Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:33](OCC)(=[O:39])[C:34](OCC)=[O:35]>CN(C=O)C>[CH2:10]([N:7]1[CH2:8][CH2:9][N:4]2[C:1](=[O:3])[CH:2]=[C:33]([OH:39])[C:34]([OH:35])=[C:5]2[C:6]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-1-benzylpiperazin-2-one (0.49 g, 2.1 mmol) in DMF (10 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (2.5 mL, 2.5 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with diethyl oxalate (0.43 mL, 3.1 mmol), and stirred at room temperature overnight. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (10 mL, 10 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:4](=[O:6])[C:3]4[CH:7]=[C:8]([N:11]([CH3:13])[CH3:12])[CH:9]=[CH:10][C:2]=4[Cl:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CN(C)c1ccc(Cl)c(C(=O)O)c1
Product: CN(C)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-chloro-5-dimethylaminobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (53% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.96, 7.39, 6.94, 6.66, 6.55, 4.14-3.32, 2.93, 1.52, 0.75-0.69, 0.48-0.42, 0.11-0.05. MS (ES+) m/z 457.4 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:7]=2)[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(-c3ccccc3)n2)cc2cn[nH]c12
Temperature: 140 °C
Yield: 81.7 %

Procedure:
To a microwave tube charged with (±)-N-(1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (24.6 mg, 0.0418 mmol, 1.0 equiv) was added phenyl boronic acid (7.1 mg, 0.0585 mmol, 1.4 equiv), Pd(PPh3)4 (4.8 mg, 0.1 equiv), toluene (1 mL), ethanol (0.2 mL), and potassium carbonate solution (2M, 0.085 mL). The vial was sealed and heated by microwave at 140° C. for 30 min. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. Flash column chromatography (10% methanol/methylene chloride) afforded the desired product (20 mg, 81.6%) as an off-white solid: MS (ESI) [M+H]+=586. 1H-NMR (400 MHz, CDCl3) δ 8.00-7.86 (m, 3H), 7.65-6.82 (m, 12H), 6.74 (d, J=7.2 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.32 (br., 1H), 5.35-5.20 (m, 1H), 4.62-4.48 (m, 1H), 4.30-4.08 (m, 4H), 3.40 (dd, J=13.2 and 4.2 Hz, 1H), 3.13 (dd, J=13.2 and 8.4 Hz, 1H), 3.02-2.83 (m, 2H), 2.42 (s, 3H), 1.80-1.55 (m, 4H). HPLC tR=1.51 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][C:27]1[C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[N:23][CH:24]=[C:25]([N+:29]([O-:31])=[O:30])[CH:26]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cnc1OC1CCNCC1
Temperature: 22 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Add trifluoroacetic acid (150 mL) to a cold solution of 4-(3-methyl-5-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (10.12 g, 30 mmol) in dichloromethane (450 mL). Stir the reaction mixture at 22° C. for 60 min. After removal of solvent, treat the residue with 1 N sodium hydroxide (150 mL) and extract with dichloromethane and ethyl acetate. Dry the combined organic phases over sodium sulfate. Removal of solvent provides 3-methyl-5-nitro-2-(piperidin-4-yloxy)-pyridine as a yellow solid (6.9 g, 97% yield). MS(ES): m/z=238.2 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([OH:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[O-:29][C:30]#[N:31].[K+]>O>[C:30]([NH:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]([OH:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:13]=2)=[CH:10][CH:11]=1)=[O:4])(=[O:29])[NH2:31]
Reactant: N#C[O-]
Reactant: NCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)NCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of 0.928 g (3.2 mmol ) of 2-[4-(N-glycylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid and 25 ml of water is treated with 1 ml (7.2 mmol) of triethylamine followed by 1.3 g (16 mmol) of potassium cyanate. After standing at room temperature overnight a 0.5 g (6.2 mmol) portion of potassium cyanate is added and the reaction mixture is allowed to stand at room temperature for another 18 hrs. The solution is concentrated in vacuo to 1/3 its volume and acidified to pH 2.5 with hydrochloric acid. The product is filtered, washed with water, ethanol, and ether to give 1.0 g of 2-[4-(N-carbamoylglycylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:16])[CH:11]=[CH:12][CH:13]([CH3:15])[CH3:14].[H][H].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:16])[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(C(=O)CCC(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
