Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][NH:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=2[CH3:23])=[CH:10][CH:9]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][NH:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][C:17]=2[CH3:23])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCNC(=O)c1ccc(OCc2ccc(Br)cc2C)cc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2C)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
A mixture of 3-[4-(4-bromo-2-methyl-benzyloxy)-benzoylamino]-propionic acid methyl ester (0.20 g, 0.49 mmol), phenyl boronic acid (0.09 g, 0.78 mmol), and Na2CO3 (0.11 g, 1.08 mmol) in toluene/water (3 mL: 1 mL) is degassed (2×). Pd(PPh3)4 (0.05 g, 0.04 mmol) is added, and the mixture is stirred at 100° C. for 12 h. The mixture is filtered through Celite. Water is added, and the mixture is extracted with EtOAc. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield 0.20 g (100%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[NH:15][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[N:15]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:16]=1[CH:17]=[O:18]
Reactant: Cc1nc(Br)c(C=O)[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(Br)c(C=O)n1Cc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
4-Cyanobenzylbromide (1.05 g, 5.39 mmol) was added to a solution of 4-bromo-2-methylimidazole-5-carboxaldehyde (1.02 g, 5.39 mmol) in dimethylacetamide (15 mL). The solution was cooled to -10° C. and powdered potassium carbonate (0.745 g, 5.39 mmol) added. The reaction was stirred at -10° C. for 2 h, and a further 4 h at 20° C. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. Solvent evaporation yielded a white solid. 1H NMR (CDCl3, 400 MHz) δ 9.68 (1H, s), 7.64 (2H, d, J=7 Hz), 7.15 (2H, d, J=7 Hz) 5.59 (2H, s), 2.40 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:24]([CH2:37][CH2:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH2:22][CH3:23]>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26][CH2:25][N:24]([CH2:21][CH2:22][CH3:23])[CH2:37][CH2:38][CH3:39])[CH2:33][CH2:32]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Solvent: CC#N
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 22 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 22% of theory. Colourless crystals, m.p. 174°-175° C. (acetonitrile).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:18][C:19]1[CH:20]=[C:21]([CH:26]([CH:31]2[CH2:34][NH:33][CH2:32]2)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:23]([F:25])[CH:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:33]2[CH2:34][CH:31]([CH:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)[C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:32]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A mixture of 263 mg (0.86 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 213 mg (0.574 mmol) of 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidine and 300 uL (1.72 mmol) of N,N-diisopropylethylamine in 6 mL of acetonitrile was heated to reflux for 3 h. Then the solution was concentrated and the residue was dissolved in 5 mL of hexane/ether. 1.5 mL of 1N HCl in ether was added to above solution to make salt. It was filtered and washed with hexane/ether. The residue was neutralized with base and was purified by silica gel chromatography with hexanes/ethyl acetate to afford one racemic diastereomer of the title compound; Mass Spectrum: m/e=465 (M+1 35Cl) and 467 (M+1 37Cl).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[C:2]([O:4]C)=O.[CH2:12]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li+].CC([N-]C(C)C)C.Cl>O1CCCC1>[CH2:12]([O:19][CH:20]([C:2](=[O:4])[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:21]([O:23][CH3:24])=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(=O)OC(C)(C)C
Reactant: COC(=O)COCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(OCc1ccccc1)C(=O)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
tert-Butyl methyl oxalate (34 g, 210 mmol) and methyl (benzyloxy)acetate (35 g, 190 mmol) were dissolved in tetrahydrofuran (250 mL) and a solution of LDA in tetrahydrofuran prepared at −78° C. was added dropwise under a nitrogen atmosphere, followed by stirring at the same temperature for 3 hours. The temperature of the reaction solution was gradually raised to −40° C., and subsequently hydrochloric acid (2 M, 210 mL) was added, followed by extraction with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford 4-tert-butyl 1-methyl 2-(benzyloxy)-3-oxosuccinate (62 g) as a yellow oil.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH-].[Na+].[CH3:9][N:10]1[C:18]([S:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1.[Li+]>O>[CH3:9][N:10]1[C:18]([S:19]([NH2:1])(=[O:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1
Reactant: Cn1nc2ccccc2c1S(=O)[O-]
Reactant: NOS(=O)(=O)O
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc2ccccc2c1S(N)(=O)=O
