Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([SH:4])(S)[CH3:2].Cl[CH:6]([C:12]([CH3:14])=O)[C:7]([O:9]CC)=[O:8].C1(C)C=CC([S:21](O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:14][C:12]1[S:4][CH2:1][CH2:2][S:21][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(S)S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1=C(C(=O)O)SCCS1

Procedure:
Ethanedithiol (94 g) and ethyl alpha-chloroacetoacetate (164.5 g) were dissolved in benzene (500 g), a trace of p-toluenesulfonic acid added, and the whole solution refluxed under a Dean-Stark trap for one hour, when 16 cc of water had collected. The solution was cooled, washed with ice-cold dilute caustic soda and the benzene removed in vacuo. Ethanolic caustic soda (80 g in the minimum amount of ethanol) was added and the solution refluxed for 30 minutes, then cooled, diluted with water (one volume), and made acid with dilute HCl. The thick white precipitate was filtered, washed with water and recrystallized from ethanol to give 5,6-dihydro-3-methyl-1,4-dithiin-2-carboxylic acid as long white needles, m.p. 173°-175°, yield 92 g (52%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC.C(OCC)(=O)C>CN(C=O)C>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloronicotinic acid (2.00 g, 12.69 mmol) in DMF (40 mL) at 0° C. is added cesium carbonate (4.96 g, 15.23 mmol) followed by iodomethane (0.95 mL, 15.23 mmol). The reaction mixture is warmed to room temperature and stirred 16 h. Dilution with ethyl acetate is followed by washing with water, 8% NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 2-chloronicotinic acid methyl ester as an oil: 1H NMR (CDCl3, 300 MHz): δ 8.55 (1H, dd), 8.18 (1H, dd), 7.33 (1H, dd), 3.97 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[CH:42][C:43]([C:46]#[N:47])=[N:44][CH:45]=2)O1>>[C:46]([C:43]1[N:44]=[CH:45][C:40]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]2)=[CH:41][CH:42]=1)#[N:47]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(C#N)nc3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (47 mg, 0.093 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (26 mg, 0.200 mmol) to afford the crude product (47 mg) as a yellow solid: ESI MS m/z 514 [C30H35N5O3+H]+.
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.[Cl:59][C:60]1[CH:61]=[C:62]([NH2:67])[CH:63]=[CH:64][C:65]=1[Cl:66]>>[Cl:59][C:60]1[CH:61]=[C:62]([NH:67][C:35]2[CH:40]=[CH:39][C:38]([C:41]([C:43]3[CH:48]=[C:47]([N:49]4[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]4)[CH:46]=[CH:45][C:44]=3[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=2)[CH:63]=[CH:64][C:65]=1[Cl:66]
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2ccc(Cl)c(Cl)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3,4-dichloro-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.4, 146.4, 145.6, 142.0, 141.9, 141.6, 135.3, 134.9, 134.3, 132.1, 131.5, 131.0, 127.6, 122.5, 120.6, 120.5, 119.7, 118.6, 118.4, 112.2, 60.1, 29.1, 21.8, 18.8
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.BrBr.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(O)C.CO.O1CCOCC1>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a mixture of 3 ml of dioxane and 1 ml of methanol were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 10 minutes. To the reaction liquid were then added 7.5 g of 4-benzylpyridine, 100 ml of ethanol and 3.28 g of anhydrous sodium acetate, and the mixture was refluxed under heating for 5 hours. The reaction mixture was then treated in the same manner as described in Example 27, whereby 11.2 g (72.6%) of ifenprodil were obtained as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[CH3:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(O)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:20]=1[CH3:19]
Reactant: Cc1cccc(N)c1C
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(C)c3C)c2cc1OC
Temperature: 100 °C
Yield: 80.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 2,3-dimethylaniline (20 μl, 0.22 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 3.5 h. After cooling the reaction mixture was diluted with water (15 ml) and made alkaline with 1 M NaOH. The precipitate was collected by filtration, rinsed with water and dried to give the title compound (48 mg, 79%).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.[CH3:21][N:22]([CH2:24][C:25](O)=[O:26])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:25](=[O:26])[CH2:24][N:22]([CH3:23])[CH3:21])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CN(C)CC(=O)O
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), dimethylaminoacetic acid (4.05 mg, 0.0392 mmol), TBTU (17.2 mg, 0.0535 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.0002 mol) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.66 (br. s., 6H), 3.54 (br. s., 2H), 4.28 (s, 2H), 7.42-7.47 (m, 1H), 7.53 (td, J=7.7, 1.3 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H). MS (ES+): m/z=366.13 (100) [MH+]. HPLC: tR=2.43 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>CO>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])=[O:13]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)c1ccc(Cl)cc1Cl
Yield: 95.1 %