Undernitrogen, 2.8 g of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone was dissolved in ethyl acetate and 0.14 g of 5% palladium/carbon was added thereto. The nitrogen in the reaction vessel was substituted by hydrogen and the reaction mixture was stirred at room temperature for 5 hours. After that, the reaction mixture was filtered through a Celite pad and the Celite pad was washed with 50 ml of ethyl acetate. The solution combined the filtrate with the washing solution was washed with 0.1% hydrochloric acid once, water twice and saturated brine once, subsequently. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to give 2.68 g of 4-hydroxy-6-methyl-3-(4-methylpentanoyl)-2-pyrone.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC.[F-].[K+]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (600 mg, 3.13 mmol) in dry DMF (10 mL) under N2 were added tributyl(1-ethoxyvinyl)stannane (1.09 mL, 3.23 mmol) and Pd(PPh3)2Cl2 (113 mg, 0.161 mmol). The mixture was stirred at 100° C. for 3 h and at rt for 16 h. The mixture was diluted with ether (20 mL), and treated with aqueous KF solution (5 g of KF in 3 mL of water). The mixture was stirred vigorously for 1 h at room temperature before being filtered through diatomaceous earth. The filtrate was washed with satd aq NaHCO3 and brine. The aqueous phase was extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 2-chloro-5-(1-ethoxyvinyl)pyrimidine (350 mg, yield 61%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([Cl:32])=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[ClH:32].[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:31])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 69.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 0.94 ml (4.96 mmol) of 4-n-butoxybenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.10 g of the desired compound (free base) (76.9%, colorless powder), mp: 98.0°-99.0° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][CH:41]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 171. (400 MHz CDCl3): 1.21 (6H, s, ar), 2.56 (8H, b, CH2), 2.80 (3H, d (J=5.03), CH3), 3.82 (2H, s, ar), 3.87-3.89 (4H, m, CH2), 4.01-4.04 (4H, m, CH2), 4.61 (1H, s, NH), 6.56 (1H, d (J=8.40), ar), 7.15 (1H, d, ar), 8.45-8.47 (1H, m, ar), 9.15 (1H, s, ar). MH+511.52
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2C2C=CC(C([O-])=O)=CC=2)=[CH:12][C:11]=1[N+:31]([O-:33])=[O:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[C@H]([O:42]C1C=CC(OC(=O)C2C=CC=CC=2)=CC=1[N+]([O-])=O)CCCCCC>>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:42])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[N+:31]([O-:33])=[O:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: CCCCCC[C@H](C)Oc1ccc(-c2ccccc2-c2ccc(C(=O)[O-])cc2)cc1[N+](=O)[O-]
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1[N+](=O)[O-]

Procedure:
The benzoyl ester of (S)-4'-(1-methylheptyloxy)-3'-nitro-4-biphenylylbenzoate was saponified using the same procedure as that used for saponification of (S)-[4-(1-methylheptyloxy)-3-nitrophenyl]-benzoate except that the reaction was carried out at 60° C. to give (S)-4'-(1-methylheptyloxy)-3'-nitro-4-hydroxybiphenyl (Compound 17, Scheme II, R2 =(S)-OCH(CH3)C6H13) as a very viscous orange liquid after flash chromatography with hexanes/ethyl acetate [88/12]; Rf [hexanes/ethyl acetate 85/15]: 0.17; 1H NMR (300 MHz, CDCl3): δ o.86(t, 3 H, J=6.6 Hz), 1.18-1.52(m, 8 H), 1.35(d, 3 H, J=6.1 Hz), 1.62(m, 1 H), 1.78(m, 1 H), 4.50(m, 1 H), 5.22(broad s, 1 H), 6.89(d, 2 H, J=8.5 Hz), 7.07(d, 1 H, J=8.8 Hz), 7.39(d, 2 H, J=8.5 Hz), 7.62(dd, 1 H, J=2.4 Hz, J=8.8 Hz), 7.92(d, 1 H, J=2.4 Hz); 13C NMR (300 MHz, CDCl3): δ 13.99, 19.49, 22.50, 25.19, 29.10, 31.65, 36.17, 76.57, 115.94, 116.17, 123.30, 127.99, 131.21, 131.64, 133.09, 141.00, 15.42, 155.52; IR (CHCl3); 350, 3300(broad), 3020, 2920, 2840, 1610, 1540, 1510, 1485, 1350, 1260, 1220, 1160, 1110, 1040, 925, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 343(M+ 5), 231(100), 185(6), 57(6), 43(12).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CN(C)[CH:32]=[O:33]>O1CCCC1.CCCCCC>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][C:23]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
A solution of 68 ml (0.4 mol) of 2,2,6,6-tetramethyl- piperidine in 1 l of tetrahydrofuran is cooled under argon to -10° and at this temperature there are added dropwise thereto while stirring 250 ml of a 1.6M solution of n-butyllithium in hexane. Subsequently, 62 ml (0.4 mol) of 1,3-bis(trifluoromethyl)-benzene are added dropwise thereto at -10° within 5 minutes. The resulting wine-red solution is stirred at -10° for a further 5 minutes and then 62 ml (0.8 mol) of N,N-dimethylformamide are allowed to flow in rapidly. The internal temperature rises by 15° as a consequence of the exothermic reaction. The dark brown solution obtained is then added slowly and under a slight argon pressure to 1.2 l of stirred, ice-cold 1M hydrochloric acid. The internal temperature rises to 10° as a consequence of the stongly exothermic reaction in spite of constant cooling. The resulting emulsion is diluted with 750 ml of hexane, the aqueous phase (1.5 l) is separated and stored for the recovery of 2,2,6,6-tetra- methylpiperidine. The organic phase (1.9 l) is extracted twice with 1 l of water each time, dried over sodium sulphate, filtered and the organic solvent is distilled off at 40° under a vacuum (20 kPa). The residue (about 100 ml) is distilled over a column having a length of 20 cm, firstly at 50° bath temperature under a vacuum of 20 kPa in order to remove the residual solvent, then the bath temperature is increased to 80° and the vacuum is increased to 1.4 kPa. A forerun is removed until the constant internal temperature of 57° has been reached and then the residue distils over as a fraction at 57°/1.4 kPa. There are obtained 68 g (70%) of 2,4-bis(trifluoromethyl)benzaldehyde with a purity (GC) of 96-98%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].CO[C:11]([CH3:13])=[CH2:12]>CC(C)=O.S(=O)(=O)(O)O>[CH3:4][C:3]1([CH2:7][OH:8])[CH2:5][O:6][C:11]([CH3:13])([CH3:12])[O:1][CH2:2]1
