Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(O)C.[C:15]([CH2:17][C:18](OCC)=[O:19])#[N:16]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18](=[O:19])[CH2:17][C:15]#[N:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: N#CCC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were heated to boiling in 150 ml of ethyl cyanoacetate. Simultaneously therewith the ethanol formed during the reaction was removed by distillation. After the reaction mixture was cooled, the precipitate formed was vacuum filtered, washed with ether and recrystallized from dilute acetic acid. The product had a melting point of 218°-221°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N+:21]([O-])=O)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:21])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2cc(S(=O)(=O)c3cccc(F)c3)cnc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc2cc(S(=O)(=O)c3cccc(F)c3)cnc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
10.13 g of 3-(3-fluorophenylsulfonyl)-8-nitroquinoline (30.5 mmol) were suspended in 150 ml of acetic acid and warmed to 110° C. 8.51 g of iron powder (152 mmol) were added in small portions with stirring. Stirring was continued for 1 h. Then, the reaction mixture was cooled to room temperature, partitioned between water and ethyl acetate. The organic phase was separated and the aqueous layer was extracted three times with ethyl acetate. Water was added to the combined organic layers and the pH was adjusted to alkaline conditions with aqueous ammonia solution under rapid stirring. The organic layer was separated, extracted twice with water, dried over magnesium sulfate, filtered and the solvents were evaporated to yield 9.2 g of the product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:14][C:15]1([CH3:31])[O:20][C:19]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]>>[CH3:31][C:15]1([CH3:14])[O:20][C:19]2[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([N:2]([CH3:1])[CH2:3][C:4]3[N:5]([CH3:13])[C:6]4[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:29])[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Reactant: CNCc1cc2ccccc2n1C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)OC(C)(C)C(=O)N2
Yield: 64.5 %

Procedure:
According to the procedure of Example 43d, methyl-(1-methyl-1H-indol-2-ylmethyl)-amine (124 mg, 0.71 mmol) and 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (160 mg, 0.64 mmol), were coupled to yield the title compound (167 mg, 64%) as a white solid and as a mixture of amide rotomers. 1H NMR (400 MHz, DMSO-d6) δ 11.03-11.04 (m, 1H), 8.15-8.20 (m, 1H), 7.89-7.94 (m, 1H), 7.41-7.56 (m, 3H), 7.39-7.41 (m, 1H), 7.00-7.12 (m, 1H), 6.14-6.99 (m, 1H), 4.87-5.05 (m, 2H), 3.68-3.72 (m, 3H), 2.99-3.10 (m, 3H), 1.39-1.44 (m, 6H); MS (ESI) m/e 405 (C23H24N4O3+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)=[CH:22]4)[C:18]=3[CH:35]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH:32]([N:28]1[C:27]([C:21]2[N:20]=[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]4[CH:16]=[CH:15][C:14]([S:13][CH:10]5[CH2:9][CH2:8][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:12][CH2:11]5)=[CH:35][C:18]=43)[CH:22]=2)=[N:31][CH:30]=[N:29]1)([CH3:34])[CH3:33]
Reactant: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)CO)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To an ice-cooled solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (0.485 mmol) in THF (20 mL) was added LiAlH4 (1.0M in THF, 1.5 mL) and the mixture was stirred at 0° C. for 1 h. To the reaction mixture was added EtOAc (0.5 mL) and stirring was continued for 10 min. Volatiles were then removed under reduced pressure and the resulting residue was partitioned between DCM and 10% aq. solution of Rochelle's salt. The suspension was stirred for 20 min and then filtered through a pad of Celite®. The filtrate was extracted with DCM and the combined organic phases were washed with water, followed by brine, then dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-13% 2M NH3/MeOH in DCM) affording 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol (229 mg, 98% over two steps). LCMS: RT 2.13/2.19 min [M+H]+ 483.2
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH3:10])(=[O:9])=[O:8])=[N:5][N:4]=[C:3]1[C:11]1[CH:16]=[CH:15]N=C[CH:12]=1.C(NN)(=O)C1C=CC=[N:20][CH:19]=1>>[CH3:1][N:2]1[C:6]([S:7]([CH3:10])(=[O:8])=[O:9])=[N:5][N:4]=[C:3]1[C:11]1[CH:12]=[N:20][CH:19]=[CH:15][CH:16]=1
Reactant: NNC(=O)c1cccnc1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Product: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O