Procedure:
43.4 g (0.267 mol) of bromine was added dropwise to a solution of 50.5 g (0.267 mol) of 2′,4′-dichloroacetophenone in 100 g of methanol at a reaction temperature of 45 to 50° C. After the addition was complete, the methanol was evaporated off from the reaction solution under reduced pressure. The resultant concentrate was dissolved in 120 g of toluene and was then washed with water (100 ml×3 times). Thereafter, the toluene was distilled off under reduced pressure, giving 68.0 g (0.254 mol) of crude brown oily 2-bromo-2′,4′-dichloroacetophenone.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:34][CH3:35])[CH2:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OCC)(=O)C>CCCC(C)C>[CH:28]1([N:27]([CH2:26][CH:25]([O:34][CH3:35])[O:24][CH3:23])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[C:9]([C:7]3[N:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)[CH:10]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)nn1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cn(C(C)C)nn2)c1)C1CCCCC1)OC

Procedure:
The subtitled compound (230 mg) was prepared from 3-(3-(1-isopropyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoic acid [Example 12, Step ii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 4, Step v) and the elution gradient to 0 to 100% ethyl acetate in isohexane. MS [M+H-MeOH]+=441 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.71-7.61 (m, 2H), 7.32 and 7.31 (2×t, J=7.7 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 4.87 (septet, J=6.7 Hz, 1H), 4.51 and 4.36 (2×t, J=5.4 Hz, 1H), 4.03-3.94 and 3.69-3.60 (2×m, 1H), 3.76-3.66 (m, 4H), 3.34 and 3.25 (2×d, J=5.3 Hz, 2H), 3.34 (s, 3H), 3.31 (s, 3H), 2.91-2.85 (m, 2H), 2.68-2.61 (m, 2H), 1.79-1.01 (m, 10H), 1.61 (d, J=6.8 Hz, 6H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [C:1]([C:6]1[CH:26]=[CH:25][C:9]2[NH:10][C:11]([S:13][CH2:14][C:15]3[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][N:16]=3)=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C([O-])(O)=[O:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:6]1[CH:26]=[CH:25][C:9]2[NH:10][C:11]([S:13]([CH2:14][C:15]3[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][N:16]=3)=[O:28])=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ccc2[nH]c(SCc3nccc(OC)c3OC)nc2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc2[nH]c(S(=O)Cc3nccc(OC)c3OC)nc2c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
5--Carbethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (95.2% pure) (1.4 g, 0.0036 mol) was dissolved in CH2Cl2 (30 ml). NaHCO3 (0.6 g, 0.0072 mol in H2O (10 ml) was added and the mixture was cooled to +2° C. m-Chloroperbenzoic acid 69.5% (0.87 g, 0.0035 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring. Stirring was continued at +2° C. for 10 min. The phases were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN (15 ml ) giving the title compound (0.76 g, 54%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:33][C@@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][CH2:35]1>C1COCC1.C(Cl)Cl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([NH:33][C@@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:36][CH2:35]1)=[O:12])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-(3-(trifluoromethyl)-benzamido)acetic acid (277 mg, 1.12 mmol, 1.2 eq) and triethylamine (0.15 mL, 1.12 mmol, 1.2 eq) were dissolved in THF (15 mL) at room temperature under nitrogen. Cooled to 0° C. Added isobutyl chloroformate (0.16 μL, 1.12 mmol, 1.2 eq) dropwise. Stirred for 10 mintues followed by the dropwise addition of tert-butyl cis-4-amino-cyclo-hexylcarbamate (200 mg, 0.93 mmol, 1 eq) in THF ((5 mL). Warmed to room temperature. Worked up after 3 hours by adding methylene chloride (25 mL) and rinsing 3 times with saturated sodium bicarbonate (25 mL). The organic layer was dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 1:1 hexanes/ethyl acetate to give tert-butyl cis-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexylcarbamate (350 mg) as an oil. MS found: (M+Na)+=466.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@:9]45[CH2:22][C@@H:10]4[CH2:11][C:12](=[O:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@:9]45[CH2:22][C@@H:10]4[CH2:11][C@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@:9]45[CH2:22][C@@H:10]4[CH2:11][C@@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C[C@H]3C[C@@]312
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@H]3C[C@@]312
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)C[C@H]3C[C@@]312
Reaction time: 8 h

Procedure:
400 mg of 3-methoxy-14β,15β-methylene-estra-1,3,5(10)-triene-17-one dissolved in 300 ml of methanol are mixed with 380 mg of sodium borohydride at 0° C. and set aside overnight at room temperature. Subsequently the mixture is reduced to half its volume in vacuum and poured into cold aqueous acetic acid. The precipitate is dried, and preparative layer chromatography on silica gel (mobile phase: benzene/acetone 3:2) yields 90 mg of 3-methoxy-14β,15β-methylene-estra-1,3,5(10)-triene-17β-ol and 210 mg of 3-methoxy-14β,15β-methylene-estra-1,3,5(10)-triene-17α-ol. Flash point 117° to 119° C., specific optical rotation: [α]D25 +104.0° (c=1; CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([NH:27][CH2:28][CH2:29][NH2:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11]([NH:30][CH2:29][CH2:28][NH:27][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCN
Product: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)nc1NC(=O)OC(C)(C)C