Temperature: 10 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution containing 9.5 g (72 mmol) of 2-methyl-2H-indazole in 200 ml of ethyl ether, was cooled to -30° C., and 61.4 g (144 mmol) of n-butyl lithium (a 15% hexane solution) was dropwise added thereto. The mixture was stirred for one hour at the same temperature, and then an excess amount of sulfurous acid gas was blown thereinto for 3 hours at a temperature of not higher than -20° C. After completion of the reaction, the mixture was returned to room temperature, stirred for 12 hours and then diluted with ethyl ether. The product was subjected to filtration. The crystals were dried to obtain crude lithium 2-methyl-2H-indazole-3-sulfinate. This product was used for the subsequent reaction without purification. 48.8 g (430 mmol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 17.2 g (430 mmol) of sodium hydroxide in water (300 ml) under cooling with ice (not higher than 10° C.). This solution was added all at once to a solution containing the crude lithium 2-methyl-2H-indazole-3-sulfinate previously prepared in water (100 ml), and then the mixture was stirred for 12 hours at room temperature. Formed crystals were collected by filtration to obtain 8.8 g (yield: 58%) of 2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 181°-183° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C1CCCCC1.[CH2:25]([O:32][C:33]1[C:34]([CH2:44][CH:45]=[O:46])=[CH:35][C:36]([Cl:43])=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C:33]1[C:34]([CH2:44][CH:45]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[S:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[CH:3]=2)[OH:46])=[CH:35][C:36]([Cl:43])=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Reactant: Cc1ccc(-c2cccc(Br)c2)s1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(C(O)Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)c2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirring solution of 2-(3-bromo-phenyl)-5-methyl-thiophene (0.395 mmol) in tetrahydrofuran (4 mL) at −78° C. was slowly added a 2M solution of n-butyllithium in cyclohexane (0.435 mmol, 1.1 eq.). The resulting solution was stirred 30 min at −78° C. and solid [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (0.395 mmol) was added. Stirring at −78° C. was continued for 10 min and the reaction was allowed to warm to room temperature and was stirred 1 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a yellow oil that was purified by column chromatography using 20% ethyl acetate/hexanes to give the final product as a light yellow solid (0.18 mmol, 46%). MS (ESI) m/z 486.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[CH:12][C:11]=1[C:21]([F:24])([F:23])[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(O)C2N=NNC=2C=1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C.[F:57][C:58]([F:72])([F:71])[CH:59]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[CH:62]=1)[NH2:60]>ClCCl>[O:19]=[C:18]([NH:60][CH:59]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:68])([F:69])[F:70])[CH:62]=1)[C:58]([F:71])([F:72])[F:57])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:12]=1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(/C=C/C(=O)O)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cc(Cl)cc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 130.1 %

Procedure:
To a solution or 980 mg (1 eq. 2.84 mmol) of (2E)-3-[4-{[(tert-butoxycarbonyl)amino]methyl}-3-(trifluoromethyl)phenyl]acrylic acid in 10 ml of dichloromethane were added 481 mg (1 eq. 2.84 mmol) of 6-chlorohydroxybenzotriazole and 707 mg (1.3 eq. 3.70 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 733 mg (2 eq. 5.68 mmol, 989 μl) of Huenig's base. The reaction mixture was stirred at room temperature for 20 min. Then 1.04 g (1.5 eq, 4.26 mmol) of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine as a solution in 1 ml of CH2Cl2 were added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and partitioned between saturated Na2CO3 solution and ethyl acetate. After drying and concentrating the solvent, 2.108 g of tert-butyl {4-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-1-en-1-yl]-2-(trifluoromethyl)benzyl}carbamate were obtained as an oil, which was converted in the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]1[OH:13].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:22][S:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]1[OH:13]
Reactant: O=C([O-])[O-]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(S)ncnc32)[C@@H](O)[C@@H]1O
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CSc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
6-mercapto-9-(β-D-arabinofuranosyl)purine is reacted at room temperature with methyl iodide in dimethyl sulphoxide in the presence of anhydrous potassium carbonate to give 6-methylthio-9-(β-D-arabinofuranosyl)purine, m.p. 99°-101° C.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])C.C1COCC1.Cl.[CH3:27][NH:28][O:29][CH3:30].C([Mg]Cl)(C)C>C(OCC)(=O)C>[CH3:30][O:29][N:28]([CH3:27])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:7]1)=[O:5]
Reactant: CNOC
Reactant: CCOC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCC(C(=O)N(C)OC)C2)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid ethyl ester (9.3 g, 33.5 mmol), THF (200 mL), N,O-Dimethylhydroxylamine hydrochloride (4.9 g, 50.3 mmol) at −10° C. (Acetone/ice bath) under a Nitrogen atmosphere. By dropwise addition, add Isopropylmagnesium chloride (50.3 mL, 100.6 mmol). Stir the reaction for 6 hours allowing the reaction mixture to warm to room temperature. Quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 1:1 Hexanes:Ethyl acetate and then 1:1 Hexanes:Ethyl acetate with 3% 1N NH3MeOH to give 9.13 g (93% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.4-1.7 (3H, m), 1.8 (1H, d), 1.9 (1H, t), 2.1 (1H, t), 2.8-3.0 (3H, m), 3.1 (3H, s), 3.5 (2H, d), 3.6 (3H, s), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 293 (M+1).
