Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>>[CH2:44]([O:43][C:41]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:17]1[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=1)=[O:42])[CH3:45]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Product: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)OCC)cc1
Yield: 99.4 %

Procedure:
2-(4-Octyloxyphenyl)-4,5-diphenylimidazole (2.5 g) was reacted with ethyl 8-bromooctanoate (2.96 g) in a method similar to Example 9. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 1-(7-ethoxycarbonylheptyl)-2-[4-octyloxyphenyl]-4, 5-diphenylimidazole (3.48 g, 94%) as an oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]([CH2:27][CH:28]=O)[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:28][CH2:27][N:16]([CH3:15])[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56]
Reactant: COCCNCCOCCOCCOCCOCCOCCOCCOC
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCN(CCOC)CCN(C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
Sodium triacetoxyborohydride (2.21 g, 10.4 mmol) was added portionwise at room temperature to benzyl methyl(2-oxoethyl)carbamate (1.66 g, 8.03 mmol), N-(2-methoxyethyl)-2,5,8,11,14,17,20-heptaoxadocosan-22-amine 135c.2 (3.19 g, 8.03 mmol), and acetic acid (0.92 mL, 16.1 mmol) in THF (50 mL). The mixture was stirred for 2 hours, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (Mg2SO4) and evaporated. The residue was purified by PTLC (10% methanol/20% ethyl acetate/dichloromethane) to give product as an oil (2.58 g, 55%); MS for C29H52N2O10 m/z 589 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)([O-:3])=[O:2].Cl.[NH2:20][OH:21].Cl>[OH-].[K+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([CH:17]=1)[C:9](=[N:20][OH:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(O)c(C(=NO)c2ccccc2)c1
Reaction time: 5 h

Procedure:
Into an autoclave, were charged 30 g of 2-chloro-5-nitrobenzophenone, 300 ml of water, and 9.70 g of potassium hydroxide. The mixture was allowed to react at 150° to 160° C. with stirring for 5 hours. Upon cooling to room temperature, there was obtained a clear liquid, reddish orange in color. The liquid was further cooled below 0° C. and strongly acidified with cold concentrated hydrochloric acid. The precipitated solids were collected by filtration, washed with water, and recrystallized from ethanol to yield 15.7 g (56.1%) of 5-nitro-2-hydroxy-benzophenone having a melting point of 122°-123° C. To 150 ml of 40-% aqueous potassium hydroxide solution, was added 25.0 g of 5-nitro-2-hydroxybenzophenone followed by 50 g of hydroxylamine hydrochloride. After 5 hours, the resulting clear liquid was cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was washed with water and a small volume of 50-% aqueous methanol, then dried in air, and recrystallized from benzene and petroleum ether to yield 5-nitro-2-hydroxybenzophenone oxime.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([O-:13])([O-])[O:9][CH2:10][CH3:11].[F:14][CH:15]([F:37])[O:16][C:17]1[C:18]([F:36])=[C:19]([C:28]([N+:33]([O-:35])=[O:34])=[C:29]([F:32])[C:30]=1[F:31])[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=O)=[O:21]>>[F:37][CH:15]([F:14])[O:16][C:17]1[C:18]([F:36])=[C:19]([C:28]([N+:33]([O-:35])=[O:34])=[C:29]([F:32])[C:30]=1[F:31])[C:20]([C:22](=[CH:23][O:25][CH2:26][CH3:27])[C:8]([O:9][CH2:10][CH3:11])=[O:13])=[O:21]
Reactant: CCOC(=O)CC(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
38 ml of acetic anhydride and 11 ml of ethyl orthoformate were added to the whole of the ethyl 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoylacetate [(XV), R1 =--OCHF2, R3' =NO2, R17 =C2H5, X=X'=F] prepared as described in step (b) above, and then the mixture was heated under reflux for 3 hours; the excess acetic anhydride and ethyl orthoformate were then removed by evaporation under reduced pressure, to give 20.6 g of ethyl 2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)-3-ethoxyacrylate as a red liquid.
Reaction SMILES: C(O[C:4]([C@H:6]1[C@@H:11]([N:12]([C:18](=[O:33])[CH2:19][C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([I:30])=[CH:29][C:23]=3[S:22](=[O:32])(=[O:31])[N:21]=2)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]2[CH2:34][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C>[OH:5][C:4]1[C@H:6]2[C@H:11]([C@H:10]3[CH2:34][C@@H:7]2[CH2:8][CH2:9]3)[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:18](=[O:33])[C:19]=1[C:20]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([I:30])=[CH:29][C:23]=2[S:22](=[O:32])(=[O:31])[N:21]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Temperature: 60 °C
Reaction time: 6 h
Yield: 36.6 %