Reactant: C=C(C)OC
Reactant: CC(CO)(CO)CO
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1,1,1-Tris(hydroxymethyl)ethane (120.2 g) and 2-methoxypropene (75.0 g) were suspended in acetone (300 ml). After adding one drop of conc. sulfuric acid at 0° C., the mixture was stirred for 1 hour and then at room temperature for additional 2 hours. After distilling off the acetone, a fraction obtained under reduced pressure (1.7 mmHg) at 70° C. was collected to give (1,4,4-trimethyl-3,5-dioxanyl)methan-1-ol (155.2 g).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:55][C:56]1[CH2:57][CH2:58][CH2:59][CH2:60][N+:61]=1[O-:62]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:62][N:61]4[CH2:60][CH2:59][CH2:58][CH2:57][C@:56]4([CH3:55])[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=[N+]([O-])CCCC1
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@@]4(C)CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 18.6 %

Procedure:
To a solution of 0.500 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 25 ml of toluene is added 0.201 g of 2,3,4,5-tetrahydro-6-methyl-pyridine 1-oxide and the reaction mixture heated at reflux for 12 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 1:2 ethyl acetate-hexanes to give 0.108 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.[C:14]1([CH2:20]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cnc2[nH]ccc2c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-Carboxylic acid (343 mg) in N,N-dimethylformamide (4 ml) was added phenylmethanol (375 μl) 4-dimethylaminopyridine (428 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (676 mg). After stirring at ambient temperature for 3 days, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform to give benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (200 mg) as a yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:35])[C@H:11]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:12][C:13](=[O:24])[CH:14]([CH2:19][S:20]C(=O)C)[CH2:15][CH2:16][CH2:17][NH2:18].[OH-].[Na+].[H][H]>CO>[NH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][SH:20])[C:13]([NH:12][C@H:11]([C:10]([OH:35])=[O:9])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:24]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCN)CSC(C)=O
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCCCC(CS)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
To a solution of N-(2-acetylthiomethyl-5-aminopentanoyl)-L-tryptophane methyl ester trifluoroacetate (3 g) in methanol (60 ml) N sodium hydroxide (60 ml) is added. After four hours the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. After washing with water, the N-(5-amino-2-mercaptomethylpentanoyl-L-tryptophane is eluted with pyridine-acetic acid buffer at pH 6.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:17]=[C:18]=[O:19])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[NH:21]1[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][C:18]([N:21]1[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23])=[O:19])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:2]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)N=C=O
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)n1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h

Procedure:
The reaction solution from Example 10 is placed in a flask and to this is added thymine (12.6 g, 0.1 mol) . The resulting solution is allowed to stir for 12 hours, then is evaporated to a solid, which is purified by column chromatography using dichlormethane:ethanol as the eluent.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]([CH2:12]O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:29])=O.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]([CH2:12][Cl:29])=[N:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccccc1-n1c(CCl)nnc1-c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
[5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl]methanol (1.81 g) was suspended in toluene (25 ml), followed by addition of thionyl chloride (1.5 ml) and chloroform (25 ml), and stirred at 60° C. for 5 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting white solid was washed with a mixture solution of n-hexane and ethyl acetate, to afford the entitled compound as white solid (1.54 g, 81%). The physico-chemical values are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Product: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.