Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:36])[CH3:35])[CH:20]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([NH:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:35])[CH3:36])[CH:20]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(NC(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(-c2ccc3ncccc3c2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc(F)c(NC(=O)Nc3cc(C(C)C)nn3-c3ccc4ncccc4c3)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
1-(5-(6-aminopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.0495 g, 0.099 mmol) was dissolved in DCM (1.0 mL), to which pyridine (0.49 mL, 6.0 mmol) and acetic anhydride (0.066 mL, 0.65 mmol) were added. The reaction mixture was stirred at RT for 12 h. The completed reaction was quenched with 2M NaHCO3 (12 mL) and extracted with EtOAc (25 mL). The organic layer was washed with H2O (15 mL) and brine (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography to afford 1-(5-(6-acetamidopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.0234 g, 44% yield) as a yellow foam. It was converted to corresponding mesylate salt by reacting with MsOH (1.0 eq.). 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.09 (s, 1H), 9.07-9.04 (m, 2H), 8.65 (d, J=8.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.11-8.07 (m, 2H), 8.02 (dd, J=8.8, 2.4 Hz, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 4.48 (dd, J=8.8, 3.2 Hz, 1H), 7.24 (m, 1H), 6.67 (m, 1H), 6.40 (s, 1H), 2.92 (m, 1H), 2.31 (s, 3H), 2.08 (s, 3H), 1.24 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 540.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccc(Nc2ccccc2)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(Nc2ccccc2)c1NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of 3-methyl-N1-phenylbenzene-1,2-diamine (381 mg, 1.92 mmol) in anhydrous DCM (10 mL) were added (R)-2-tertbutoxycarbonylaminopropionic acid (399 mg, 2.11 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (404 mg, 2.11 mmol) and the mixture was stirred at RT for 2 h. After this period of time, additional amounts of (R)-2-tertbutoxycarbonylaminopropionic acid (145 mg, 0.77 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) were added. Stirring was continued for 20 h and then additional amounts (R)-2-tertbutoxycarbonylaminopropionic acid (545 mg, 2.88 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) were added. Stirring was continued for 24 h and then the crude mixture was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording [(R)-1-(2-methyl-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an orange oil (456 mg, 64%). LCMS: RT 3.69 min [M+H]+ 370.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]1[S:21][C:14]2[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=2[C:12]=1[C:22]([O:24]C(C)(C)C)=[O:23])=[O:7]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]1[S:21][C:14]2[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=2[C:12]=1[C:22]([OH:24])=[O:23])=[O:7]
Reactant: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)O)CC(C)(C)OC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of 40% v/v TFA/DCM (20 mL) was added to tert-butyl 2-(3-(3-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.32 g, 0.67 mmol) and the mixture was stirred at room temperature for 1 h. The volatiles were removed at 30° C. and the material was purified by reverse-phase chromatography (10-100% MeCN/water). 2-(3-(3-Methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (0.114 g, 0.26 mmol, 39% yield) was isolated as a pale, yellow solid. 1H NMR (500 MHz, DMSO) δ 14.84 (s, 1H), 13.39 (s, 1H), 11.78 (s, 1H), 7.58-7.54 (m, 1H), 7.54-7.51 (m, 1H), 7.45 (apparent t, J=7.9 Hz, 1H), 7.22 (apparent ddd, J=8.3, 2.6, 0.9 Hz, 1H), 4.66 (s, 2H), 3.85 (s, 3H), 2.74 (s, 2H), 1.23 (s, 6H). 13C NMR (126 MHz, DMSO) δ 174.24, 166.41, 165.25, 158.88, 146.70, 133.23, 129.51, 128.99, 123.98, 120.94, 119.29, 116.40, 113.19, 70.04, 58.71, 55.33, 37.16, 26.08. LCMS retention time: 3.199 min; LCMS purity at 214 nm=97%. HRMS m/z calculated for C19H21N2O5S2 [M+1]: 421.0886. found 421.0889. Melting point 199.3° C., decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[O:19]1[CH2:24][CH2:23]OCC1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([CH:23]1[C:24](=[O:19])[CH2:10][CH2:2][CH2:3][C:4]1=[O:6])=[O:6]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Reaction time: 0.25 h