Procedure:
The crude (1S,2R,3S,4R)-3-[[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.546 mmol) was dissolved in ethanol (5 mL), and a 21 wt. % solution of sodium ethoxide in ethanol (1 mL, 2.73 mmol) was added into the above solution. The mixture was stirred at 60° C. for 6 h and allowed to cool to 25° C. The mixture was poured into 0.5 M aqueous hydrochloric acid solution (100 mL). The product started to precipitate and was collected by vacuum filtration. The precipitate was purified by flash column chromatography (Teledyne Isco RediSep column; 40% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(3-methyl-butyl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.122 g, 0.2 mmol, 40.3% over two steps), as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.92 (6H, d, J=5.4 Hz), 1.16-1.63 (9H, m), 2.99-3.12 (2H, m), 3.62-3.71 (2H, m), 7.37 (1H, d, J=8.3 Hz), 7.99 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 8.08 (1H, s). LC-MS (ESI) calcd for C22H26IN3O4S 555.07, found 556.3 [M+H+].
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].C1C2C(=CC=CC=2)CCC1C([Cl:36])=O>>[CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:36])=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccc(C(=O)O)cc1)C1CCc2ncsc2C1
Reactant: O=C(Cl)C1CCc2ccccc2C1
Product: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1

Procedure:
4-{[Propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amino]-methyl}-benzoyl chloride (42C) is prepared from 42B as described for 23A. The crude product is obtained in almost quantitative yield.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH2:8]=[O:9]>ClCCl.[OH-].[Na+]>[OH:9][CH2:8][NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: C=O
Reactant: CC(C)(C)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a mixture of 2,2-dimethylpropanamide (5.0 g, 49.4 mmol, 1.0 equiv) and aqueous sodium hydroxide (1 M, 0.494 mL, 0.494 mmol, 0.01 equiv), add aqueous formaldehyde (13.31 M, 3.71 mL, 49.4 mmol, 1.0 equiv). Stir at room temperature for 2 h, and concentrate under reduced pressure to give a white solid. Dilute the crude material with dichloromethane, dry over MgSO4, filter, and concentrate under reduced pressure to give the title compound as a white solid (6.4 g, 99%). 1H NMR (DMSO-d6, 400 MHz): δ 8.14 (br s, 1H), 5.40 (t, 1H, J=6.7 Hz), 4.46 (app t, 2H, J=6.6 Hz), 1.06 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:25][NH2:26]>C1COCC1>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:25][NH2:26])=[O:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)COc1ccc(Br)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)COc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of (4-bromophenoxy)acetic acid (1.0 g, 4.3 mmol) in THF (15 mL) was added N,N-Carbonyldiimidazole (0.84 g, 5.2 mmol). After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was added to the reaction mixture slowly with a syringe at 0° C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as a white solid. LCMS calculated for C8H10BrN2O2 (M+H): 245.0. found: 244.9, 246.9.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)=[O:30])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Product: COc1cccc(NC(=O)Nc2ccc(OCCN(C)C)c(-c3ccnn3C)c2)c1
Yield: 71.1 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 3-methoxyphenyl isocyanate (13.8 μL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 146 as a colorless waxy solid in 71.1% yield. LCMS m/z (%)=410 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.70 (s, 1H), 8.63 (s, 1H), 7.45-7.42 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.18-7.10 (m, 3H), 6.91 (dd, J=8.02 Hz, 1.2 Hz, 1H), 6.53 (dd, J=7.71 Hz, 2.05 Hz, 1H), 6.24 (d, J=1.83 Hz, 1H), 4.03 (t, J=5.80 Hz, 2H), 3.72 (s, 3H), 3.67 (s, 3H), 2.52 (t, J=5.80 Hz, 2H), 2.12 (s, 6H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].[CH2:10]=[O:11].[K]>C(O)C>[OH:11][CH2:10][N:7]1[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]1=[O:9]
Reactant: CCCC1CNC(=O)C1
Reactant: C=O
Agent: [K]
Solvent: CCO
Product: CCCC1CC(=O)N(CO)C1
Yield: 100 %