Procedure:
The title compound was prepared analogously to 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine as described herein, via the corresponding sequence consisting of the corresponding steps, by starting from nicotinohydrazide instead of isonicotinohydrazide. 1H NMR: 3.59 (s, 3H), 3.99 (s, 3H), 7.52 (m, 1H), 8.02 (dt, 1H), 8.83 (dd, 1H), 8.91 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[Br:14][C:15]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[Br:14][C:15]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:26])[N:7]([C:6]2[CH:12]=[CH:13][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH2:8][CH:9]([CH3:10])[CH3:11])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CCc1ccc(NCC(C)C)cc1
Solvent: c1ccncc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)c(C(=O)OC)c2)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-ethyl-N-isobutylaniline (400 mg, 2.256 mmol) in pyridine (2 mL) stirred in air at 20° C. was added methyl 2-bromo-5-(chlorosulfonyl)benzoate (707 mg, 2.256 mmol) portionwise, over 30 minutes. The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand overnight. The solvent was evaporated in vacuo to give the crude product as a sticky yellow solid. This was triturated with methanol and filtered and dried to give the desired product as a white solid, 600 mg. LCMS [LCMS1] Rt 1.41 min, m/z (ES+) 454/456 (M+H).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][CH2:9][C:10]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH2:15][CH2:14][CH2:13][N:12]([C:16](OC(C)(C)C)=[O:17])[CH2:11]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C(OC(=O)C)(=O)C>ClCCl>[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C:10]([CH2:9][OH:8])([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH2:11]1)(=[O:17])[CH3:2]
Reactant: Cc1ccc(CC2(CO)CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCC(CO)(Cc2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (12.5 ml) was added to a solution of the product from STEP 3 (0.48 g, 1.4 mmol) in 12.5 ml dichloromethane at 0° C. The reaction was allowed to warm to room temperature. After 2 h, the reaction was concentrated, and dried in vacuo. The residue was dissolved in 20 ml dichloromethane, then triethylamine (1.82 g, 18.0 mmol) and dimethylaminopyridine (30 mg) were added. Acetic anhydride (1.13 ml, 12.0 mmol) was added to the above mixture at 0° C. The reaction mixture was allowed to warm to room temperature. After 18 h, the reaction was diluted with 150 ml dichloromethane, washed with 10 ml H2O, 5 ml brine, dried with MgSO4, and concentrated. The residue was dissolved in 25 ml methanol. An aqueous saturated K2CO3 solution (15 ml) was added at 0° C. The reaction was allowed to warm to room temperature. After 1.5 h, glacial acetic acid was added to adjust PH value to 6.5. The reaction was concentrated and product was extracted with ethyl acetate. The organic extracts were washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH=90/10/0.2) to afford 0.14 g of an viscous oil. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1>CC(C)=O>[CH:8]1([CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: OC1CCC(C2CCCCC2)CC1
Solvent: CC(C)=O
Product: O=C1CCC(C2CCCCC2)CC1
Temperature: 0 °C
Yield: 79.2 %

Procedure:
To a solution of 4-hydroxycyclohexylcyclohexane (25 g) in acetone (250 ml) was added dropwise with stirring 2.67N Jone's regend (77 ml) at 0° C. The mixture was then stirred for 1 hour at 0° C. The organic layer was collected and evaporated. The reaction mixture was added to a mixture of water and diethyl ether. The organic layer was washed with water, sodium hydrogen carbonate solution and brine. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 4-cyclohexylcyclohexanone (19.57 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][N:14]([CH3:16])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:17]1([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([NH:20][C:21]([C:22]2[CH:27]=[C:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([CH2:13][N:14]([CH3:16])[CH3:15])=[N:10][N:9]=4)=[CH:4][CH:3]=3)[C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:38])[CH2:18][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)Cc1nnc(-c2ccc(I)cc2)o1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN(C)C)o2)cc1

Procedure:
Example 16 was prepared from [5-(4-iodophenyl)-[1,3,4]oxadiazol-2-ylmethyl]-dimethylamine (Intermediate 11) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=N.[H-].[Na+].[C:19]([NH:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1)(OCC)=[O:20].C(O)C.[N:34]1C=CC=CC=1>>[NH2:34][N:6]=[CH:4][NH:3][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:19]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:20])[N:11]=1
Reactant: CCOC(=O)Nc1nc(C)cs1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: c1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1csc(NC(=O)NCCSCc2csc(NC=NN)n2)n1