Procedure:
42.5 g of 2-chloro-4-methylsulfonylbenzoic acid were boiled in 160 ml of dioxane with 5 drops of dimethylformamide and 25.1 ml of thionyl chloride until the evolution of gas subsided. The solvent was stripped off with the exclusion of moisture on a rotary evaporator. To the oily residue there were added at 0° C. 19.7 g of 1,3-cyclohexanedione in 250 ml of acetonitrile, and 63.1 ml of triethylamine were then added dropwise at this temperature. Stirring was continued for 15 minutes, 15.3 ml of acetone cyanohydrin were added, and the mixture was allowed to stand overnight. The reaction mixture was concentrated under reduced pressure on a rotary evaporator, the residue was taken up in ethyl acetate/water, and the organic phase was washed with 2N hydrochloric acid. The product was extracted from the organic phase using 5% K2CO3 solution, and precipitated at a pH of 2-3 using concentrated hydrochloric acid, with cooling. After filtration with suction and drying, 48.4 g of 2-[2-chloro-4-(methylsulfonyl)benzoyl]-1,3-cyclohexanedione of melting point 141°-142° C. were obtained.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:52])[CH:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[CH3:37].CCOC(/N=N/C(OCC)=O)=O>>[CH2:36]([O:38][C:39](=[O:52])[CH:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:10][CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:44][CH:43]=1)[CH3:37]
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCC(c2ccccc2)c2ccccc2)cc1)OCC
Yield: 55.5 %

Procedure:
Reaction of 3,3-diphenyl-propan-1-ol (110 mg, 0.5 mmol), triphenylphosphine (145 mg, 0.55 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (140 mg, 0.6 mmol) and diethylazodicarboxylate (0.09 mL, 0.55 mmol) in an identical manner to Example 1 gave the title compound (120 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:5]=[C:4]([CH3:19])[N:3]=1.[CH2:20]([NH:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[CH2:21][CH3:22].[NH4+].[OH-]>CN1CCCC1=O>[CH:25]1([CH2:24][N:23]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C:7]([CH3:18])([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]=3[N:5]=[C:4]([CH3:19])[N:3]=2)[CH2:20][CH2:21][CH3:22])[CH2:27][CH2:26]1
Reactant: CCCNCC1CC1
Reactant: Cc1nc(Cl)c2c(n1)C(C)(c1ccccc1)CCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCN(CC1CC1)c1nc(C)nc2c1CCCC2(C)c1ccccc1
Yield: 36.8 %

Procedure:
A solution of 4-chloro-2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydroquinazoline (180 mg, 0.7 mmol), N-propylcyclopropanemethylamine (1 mL, 7 mmol) and 1 mL of 1-methyl-2-pyrrolidinone was heated in an oil bath at 160-170° C. for 3 h. After cooling, the mixture was added to aqueous NH4OH and extracted with ethyl acetate. The extract was washed with 1N NaOH and brine, dried, (sodium sulfate) and evaporated. Purification by flash chromatography (15% ethyl acetate/hexane) afforded 90 mg of cyclopropylmethyl-(2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-propyl-amine as an oil. MS MH+ 349.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrC1=Cc2ccccc2C1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Product: C1=C(Cc2ccccc2)Cc2ccccc21
Temperature: 0 °C