Procedure:
Analogously to the preparation of Example 33A, 650 mg (2.3 mmol) of methyl 2-[(tert-butoxycarbonyl)amino]-6-chloropyridine-3-carboxylate (Example 51A) and 363 mg (2.3 mmol) of N-Boc-ethylenediamine gave 500 mg (50% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23](O)=[O:24].S(Cl)(Cl)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:24]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)N1CCN(C)CC1
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a mixture of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylic acid (5 g), dichloromethane (45 ml) and N,N-dimethylformamide (11 ml), thionyl chloride (2.1 g) was added at 7° C. under ice cooling. After stirring for 1.5 hours at the same condition, to a solution of N-methylpiperazine (3.7 g) in dichloromethane (37 ml), the reaction mixture was added under ice cooling and stirred for 2 hours. The reaction mixture was adjusted to pH=8.5 by saturated potassium carbonate and extracted with chloroform. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was distilled off to give a residue, which was chromatographed on alumina eluting with a chloroform. The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford 6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenyl-pyrimidine (3.5 g).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].CO.[H][H]>CO.O1CCCC1.C(C1C=C(C(C)(C)C)C2OP([C-]3C=CC=C3)OC3C(C(C)(C)C)=CC(C(C)(C)C)=CC=3C=2C=1)(C)(C)C.[C-]1(P2OC3C(C(C)(C)C)=CC(C(C)(C)C)=CC=3C3C=C(C(C)(C)C)C=C(C(C)(C)C)C=3O2)C=CC=C1.[Fe+2]>[CH3:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: [H][H]
Agent: [Fe+2]
Agent: CC(C)(C)c1cc(C(C)(C)C)c2op(-[c-]3cccc3)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(C)C(=O)OC
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 33 mg (0.031 mmol) of the ferrocenyl bis(phosphonite) prepared in Example 1 and 12 mg (0.031 mmol) of bis(bicyclo[2.2.1]hepta-2,5-diene)rhodium(I) perchlorate in 2 mL of methanol/tetrahydrofuran (1:1) solution is stirred for two hours. Then, to the resultant solution of rhodium complex is added a solution of 490 mg (3.1 mmol) of dimethyl itaconate and 13 mL of methanol in a pressure reactor. The reactor is then pressurized to 1018 psi with hydrogen and the reaction is stirred at ambient temperature for 88 hours. 1H nmr analysis of the reaction mixtures shows a 100% conversion of dimethyl itaconate starting material to product. Workup of the reaction mixture gives 492 mg (99% yield) of desired dimethyl 2-methylsuccinate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[C:14]([CH:16]=[CH:17][NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:15]=[C:14]([CH:16]=[CH:17][NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:26][CH:23]([CH3:25])[CH3:24])[CH:2]=[CH2:3]
Reactant: CC(C)N
Reactant: C=CCOc1cc(C=CNC(=O)OC)ccc1OCC1CO1
Solvent: CC(C)O
Product: C=CCOc1cc(C=CNC(=O)OC)ccc1OCC(O)CNC(C)C
Temperature: 80 °C

Procedure:
4.45 g (0.0146 mol) of 1-[2-allyloxy-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are heated with a solution of 1.26 ml (0.0146 mol) of isopropylamine in 100 ml of isopropanol for 3 hours under reflux to 80° C. The mixture is then evaporated under reduced pressure and the resulting crude base is crystallised from acetone-ether. 1-[2-Allyloxy-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylamino-propane of melting point 91°-92° is obtained. From this, the fumarate, melting point 169°-170° (after recrystallisation from methanol-isopropanol) is obtained after dissolving in isopropanol and adding the calculated amount of fumaric acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: COc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)cc1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.058 mMol 4-methoxybenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[F-:40].[K+].O>C(O)CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:15]2[C@H:16]([OH:21])[C@@H:17]([OH:20])[C@H:18]([OH:19])[C@@H:13]([CH2:12][F:40])[O:14]2)=[CH:23][C:24]=1[CH2:29][C:30]1[S:31][C:32]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=[CH:33][N:34]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](CF)[C@H]1O
Yield: 10.7 %

Procedure:
The solution of toluenesulfonate 90 (200 mg, 0.34 mmol) and potassium fluoride (23.5 mg 0.41 mmol) in ethylene glycol (3.5 mL) was stirred at 100° C. for 20 h. H2O was added to the reaction mixture and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the titled compound 94 (16 mg, 11%) as a solid.
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 87%).