Procedure:
To 4.60 g (15.1 mmole) of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole dihydrochloride stirred under flowing nitrogen in 170 ml of dry pyridine is added 1.38 g (ca. 30.3 mmole) of a 50 percent dispersion in oil of sodium hydride. After about 1 hour 2.80 g (15.0 mmole) of 2-carbethoxyamino-4-methylthiazole is added, and the resultant mixture is heated at reflux for 2 days. After partial cooling, the mixture is decanted through a sintered glass funnel using suction, all residues being discarded, and the filtered supernatant is concentrated in vacuo to a thick gum. Residual mineral oil is removed by trituration with several portions of diethyl ether and pentane, and the residue is purified by column chromatography* on silica gel. Fractions containing the product are combined, partially concentrated, filtered, and thoroughly dried by concentration in vacuo, giving 1.20 g (3.1 mmole) of the desired product as an ethanol solvate. Structure assignment and solvation by one quarter mole of ethanol per mole of product are supported by nmr.
Reaction SMILES: [C:1]1([CH3:47])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:16][CH2:17][N:18]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:19][CH2:20][N:21]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:22][C:23]([O:25]C)=[O:24])[CH2:11][C:12]([O:14]C)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[C:33]1([CH3:36])[CH:34]=[CH:35][C:30]([S:27]([N:21]([CH2:20][CH2:19][N:18]([S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])[CH2:17][CH2:16][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:47])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:11][C:12]([OH:14])=[O:13])[CH2:22][C:23]([OH:25])=[O:24])(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: COC(=O)CN(CCN(CCN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(CCN(CC(=O)O)S(=O)(=O)c2ccc(C)cc2)CCN(CC(=O)O)S(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 72 h
Yield: 93 %

Procedure:
Dimethyl 3,6,9-tris(p-toluenesulfonyl)-3,6,9-triazaundecanedioate prepared as in Example 28E (16 g, 22.5 mmol) was slurried in tetrahydrofuran (100 ml). Sodium hydroxide (2N, 160 ml) was added dropwise over a 1 h period. After 72 h, the solvent was evaporated under reduced pressure, and hydrochloric acid (1N) was added to lower the pH to 4. This aqueous phase was extracted several times with ethyl acetate. The combined ethyl acetate layers were washed twice with brine, dried (MgSO4), filtered, and evaporated to give a white solid, 14.22 g (93% yield): mp 177°-80° C.; 1H NMR (DMSO-d6) δ 2.38 and 2.40 (2 s, 9H), 3.10 (m, 4H), 3.29 (m, 4H), 3.73 (s, 4H), 7.37 and 7.41 (2 d, J=7.9, 8.2 Hz, 6H), 7.61 and 7.66 (2 d, J=8.2 , 8.0 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](O)=[O:20])[CH:15]=2)[C:10]1=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C=O)C.O>[CH3:44][C:45]1[CH:46]=[C:47]([NH:48][C:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:22])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[C:17]3=[O:18])=[O:20])[CH:49]=[CH:50][C:51]=1[CH3:52]
Reactant: Cc1cccc(C)c1N1C(=O)c2ccc(C(=O)O)cc2C1=O
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)C(=O)N(c2c(C)cccc2C)C3=O)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (130 mg), EDCI (85 mg) and HOBt (60 mg) in DMF (3 mL) was added 3,4-dimethylaniline (53 mg) and the mixture was stirred at room temperature for 24 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2 as eluent to give 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale-yellow solid, mp=223-225° C.; MS (m/z) 397 (M−1); 1H NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.09 (d, J=8.34 Hz, 1H), 7.81 (s, 1H), 7.45 (s, 1H), 7.37-7.15 (m, 5H), 2.30 (s, 3H), 2.27 (s, 3H), 1.54 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[CH3:17][O:18][C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:22](N)[CH:21]=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:17][O:18][C:19](=[O:35])[C:20]1[CH:21]=[CH:22][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:24]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH:9]([CH3:10])[CH3:11])=[N:5][C:4]=3[N:12]=[CH:13][N:14]=2)[CH:25]=1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
A suspension of N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (0.75 g, 3.5 mmol) and 3-amino-4-(4-hydroxy-phenylsulfanyl)-benzoic acid methyl ester (0.96 g, 3.5 mmol) in AcOH (15 mL) was heated at 120° C. for 10 minutes under N2. The reaction mixture was portioned between AcOEt (10 mL) and H2O (150 mL) and made basic to pH 9 with K2CO3 under stirring. The resulting solid was collected by filtration, washed with H2O and AcOEt, and dried at 50° C. overnight under reduced pressure to give the title compound as pale brown crystal (1.27 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:10][CH2:11][N:12]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:13][CH2:14]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCc1cnc(Cl)nc1
Reactant: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4[nH]3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.6 %