Reaction SMILES: [H][H].[CH2:3]([OH:11])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH3:10]>CCCCCC.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:3]([OH:11])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCC#CCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: CCCC/C=C\CCO

Procedure:
The hydrogen reduction of this 3-octyn-1-ol is carried out by dissolving the compound in n-hexane with addition of 3 to 20% by weight of a Lindlar catalyst and introducing hydrogen at room temperature with agitation (reaction (iii)). Removal of the catalyst by filtration and n-hexane by distillation from the reaction mixture gives cis-3-octen-1-ol in an almost quantitative yield.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][NH2:19].[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][NH:19][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][Cl:20])=[CH:23][CH:24]=1
Reactant: NCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Triethylamine (0.152 mL; 1.08 mmol) was added at 0° C. to a mixture of (5-chloro-1H-indol-3-yl)methanamine (0.150 g; 0.830 mmol) and 4-(chloromethyl)benzoyl chloride (0.170 g; 0.872 mmol) in dichloromethane (12 mL). The mixture was stirred for 15 minutes at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 0.262 g (95%) of N-((5-chloro-1H-indol-3-yl)methyl)-4-(chloromethyl)benzamide as a white solid.
Reaction SMILES: C([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=O)=[CH:16][CH:15]=2)[N:9]=1)CCCCCC.[CH2:23](Cl)[CH2:24]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:16]([C:13]1[CH:12]=[N:11][C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:20])=[CH:21][CH:22]=2)=[N:9][CH:8]=1)[CH2:15][CH2:14][CH2:22][CH2:21][CH2:23][CH3:24]
Reactant: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
1.9 g. of 4-(4-n-heptylpyrimid-2-yl)benzoic acid amide are left for 80 minutes under reflux in a mixture of 40 ml. of ethylene chloride and 0.63 ml. of phosphorus oxychloride, with stirring. The reaction mixture, diluted with ether, is washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, drying over sodium sulfate, 1.9 g. of 5-n-heptyl-2-(4-cyanophenyl)-pyrimidine result, which are distilled in a high vacuum, having a m.p. of 44.2°-44.7°; cl.p. 50.1°-50.4°.
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])=[CH:13][CH:14]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1
Yield: 104.6 %

Procedure:
Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid (7.6 g), p-toluenesulfonic acid (1 g) and benzene (300 mL) were refluxed with continuous water separation for 8 hours. The mixture was cooled and washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation of the solvent in vacuo gave 12.24 g of cyclohexyl 4-hydroxyphenylacetate. That compound can be represented by the formula: ##STR24##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH3:10])[C:4](=[O:18])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:8][C:6]1[N:5]([CH:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH3:10])[C:4](=[O:18])[CH:3]=[C:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:7]=1
Reactant: Cc1ccc(C(C)n2c(C)cc(O)cc2=O)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(C)n(C(C)c3ccc(C)nc3)c(=O)c2)cc1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A stirred mixture of the product from Step 1 (475 mg, 1.947 mmol) and 4-methylbenzenesulfonyl chloride (371 mg, 1.947 mmol) in anhydrous dichloromethane (16 ml) was treated with anhydrous triethylamine (0.81 ml, 5.839 ml) and stirring was continued at ambient temperature for 18 h. The reaction mixture was diluted with dichloromethane (150 ml), washed with water (100 ml) followed by brine (100 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash silica chromatography eluting with ethyl acetate to give toluene-4-sulfonic acid 6-methyl-1-[1-(6-methyl-pyridin-3-yl)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl ester (609 mg) as a colourless gum which solidified on standing. LC-MS m/z 399 [M+H]+ Rt=2.10 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:23]([C:22]4[CH:26]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:24])[CH2:12][CH:11]3[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4cc(F)ccc4-c4ncccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and Intermediate 13. MS MS (ESI): mass calculated for C23H23FN6O, 418.47; m/z found 419.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 2.58 g, 14.2 mmol) and triethylamine (1.43 g, 14.2 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1.63 g, 14.2 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 3.15 g (85%). 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 5.56 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (Cl) 261 (MH+); [α]D+53.8 (c, 1.1, MeOH).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]1=[O:15].[Br:16]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3](=[O:15])[N:2]2[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc2c(c1)n(C)c(=O)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1Br)n(C)c(=O)c(=O)n2C
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 1,4,6-trimethyl-1,4-dihydro-quinoxaline-2,3-dione (0.66 g, 3.2 mmol) in acetic acid (40 mL) was added bromine (0.52 g, 3.2 mmol) and the solution stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and poured into water. The solution was neutralized with aqueous NaOH to Ph=7, extracted with dichloromethane and washed with brine, dried (Mg2SO4), filtered and evaporated to give 0.9 g of 6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 2.47 (s, 3 H), 3.64 (s, 6 H), 7.09 (s, 1 H), 7.40 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[C:2]([C:52]3[CH:53]=[CH:54][C:49]([O:48][CH3:47])=[CH:50][CH:51]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Product: COc1ccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 81.9 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-methoxy-phenyl boronic acid (0.106 mg, 0.69 mmol) by following general procedure D yielding the title compound (85 mg, 80%) as a white solid.