Hz, 2H), 4.90 (dd, J=7.6, 5.6 Hz, 1H), 5.32 (ABq, JAB =16.1 Hz, 2H), 6.87-7.03 (m, 4H), 7.38 (d, J=8.5 Hz, 1H), 7.43-7.48 (m, 2H), 7.67 (s, 1H), 7.75-7.84 (m, 3H); MH+ at m/z=334; Anal. Calc'd for C21H19NO3 : C, 75.66; H, 5.74; N, 4.20. Found: C, 75.65; H, 5.71; N, 4.02.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(O[CH2:17][CH3:18])(=O)C>N1C=CC=CC=1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:2][C:1]2[CH:3]=[CH:4][CH:5]=[CH:6][C:17]=2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1NS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
O-toluidine (Fluka; 0.118 mL, 1.1 mmol) was added to a clear light yellow solution of 4-cyano-benzenesulfonyl chloride (ABCR GmbH & Co. KG; 202 mg, 1 mmol) in pyridine (5 mL). The resulting clear red-brown solution was then stirred at room temperature for 18 hrs. Subsequently the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The liquid layers were separated and the aqueous fraction was re-extracted twice with ethyl acetate (25 mL). The combined organic layers were washed with 0.1 M hydrochloric acid and brine (50 mL each), dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was dried under high vacuum to give 4-cyano-N-o-tolyl-benzenesulfonamide (314 mg, 0.92 mmol, 92% yield) as pale brown oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:8].N.C(OCC)C>C(OCC)(=O)C.CO>[NH4+:9].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O-:17])=[O:16])[CH2:10]1)=[O:8]
Reactant: O=C(O)[C@H]1CCCN(C(=O)Cc2cccs2)C1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C([O-])[C@H]1CCCN(C(=O)Cc2cccs2)C1
Product: [NH4+]

Procedure:
A small amount of (S)-1-(2-thiopheneacetyl)-3-piperidine carboxylic acid was dissolved, with warming, in ethyl acetate. An excess amount of ammonia in methanol was added. Diethyl ether was then added to the cloudy mixture and a precipitate formed. The product was isolated by centrifugation and decanting, and was then dried under reduced pressure at ambient temperature. This gave (S)-1-(2-thiopheneacetyl)-3-piperidinecarboxylic acid ammonium salt as a white solid. MS m/z (positive ion) 254 (MH+; 100).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]=1[CH3:11])#[CH:2].C([Li])CCC.[Cl:17][CH:18]=[CH:19][C:20](=[O:22])[CH3:21].C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:17]/[CH:18]=[CH:19]/[C:20]([CH3:21])([OH:22])[C:2]#[C:1][C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]=1[CH3:11]
Reactant: CC(=O)C=CCl
Reactant: C#CC1=C(C)CCCC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1=C(C#CC(C)(O)/C=C/Cl)C(C)(C)CCC1
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of 1.48 g (10 mmol) of 2-ethynyl-1,3,3-trimethyl-cyclohexene in 90 ml of dry tetrahydrofuran in a 250 ml three-necked reaction flask equipped with a magnetic stirrer, a rubber septum and argon gasification means was cooled under an argon atmosphere in a dry ice bath. It was treated dropwise with 7.5 ml (12 mmol) of a 1.6 M solution of n-butyllithium in hexane as fast as the temperature could be maintained at −70 to −60° C. The addition was completed within 10 minutes. After the reaction mixture had been stirred for an additional 30 minutes at −70° C., a solution of 1.045 g (10 mmol) of 4-chloro-buten-2-one in 10 ml of dry tetrahydrofuran was added slowly. After further stirring for 3 hours at −70° C. the reaction mixture was poured into 250 ml of ice water and extracted with three 70 ml quantities of hexane. The combined organic phases were washed with three 100 ml quantities of water and 50 ml of brine, and dried over anhydrous magnesium sulphate. All the volatile material was removed under a reduced pressure of 100–200 mbar (10–20 kPa), and 2.57 g of crude product were obtained. Chromatography through 60 of silica gel (0.04–0.063 mm) with a 95:5 (v/v) mixture of hexane and ethyl acetate afforded 1.19 g (4.7 mmol, 47% yield) of the pure product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[S-:14][C:15]#[N:16].[NH4+].[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[CH:21][CH:20]=1>CC(C)=O>[CH2:26]([O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:15]([NH:16][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[S:14])=[CH:31][CH:30]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCCCOC(=O)c1ccc(NC(=S)NC(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Naphthoyl chloride (190 mg, 1 mmol) is added to a solution of ammonium thiocyanate (200 mg, about 3 mmol) in acetone (5 ml) and stirred at room temperature for 1 hour. Butyl 4-aminobenzoate (180 mg, 0.93 mmol) is added to the reaction mixture. Stirring is continued overnight at room temperature. The solid, which forms is filtered and washed with water (2×5 ml) followed by acetone/hexane (3:1) (2×10 ml) and dried.
Reaction SMILES: C([O-])(=[O:3])C.[Cs+].Cl[CH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1>CN(C=O)C>[OH:3][CH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1
Reactant: O=c1[nH]c(CCl)nc2cc3c(cc12)CCC3
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(CO)nc2cc3c(cc12)CCC3
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of caesium acetate (14.4 g, 75.2 mmol) in dry DMF (40 ml) was heated to 60° C. under argon for 30 min. The mixture was cooled to 40° C. and a suspension of 2-chloromethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (L. Skelton, V. Bavetsias, A. Jackman, WO 00/050417-A1; 2.2 g, 9.4 mmol) in dry DMF (60 ml) was added via a cannula. The mixture was heated to 80° C. under argon for 16 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in water (50 ml) and MeOH (20 ml). The pH was adjusted to 12.5 with 1M sodium hydroxide solution and the brown suspension was stirred for 2 h at room temperature. The insoluble brown solid was removed by filtration and the resulting solution was acidified to pH 5 with 1M hydrochloric acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[C:11]([C:18]([CH3:23])([CH3:22])[CH:19]([NH2:21])O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.P([O-])(O)(O)=O.[Na+]>C(Cl)Cl>[C:11]([C:18]([CH3:23])([CH2:19][NH2:21])[CH:22]=[O:3])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)C(N)O
Reactant: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C)(C=O)CN
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A solution of oxalyl chloride (15.24 g, 120 mmol) in 200 mL of MeCl2 was stirred and cooled to −60° C. followed by the drop wise addition of dimethylsulfoxide (19.7 g, 252 mmol) in 60 mL of MeCl2. After 10 min, a solution of 2-Boc-amino-2-methyl-1-propanol (18.9 g, 100 mmol) in MeCl2 (60 mL) was added drop wise at −70° C. The reaction mixture was allowed to warm to −40° C. for 10 min followed by cooling to −70° C. before the addition of a solution of triethylamine (28.28 g, 280 mmol) in MeCl2 (60 mL). The reaction mixture was allowed to warm to room temperature over a two-hour period and 40 mL of saturated sodium dihydrogen phosphate was added. The organic layer was washed with brine and dried over MgSO4. The solvent was removed to yield 17.3 g of 2-Boc-amino-2-methylpropionaldehyde.