Procedure:
Intermediate 1 (500 mg, 1.69 mmol) and 2-chloro-5-ethylpyrimidine (264 mg, 1.86 mmol) were dissolved in propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine (1.8 ml, 10.1 mmol) added and stirred at 90° C. for 12 h. After completion of the reaction, propan-2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOET and Petether (40:60) as eluent to afford the titled compound (0.2 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=O)[NH:12][CH:13]=[N:14]2)[C:3](=[O:5])[CH3:4].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:31])=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:31][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH2:6][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[N:14]=[CH:13][N:12]=1
Reactant: CC(=O)N(C)CCOc1cccc2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C)CCOc1cccc2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
N-Methyl-N-{2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]ethyl}acetamide (261 mg, 1.00 mmol) and diiso-propylethylamine (522 μl, 3.00 mmol) were dissolved in DCM (25 ml), and the mixture cooled to 0° C. Phosphorus oxychloride (930 μl, 10 mmol) was added drop wise; the solution was warmed to ambient temperature and stirred for 2 hours. The mixture was cooled to 0° C., and saturated sodium hydrogen carbonate solution (30 ml) was added with vigorous stirring. The stirred mixture was allowed to warm to ambient temperature over 20 minutes. The DCM layer was separated, washed with saturated sodium hydrogen carbonate solution (30 ml), water (30 ml) and brine (30 ml), filtered through a silicone-treated filter paper, and evaporated to give N-{2-[(4-chloroquinazolin-5-yl)oxy]ethyl}-N-methylacetamide as an orange solid (90 mg, 32%); NMR Spectrum (DMSO-d6, 400 MHz, CDCl3) 2.05 (s, 3H), 3.17 (s, 3H), 3.85 (t, 2H), 4.28 (t, 2H), 6.99 (d, 1H), 7.58 (d, 1H), 7.76 (dd, 1H), 8.87 (s, 1H); Mass spectrum 276.4 MH+ (4-OMe derivative—product quenched with MeOH in instrument).
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]([CH2:21][C@H:22]([NH2:26])[C:23]([OH:25])=O)=[O:20])=[CH:13][CH:12]=1.Cl[CH2:28]Cl>C(N(CC)CC)C>[CH3:1][C:2]1([C:8]([NH:26][CH:22]([C:23](=[O:25])[CH3:28])[CH2:21][C:19]([O:18][CH2:17][C:14]2[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=2)=[O:20])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: ClCCl
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Product: CC(=O)C(CC(=O)OCc1ccccc1)NC(=O)C1(C)CCCCC1

Procedure:
1-Methylcyclohexylcarbonyl chloride (1.6 g) was added dropwise to a mixture of L-aspartic acid β-benzyl ester (2.23 g), dichloromethane (30 ml) and triethylamine (30 ml) with ice-cooling and stirring. The resulting mixture was stirred with ice-cooling for an hour, washed with 1N hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the oily residue (3.2 g) was dissolved in dimethoxyethane (30 ml). Acetic anhydride (4 ml), pyridine (4.8 ml) and 4-dimethylaminopyridine (0.12 g) were added and the mixture was refluxed for 1.5 hours. Acetic acid (2 ml) was added and the whole mixture was refluxed for 2.5 hours. The solvent was distilled off and water was added. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water in that order, and dried over anhydrous magnesium sulfate. The residue (2.0 g) was purified by chromatography on silica gel (40 g) [eluent: hexane-acetone (9:1)] to give benzyl 3-(1-methylcyclohexylcarbonylamino)-4-oxovalerate as an oil; yield 1.2 g (34.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>ClCCl>[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([N:10]2[CH2:11][CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:31])=[CH:27][CH:28]=1
Reactant: Fc1ccc(C2=NNCC2c2ccc(F)cc2)cc1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)F)cc1)N1CC(c2ccc(F)cc2)C(c2ccc(F)cc2)=N1
Temperature: 25 °C

Procedure:
9.85 g (0.038 mol) 3,4-bis-(4-fluorophenyl)-4,5-dihydropyrazole in 80 ml dichloromethane was treated with 7.03 g (0.038 mol) 4-difluoromethoxyphenyl isocyanate, with stirring at room temperature and stirred for an hour at room temperature. The reaction mixture was filtered through silica gel and the filtrate was concentrated. The residue was treated with 100 ml diisopropyl ether. The precipitated crystals were separated and dried in vacuo (100 Torr).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:11]=[C:10]([CH3:26])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=4)[CH:11]=[C:10]([CH3:26])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COc1cc(-c2cc(C)nc(-c3ccnc(Cl)c3)c2)ccc1C(F)(F)F
Product: COc1cc(-c2cc(C)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)c2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2′-chloro-4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-[2,4′]bipyridinyl (example E.99) (0.378 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.390 g, 70%). MS (ISP) 556.5 [(M+H)+]; mp 189° C.