Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[O:5]([C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH2:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(N(CC)CC)C.O1CCOCC1>[O:5]([C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH:14][C:3]([NH:2][CH3:1])=[O:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cc(Cl)c(Cl)cc1Oc1ccccc1
Reactant: CN=C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cc(Cl)c(Cl)cc1Oc1ccccc1
Reaction time: 15 h

Procedure:
2.0 gm (35 mmols) of methylisocyanate and two drops of triethylamine are added to a solution of 6.35 gm (25 mmols) of 2-phenoxy-4,5-dichloroaniline in 50 ml of anhydrous dioxan. The resulting solution is kept at 50°-60° C. for 15 hours. Then about 40 ml of dioxan are distilled off in vacuo and the residue is stirred with 50 ml of petrol. After cooling to 5°-10° C. for one hour, the crystalline product is suction filtered, washed with 20 ml of petrol and dried.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]([CH2:26][CH3:27])[C:10](=O)[CH:11]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH3:8]>C1COCC1>[CH2:26]([N:9]([CH2:7][CH3:8])[CH2:10][CH:11]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH3:27]
Reactant: CCN(CC)C(=O)C(c1ccccc1C)N1CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CC(c1ccccc1C)N1CCNCC1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To LAH (0.08 g, 2.23 mmol) in THF (10 mL) was added N,N-Diethyl-2-piperazin-1-yl-2-o-tolyl-acetamide (548) (0.22 g, 0.74 mmol) in THF (10 mL). The reaction mixture was allowed to stir at reflux for 8 h. Reaction was allowed to cool to room temperature and was then quenched by the addition of H2O (0.08 mL), 15% NaOH (0.25 mL) and H2O (0.08 mL) again. The resulting aluminum salts were allowed to stir at room temperature for 1 h and then removed by filtration. The filtrate was concentrated to dryness yielding 0.20 g (98%) product.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (74 mg, 90%), MS (ISP) m/z=330.5 [(M+H)+], mp 270° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[CH2:23][OH:24]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:24][CH2:23][C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[F:14])[CH:3]=2)[CH2:9][C@@H:10]1[CH3:13]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)c(F)cc1F
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(F)cc3F)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,4,5-trifluorophenyl)methanol.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH:9](O)[C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2].C(N(S(F)(F)[F:31])CC)C>ClCCl>[CH2:1]([N:3]1[C:8]([CH:9]([F:31])[C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2]
Reactant: CCn1c(C(O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCn1c(C(F)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a solution of 3-[(3-Ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-hydroxy-methyl]-5-methyl-benzonitrile (100) (55.7 mg, 0.17 mmol) in dichloromethane (2.0 mL) at 0° C. was added (diethylamino)sulfur trifluoride (33 μL, 0.255 mmol) and reaction mixture stirred for 1 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (2×). The combined organic layer was dried (MgSO4), concentrated and purified by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give a white powder after lyophilization (45 mg, 80%). 1H NMR (300 MHz, CD3OD): 7.60 (s, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.04 (d, J=45.9 Hz, 1H), 3.75-3.57 (m, 2H), 2.94-2.89 (m, 1H), 2.40 (s, 3H), 1.24 (d, J=6.9 Hz, 3H), 1.1-1.0 (s, 6H); %). 19F NMR (CD3OD): −180.5; Mass Spectrum: 330.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:19]([O-])([O-])=O.[Na+].[Na+].O>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 3-hydroxy-5-nitrobenzoic acid (2.00 g, 11 mmol) and concentrated sulfuric acid (0.5 mL) in MeOH (15 mL) was refluxed overnight, cooled to room temperature, and poured into mixture of Na2CO3 (saturated solution, 25 mL), water (150 mL), and ice (50 g). Resulting precipitate was filtered, washed with water (3×30 mL), and air-dried. Yellow microcrystals, yield 1.37 g (63%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.94 (s, 1H); 8.09 (s, 1H); 7.78 (s, 1H); 7.71 (s, 1H); 3.90 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[N:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[Cl:19])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:27](=[O:29])[CH3:28].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:10]=[C:8]([C:6]1[N:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[CH:4][CH:5]=1)[CH3:9]
Reactant: CC(=O)N(C)C
Reactant: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2.00 g (0.0059 mol) of [1-(6-bromopyridin-2-yl)ethylidene](2-chloro-4,6-dimethylphenyl)amine were dissolved in 25 ml of diethyl ether and cooled to −70° C. 3.70 ml (0.0059 mol) of a 1.6 M solution of butyllithium in hexane were added dropwise over a period of 15 minutes. The temperature rose to −40° C. and the mixture was stirred for another 30 minutes. The mixture was cooled to −70° C. and 0.52 g (0.0059 mol) of N,N-dimethylacetamide was added dropwise and the mixture was stirred at room temperature for another three hours. The reaction mixture was stirred with 5 ml of a saturated ammonium chloride solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over Na2SO4, filtered and the solvent was distilled off under reduced pressure. This gave 0.83 g (0.0028 mol) of the product in a yield of 47%.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[N:8]=[CH:9][NH:10][C:11](=[O:13])[CH:12]=1)[C:3]([F:6])([F:5])[F:4].[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:12]1[C:11](=[O:13])[NH:10][CH:9]=[N:8][C:7]=1[C:2]([F:1])([F:14])[C:3]([F:6])([F:5])[F:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(C(F)(F)C(F)(F)F)nc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc(C(F)(F)C(F)(F)F)c1Cl
Temperature: 25 °C