Procedure:
A solution of 4-propylpyrrolidin-2-one x1 (30 g, 0.236 mol), aqueous formaldehyde (37%, 3.5 eq, 0.826 mol, 71 ml), and potassium hydroxyde (0.05 eq, 0.012 mol, 0.662 g) in 150 ml of ethanol is refluxed for 24 hours. After evaporation of the solvent under reduced pressure, the crude product is poured in saturated NaHCO3 aqueous solution and then extracted with CH2Cl2. The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure to yield compound 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[NH4+].[Cl-]>[NH4+].[Cl-].CO.[Zn]>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1N
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of 5-amino-3-(4-nitrophenyl)isothiazole-4-carboxamide (63 mg, 0.24 mmol), 12 drops saturated aqueous NH4Cl, and catalytic Zn powder in 4 mL MeOH was rapidly stirred at rt. After 1.5 hours additional saturated aqueous NH4Cl (6 drops) and catalytic Zn powder was added and the reaction heated at 55° C. Then additional solid NH4Cl and catalytic Zn powder was added to push the reaction to completion. At 4 hours the reaction was filtered using Celite and the solids rinsed with MeOH and EtOAc, the filtrate evaporated and treated to an aqueous workup using EtOAc and saturated aqueous NaHCO3 to give a yellow gummy solid. This material was triturated with 20% EtOAc/hexane to give the title compound as a yellow-beige solid (53 mg, 94%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O[C:13](=[O:20])[C@H:14](CC(C)C)N)C.[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH2:24][S:25][CH3:26]>>[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH2:24][S:25][CH3:26].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]1[CH:6]=[CH:14][C:13]([OH:20])=[CH:22][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CSCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The papain-catalyzed synthesis of leucine and HMB co-oligomers was performed. Synthesis of leucine oligomers and HMB-leucine co-oligomers was initiated with leucine ethyl ester and HMB ethyl ester as the substrates. The overall synthesis and purification approach was similar to the one used in the case of methionine and HMB-methionine. Reaction rates similar to those obtained with methionine and tyrosine were achieved. Approximate oligomer yield was 58%. The freeze-dried oligomer precipitates were solubilized in DMSO. The solution concentration was brought to approximately 2 μg/μl The solution was mixed with 1:1 acetonitrile:water mixture containing 0.1% acetic acid. The total fluid volume entering the ESI-MS was maintained at 0.2 mL min.−1 The positive mass spectrum of the leucine oligomers is shown in FIG. 33A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[N:14]1[CH2:15][CH2:16][CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 33.1 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 3,4,5-trichloropyridine (141 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (51 mg), a white solid, in 33% yield.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][C@H:22]([C@H:34]([CH3:38])[CH2:35][CH2:36][CH3:37])[CH:23]=[N:24][S:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[C:17]([O:16][C:13](=[O:15])[CH2:14][C@@H:23]([NH:24][S:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26])[C@H:22]([CH3:21])[C@H:34]([CH3:38])[CH2:35][CH2:36][CH3:37])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCC[C@@H](C)[C@@H](C)C=NS(=O)c1ccc(C)cc1
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OC(C)(C)C)NS(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
Butyl lithium (26.3 mL, 42.04 mmol) was added to a solution of diisopropylamine (4.6 g, 45.6 mmol) in dry THF (40 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. followed by the addition of t-butyl acetate (4.1 g, 35.0 mmol) and stirred at that temperature for 45 minutes. Chlorotitanium triisopropoxide (9.4 g, 36.2 mmol) was added dropwise and stirring was continued for 30 minutes at −78° C. A −50° C. solution of 4-methyl-benzenesulfinic acid ((2R,3R)-2,3-dimethyl-hexylidene)-amide (3.1 g, 11.7 mmol) in dry THF (10 mL) was added to the reaction and the resulting mixture was stirred at −78° C. for 4 hours. The reaction was quenched with a saturated solution of NaH2PO4 and extracted into ethyl acetate. The solution was dried over MgSO4 and concentrated. The resulting residue was chromatographed on silica, eluting with 15% ethyl acetate in hexane to give the titled compound (2.4 g, 53.9% yield) as white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 6H) 1.0 (d, J=6.6 Hz, 3H) 1.1 (m, 1H) 1.3 (m, 2H) 1.4 (m, 9H) 1.5 (m, 2H) 2.4 (s, 3H) 2.6 (m, 2H) 3.8 (m, 1H) 4.4 (d, J=10.0 Hz, 1H) 7.3 (d, J=8.1 Hz, 2H) 7.6 (d, J=8.1 Hz, 2H). MS, m/z (relative intensity): 382 [M+1H, 100%], 326 [M+1H—C(CH3)3, 50%].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: ClCc1ccncc1
Reactant: CCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(OCc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-diethylurea, 83 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 57 mg (yield 56%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11](OC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)=O
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chlorophenylhydrazine hydrochloride (CAS No. 2312-23-4) (14.2 g) in acetic acid (60 mL) was added methyl acetoacetate (10.70 mL). The reaction was allowed to stir overnight at 60° C. and the volatiles were removed under reduced pressure and partitioned between saturated sodium bicarbonate and EtOAc. The organic layer was separated and concentrated under reduced pressure and purified by silica gel column chromatography using a gradient of 0-75% EtOAc in heptanes. The resulting solid was triturated with heptanes to give the title compound (10.3 g) having the following physical data as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.1 g, 10 mmol), o-tolylboronic acid (1.5 g, 1.1 eq), tetrakis(triphenyl-phosphine)palladium (575 mg, 0.05 eq), and sodium carbonate (5.5 g, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-o-tolylquinoline-3-carbaldehyde was obtained as white solid. 1H-NMR (CDCl3) 9.96 (s, 1H), 8.83 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.74 (d, J=6.3 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.36-7.46 (m, 4H), 2.84 (s, 3H), δ 2.30 (s, 3H). Mass Spectrum (ESI) m/e=262 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH2:4][CH2:3]1.[CH3:18][N:19]1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1=[O:25]>C1(C=CC(O)=CC=1)O.C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH:9]2[CH:8]=[C:6]3[CH:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH2:7]3)[CH:21]3[C:20](=[O:25])[N:19]([CH3:18])[C:23](=[O:24])[CH:22]23)=[CH:15][CH:14]=1
Reactant: COc1ccc(C=CC2=CCCN(C)C2)cc1
Reactant: CN1C(=O)C=CC1=O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2C=C3CN(C)CCC3C3C(=O)N(C)C(=O)C23)cc1
Yield: 35.5 %