Procedure:
A 500 mL 3 neck flask was charged with 2.5 g (13 mmol) of 2-bromo-indene, 50 mg of NiCl2(1,3-bis(diphenylphosphino)propane) (0.06 mmol) and 150 mL of diethyl ether. To this mixture was added dropwise 12.8 mL of 1.0 M benzyl magnesium chloride in ether (12.8 mmol). The reaction was heated to reflux overnight and then quenched by cooling to 0° C. and adding 150 mL of 1.0 M aqueous hydrochloric acid. The organic layer was separated and washed twice with 50 mL of ether. The organic extracts were combined, dried over magnesium sulfate, filtered and the volatiles removed in vacuo to leave a dark oil. The sample was dissolved in a small amount of hexanes and purified by flash column chromatography using silica and hexanes as the elutent. Yield: 1.75 g, 66 percent
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=[C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]1=[O:11]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-methyl-2-oxindole (147 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 3-(1H-indol-2-ylmethylene)-4-methyl-1,3-dihydro-indol-2-one.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH:17](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCC(CO)Nc1ccc2ncc(Br)n2n1
Reactant: CCCC/C=C/B(O)O
Product: CCCC/C=C/c1cnc2ccc(NC(CC)CO)nn12
Yield: 38 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (27 mg, 38%) as an off-white solid; 1H NMR (500 MHz, CD3OD) δ 7.51 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.76-6.70 (m, 1H), 6.66 (d, J=9.7 Hz, 1H), 6.61 (d, J=16.1 Hz, 1H), 3.93-3.89 (m, 1H), 3.70-3.67 (m, 2H), 2.35-2.30 (m, 2H), 1.81-1.76 (m, 1H), 1.69-1.65 (m, 1H), 1.53-1.48 (m, 2H), 1.45-1.40 (m, 2H), 1.04-1.01 (t, J=7.3 Hz, 3H), 0.55 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 155.6, 138.2, 133.3, 129.1, 128.9, 125.8, 117.2, 114.1, 64.2, 56.1, 34.8, 33.2, 35.4, 23.7, 14.7, 11.4; HPLC tR=12.9 min (Luna), 95.1%; ES-MS: (M+H)=289 m/z.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:18]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:30][C@H:25]1[O:26][C@@H:27]([CH3:29])[CH2:28][N:23]([C:19]2[CH:18]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[CH:22]=[CH:21][N:20]=2)[CH2:24]1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(c2cc(Cl)ccn2)C[C@H](C)O1
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: C1COCCO1
Solvent: O
Product: Cc1occc1-c1ccnc(N2C[C@@H](C)O[C@@H](C)C2)c1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (0.918 g, 4.41 mmol) was added to a solution of cis-4-(4-chloro-2-pyridinyl)-2,6-dimethylmorpholine (1 g, 4.41 mmol) in a mixture of 1,4-dioxane (17 mL), water (2.83 mL) and sodium carbonate (0.935 g, 8.82 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (0.510 g, 0.441 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 4 hours. Crude LC/MS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (336 mg, 1.172 mmol, 26.6% yield). LC/MS [M+H]+=273.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([Cl:16])[CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=O)C.O.[NH2:21][NH2:22]>C(O)C>[Cl:16][C:13]1[CH:12]=[C:11]([Cl:17])[C:10]([O:18][CH3:19])=[C:9]2[C:14]=1[CH:15]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[CH:7]=[N:8]2
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1c(Cl)cc(Cl)c2cc(C(=O)NN)cnc12
Yield: 79.5 %

Procedure:
A solution of 5,7-dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester 27 (404 mg, 1.35 mmol) and hydrazine monohydrate (1.0 g) in ethanol (10 ml) was heated under reflux for 5 hours. Upon cooling, a white crystalline solid was deposited. This was isolated via filtration, washed with ethanol, and dried, yielding the hydrazide 28 (307 mg, 80%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 10.32 (br, 1 H), 9.33 (d, J=2.4, 1 H), 8.89 (d, J=2.4, 1 H), 8.02 (s, 1 H), 4.66 (br, 2H), 4.06 (s, 3 H).
Reaction SMILES: C([O:8][C:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28](=[O:31])[N:29]=[N:30][C:10]=12)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28](=[O:31])[N:29]=[N:30][C:10]=12
Reactant: [H][H]
Reactant: O=c1nnc2c(OCc3ccccc3)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2
Agent: [Pd]
Solvent: CCO
Product: O=c1nnc2c(O)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2