Procedure:
A solution of 4-pentafluoroethylpyrimidin-6-one (0.4 g) and N-chlorosuccinimide (0.27 g) in dry dimethylformamide (5 ml) was heated to 80° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was poured into water, and extracted into ethyl acetate. The organic layer was dried, over anhydrous maqnesium sulphate, filtered, and evaporation of the solvent under reduced pressure gave a brown oil. Recrystallisation from water gave 5-chloro-4-pentafluoroethylpyrimidin-6-one
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C@@H:24]([OH:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:26][C@H:25]2[C@H:29]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23][C@@H:24]2[OH:30])[CH2:28]1)=[O:12]
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
0.49 g of N,N'-carbonyldiimidazole is added to a solution of 0.52 g of 2-dimethylaminophenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5° C. and then a solution of 0.93 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and 0.84 cm3 of triethylamine in 10 cm3 of dichloromethane, is added. The reaction mixture is stirred for 2 hours at +5° C. and then washed with 10 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2 cm, height 35 cm), eluting with ethyl acetate and collecting fractions of 30 cm3. Fractions 8 to 27 are pooled, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised-from a mixture of 4 cm3 of acetonitrile and 20 cm3 of ethyl ether. The crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR,4S,7aR)-2-[(2-dimethylaminophenyl)-acetyl]-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of a white solid; melting point 160° C., [α]D20 =-162° (c=0.5, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:44]([O-])=[O:45])C=1.[CH3:47][C:48]([CH3:52])([CH3:51])[CH2:49][NH2:50]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:44]([NH:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH3:47])=[O:45])=[CH:3][C:4]=3[C:30]([F:32])([F:33])[F:31])[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3C(F)(F)F)CC2)c1
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a stirred solution of 3-((4-(4-amino-2-(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.123 mmol, 57 mg) in dichloromethane (2 mL) was added 4-nitrophenylchloroformate (0.123 mmol, 24.84 mg). After 1 hour stirring, 2,2-dimethylpropan-1-amine (0.123 mmol, 10.74 mg) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure and the residue dissolved in methanol (1 mL). Purification by basic reverse phase HPLC gave the title compound (27 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:24][CH:25]=[C:26]([O:28][CH3:29])[N:27]=1
Reactant: COc1ccc(C(=O)O)c(OC)n1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)n1
Yield: 24 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (500 mg, 2.30 mmol) was converted using 2,6-dimethoxynicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 40:60, 204 mg, 24%) which was obtained as a white solid. MS: m/e=365.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:16][OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:24][CH3:25])[C@@H:11]([CH2:16][OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Compound 5 (10 g, 30 mmol) dissolved in DMF (100 ml) was added with K2CO3 (1.1 equiv., 4.56 g) and ethyl iodide (1.1 equiv., 3.16 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 10 g of a semisolid. Yield=93%. 1HNMR (DMSO, 200 MHz) δ 1.17 (3H, t, J=7 Hz), 3.40 (2H, q), 3.54 (3H, s), 3.80 (2H, t, J=5.8 Hz), 4.50 (1H, t), 5.00 (1H, bt), 7.28 (1H, dd, J=4 Hz, J′=1 Hz), 7.57 (1H, dd, J=4.2 Hz, J′=1 Hz).
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].[CH3:17][S:18][CH:19]1[NH:22][C:21](=[O:23])[CH2:20]1.O>C1C=CC=CC=1>[OH:4][CH:3]([N:22]1[CH:19]([S:18][CH3:17])[CH2:20][C:21]1=[O:23])[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: CSC1CC(=O)N1
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccccc1
Product: CSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 106.3 %

Procedure:
p-Nitrobenzyl glyoxylate monohydrate (1.11 g, 4.87 mmoles) was added to a solution of 4-methylthio-2-azetidinone (570 mg, 4.87 mmoles) in benzene (30 ml) and the resulting solution was heated, whilst the water produced was removed by azeotropic distillation. After the water had been distilled off completely, the mixture was concentrated and heated at a bath temperature of 100°-110° C. for 12 hours. The solvent was then distilled off under reduced pressure to give 1.69 g of the desired compound as a viscous oil. This product may be employed in subsequent reactions without purification, although it contains a small amount of the starting compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH-:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH3:28])[N:17]=[CH:16][N:15]=1>CN(C=O)C>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][CH:3]=2)[CH:19]=1)[CH3:28]
Reactant: CCOc1ccccc1-c1cc(Cl)ncn1
Reactant: [NH-]S(=O)(=O)Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(Nc2ccc(CS(N)(=O)=O)cc2)ncn1
Temperature: 80 °C