Procedure:
A solution of 15 g (0.065 moles) 1,2,3,6-tetrahydro-1-methyl-5-p-methoxystyrylpyridine (free base), 15 g N-methylmaleimide, 150 ml toluene and 20 mgs hydroquinone is refluxed under nitrogen overnight. The solution is allowed to cool and evaporate. Benzene is added and evaporated twice. Water is added, and the oil is extracted with benzene. The organic layers are evaporated. The residue crystallizes and filtration and washing with ether yields 7.85 g 3a,4,6,7,8,9,9a,9b-octahydro-4-(p-methoxyphenyl)-2,7-dimethyl-2H-pyrrolo[3,4-f]-isoquinoline-1,3-dione. Chromatography of the mother liquor on basic alumina (activity II) yields an additional 3.2 g (50%) cyrstals.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].CC(C)([O-])C.[K+].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+].II.S([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C.O>[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:4][N+:1]([O-:3])=[O:2])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccc(I)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: II
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])CS(=O)(=O)c1ccc(I)cc1
Reaction time: 0.5 h
Yield: 2.4 %

Procedure:
Nitromethane (12.0 g, 100 mmol) was added dropwise to a stirred solution of potassium t-butoxide (20 g, 178 mmol) in dry DMF (200 ml), the temperature being controlled at 0°-5° C. by external cooling. After addition was complete the mixture was stirred for an additional 30 minutes at 0°-5° C. Sodium 4-iodobenzenesulphinate (29.0 g, 100 mmol) was then added, followed by iodine (22.8 g, 90 mmol). The mixture was stirred at ambient temperature for 2 hours and then poured into water (3 liters). A concentrated solution of aqueous sodium sulphite was added to partially decolourise the reaction mixture, which was then acidified with 2M hydrochloric acid. The precipitated solid was collected by filtration, washed with water and then recrystallised 4 times from ethanol to give (4-iodophenylsulphonyl)nitromethane as a crystalline solid (0.8 g), m.p. 177°-179° C., microanalysis, found C, 25.56; H, 1.83; N, 4.18% C 7 H6INO4S requires: C, 25.70; H, 1.85; N 4.30%.