Procedure:
44.6 g of 4-(benzyloxy)-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 400 ml of ethanol containing 2.0 g of 10% palladium-on-charcoal is hydrogenated at an initial hydrogen pressure of 40 p.s.i. After 0.1 mole of hydrogen has been absorbed, the reaction is stopped, filtered and the solvent evaporated. The residue is triturated with ether and the title compound filtered off and dried.
Reaction SMILES: [C:1]([C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1)([O:3]C)=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O=S(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:11]([C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]=2[C:1]([OH:3])=[O:2])=[O:13])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccncc1C(=O)O
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccncc1C(=O)c1ccc(F)cc1

Procedure:
A mixture of 4-carbomethoxynicotinic acid (2.0 g, 11.04 mmol) in 20 mL of SOCl2 is heated to reflux for 4 hours, then allowed to cool. Evaporation of excess SOCl2 results in 4-carbomethoxynicotinoyl chloride HCl which is suspended in fluorobenzene (15 ml) and treated with AlCl3 (4.04 g, 30.3 mmol). After heating at reflux for 2 hours, the reaction is quenched with ice and neutralized with aqueous NaOH to generate a precipitate which is filtered. The aqueous fraction of the biphasic filtrate is separated, washed with several portions of EtOAc and acidified to pH 3.5 with 5% aqueous HCl to generate a white solid. The solid is collected by filtration, washed with H2O, and dried by suction to generate 3-(4-fluorobenzoyl)pyridine-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>COCCOC.C(=O)(O)[O-].[Na+].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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]3[CH:30]=[CH:31][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)[S:22][C:13]=12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
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: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (240 mg, 0.50 mmol), 4-formylphenylboronic acid (150 mg, 1.0 mmol) and 4 mg of tetrakis(triphenylphosphine)palladium(0) in 20 mL of ethylene glycol dimethyl ether and 16 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with chloroform to provide 160 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 261-262° C.; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.90-8.03 (m, 4H), 8.15 (s, 1H), 8.65 (s, 1H), 9.83 (s, 1H), 10.05 (s, 1H); MS 454.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:31][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:30])(=[O:29])[NH2:28])[CH:22]=4)=[N:18][C:19]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([O:5][C:6]([C:8]1[S:31][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:29])(=[O:30])[NH2:28])[CH:22]=4)[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
2-(3-Sulfamoyl-phenylamino)-5,6-dihydro-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (4.90 g, 10.69 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.85 g, 21.37 mmol) were suspended in dry 1,4-dioxane (300 mL) and heated at reflux overnight. After allowing the reaction to cool to room temperature the mixture was concentrated under reduced pressure and partitioned between ethyl acetate and 1:1 saturated Na2CO3:brine. The organic layer was washed with further portions of 1:1 saturated Na2CO3:brine (2×200 mL), dried over Na2SO4, and filtered. Silica (˜60 mL) was added to the filtrate and the resulting suspension was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography (80-90% EtOAc in hexanes on ˜800 mL of silica) to afford the title compound as a yellow solid (1.84 g, 38% yield) and further impure material (˜2 g). MS (ES+) 457. δH (d6 DMSO) 1.6 (9H, s), 7.3 (2H, br s), 7.4-7.6 (2H, m), 7.8-7.9 (1H, m), 8.0 (2H, m), 8.7 (1H, s), 9.1 (1H, br s), 9.4 (1H, s), 10.4-10.5 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)=[N:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:25])#[N:29]
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: COc1ccc(CN(CCN(C)CCCCCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.57 g (1.5 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil that crystallises from ether at -20° C.; MS (+FAB method): m/z (rel. int. [%])=652 ([M+H]+, 12), 121 (100); IR (KBr): 2162 cm-1 (C≡N); m.p.: 52° C. (ether).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]>>[C:1]([O:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: CC(=O)Cl
Product: CC(=O)OC(Cc1ccccc1)C(=O)O
Yield: 100.4 %

Procedure:
4.83 g (61.53 mmol) of acetyl chloride are added to 8.88 g (53.49 mmol) of (RS)-2-hydroxy-3-phenyl propanoic acid. The mixture is refluxed for 30 minutes. The excess acetyl chloride is evaporated. 11.18 g of (RS)-2-acetyloxy-3-phenyl propanoic acid are obtained.