Procedure:
A mixture of (4-aminophenyl)methanesulfonyl amide (0.093 g, 0.50 mmol) and 4-chloro-6-(2-ethoxyphenyl)-pyrimidine (0.117 g, 0.50 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control). Then the reaction mixture was concentrated in vacuo and the residue recrystallized from isopropanol to give {4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 6)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([N:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26])=[O:22])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CNC
Product: CCOC(=O)CN(C)C(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl sarcosinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]sarcosinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]sarcosine (M.P. 103° to 105°).
Reaction SMILES: Cl.Cl.Cl.[CH:4]1([N:10]2[CH2:27][CH2:26][C:13]3([CH2:17][N:16]([CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=O>>[CH:4]1([N:10]2[CH2:27][CH2:26][C:13]3([CH2:17][N:16]([CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([N:25]([CH2:33][C:29]5[NH:28][CH:32]=[CH:31][N:30]=5)[CH2:33][C:29]5[NH:30][CH:31]=[CH:32][N:28]=5)[CH2:23][CH2:24]4)[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=Cc1ncc[nH]1
Reactant: N[C@H]1CC[C@H](CN2CCC3(CCN(C4CCCCC4)CC3)C2)CC1
Agent: Cl
Product: c1c[nH]c(CN(Cc2ncc[nH]2)[C@H]2CC[C@H](CN3CCC4(CCN(C5CCCCC5)CC4)C3)CC2)n1

Procedure:
With the compound produced in Example 25 and 1H-imidazole-2-carbaldehyde, the same operation as in Example 2 was performed to obtain the title compound having the following physical properties.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.[Pd]>[NH2:11][C@@H:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:15]
Reactant: C1COCCN1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
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: CC(C)(C)[C@H](N)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of (S)-2-(benzyloxycarbonylamino)-3,3-dimethylbutanoic acid (2.0 g, 7.54 mmol) in DMF (10 mL) were added morpholine (1.31 g, 15.1 mmol) and DIEA (3.95 mL, 22.62 mmol). TBTU (3.63 g, 11.31 mmol) was added in three portions 15 minutes apart. The reaction stirred at room temperature for 2 hours. DMF was removed under vacuum and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material (2.11 g, 7.54 mmol) was combined with palladium on carbon, 10% dry basis, (0.29 g, 2.69 mmol) in MeOH (15 mL) and placed on a Parr Shaker under H2 atmosphere, 20 psi, for 3 hours. The reaction was filtered through a celite plug and concentrated under reduced pressure to provide 1.46 g (7.31 mmol) of intermediate 77D. LCMS (+ESI) m/z 201.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Reactant: C1CCNCC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCCCC3)cc2F)CC1
Yield: 30 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.4 g, 3.1 mmol) by using piperidine (3.1 ml) as an amine to yield the titled compound (487 mg, 30%).
Reaction SMILES: [F:1][CH:2]([F:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1.Cl>O>[F:22][CH:2]([F:1])[N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1
Reactant: CCOC(=O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3
Agent: Cl
Solvent: O
Product: O=C(O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3
Yield: 97.9 %

Procedure:
A mixture of 27.5 g of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester and 600 ml of 6N hydrochloric acid is heated under reflux for 1.5 hours. The mixture is diluted with 1 liter of water, cooled, and filtered. The solid product is triturated with cold ethanol and filtered to give 24.5 g of the desired product, m.p. 327°-8° C. (dec).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.CCOC(C)=O>C1COCC1>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)=[O:21])[CH:15]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn(C(=O)c2cc(Cl)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 120 mg (3.00 mmol) sodium hydride (60% in mineral oil) were added batchwise to 380 mg (2.90 mmol) 3-methylindole in 15 mL THF and the mixture was stirred for 30 min at RT. 500 mg (2.83 mmol) 6-chloropyrimidine-4-carboxylic acid chloride were added batchwise and then the reaction mixture was stirred for 2 h at RT. Then 50 mL EtOAc were added and the mixture was washed with 50 mL saturated sodium hydrogen carbonate solution (1×), 30 mL water and with 50 mL 1 M hydrochloric acid. The organic phase was dried on sodium sulphate, filtered and then evaporated down i. vac. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH2:38][CH3:39]>>[CH2:38]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[CH3:39]
Reactant: CCI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)c2)o1
Product: CCN(Cc1ccc(Oc2ccccc2)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 776,(1H, s), 7.55-7.48,(5H, m), 7.40-7.36,(3H, m), 7.24,(1H, b), 7.13,(1H, t), 7.00,(4H, m), 4.694.51,(2H, m), 3.39-3.22,(2H, m), 2.55,(3H, s), 2.31,(3H, s), 1.08,(3H, b). LCMS; retention time 3.93 min, MH+ 504.