Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[CH:11]=[CH:12][C:13]=1[NH:14]C(OC(C)(C)C)=O)(C)(C)C>Cl.O1CCOCC1>[F:33][C:31]([F:32])([F:34])[S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:10]1[CH:11]=[CH:12][C:13]([NH2:14])=[C:8]([NH2:7])[CH:9]=1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(=O)(=O)C(F)(F)F)cc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccccc2S(=O)(=O)C(F)(F)F)cc1N
Yield: 59.6 %

Procedure:
A solution of (4-tert-butoxycarbonylamino-2′-trifluoromethanesulfonyl-biphenyl-3-yl)-carbamic acid tert-butyl ester (0.072 g, 0.228 mmol) in 4M HCl in dioxane (3 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, and the solution was washed with saturated sodium bicarbonate and water (pH=7). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to provide the title compound as a yellow oil (0.043 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (30 mg, 0.1 mmol) in DMF (1 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (34 mg, 0.1 mmol), N,N-diisopropyl ethyl amine (83 μL, 0.48 mmol) and 4-aminotetrahydropyran (11 mg, 0.1 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and purification by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) afforded the title compound (29 mg, 76%) as a white solid. MS: m/e=395.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.C(O)(=O)C.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[S:3][C:4]([CH2:7][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][N:6]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cnc(Br)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1ncc(CN2CCCCC2)s1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
2-Bromo-5-formylthiazole (198 mg, 1.034 mmol, available from Fluorochem) was mixed with acetic acid (0.148 mL, 2.58 mmol) and Piperidine (0.128 mL, 1.292 mmol), dissolved in Dichloromethane (DCM) (9.5 mL) and stirred under nitrogen for 30 minutes. sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was allowed to stir under nitrogen for 45 minutes. A second sample of sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was left to stir under nitrogen for 4.5 days. The reaction was loaded onto a 5 g SCX-column, eluting with MeOH (40 mL) followed by 2M MeOH/NH3 (40 mL). Product-containing fractions were evaporated to dryness to give a yellow solid. This was partitioned between sodium bicarbonate (20 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (70 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid (214 mg). This was purified on a 25+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 49:1, 22 CV). Product-containing fractions were evaporated to dryness to give a dark yellow solid (134 mg)
Reaction SMILES: C(S)C.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCS
Product: O=C(O)CC(CC(=O)O)c1ccc(O)cc1
Temperature: 165 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
To a stirred suspension of 57% sodium hydride-paraffin (6.45 g), in dry dimethylformamide (70 ml) is slowly added ethanethiol (11.89 ml) in dry dimethylformamide (20 ml). After stirring the resultant slurry for 15 minutes, a solution of 3-(4-methoxyphenyl)glutaric acid (3.0 g) in dry dimethylformamide (20 ml) is added. The slurry is heated in a bath at 165° C. for 5.0 hours and most of the solvent is removed by distillation in vacuo. The residue is diluted with water, acidified with concentrated hydrochloric acid and extracted twice with ether (the extracts are discarded). The solution is saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is washed once with brine, dried and the residue crystallized from chloroform-hexane to afford 2.3 g of 3-(4-hydroxyphenyl)-glutaric acid, melting point 168°-170° C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1cccnc1)c1ccccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1cccnc1)c1ccccn1)NO
Reaction time: 24 h
Yield: 23 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (140 mg, 0.43 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:25) to furnish III as a yellow oil (31 mg, 23%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:27]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH2:32])[CH3:28].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH:32][C:15]([C:10]1([CH2:9][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16])[CH3:28]
Reactant: CCOC(=O)[C@@H](N)CCSC
Reactant: CC(C)(C)OC(=O)C(CCc1ccccc1)CC1(C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCSC)NC(=O)C1(CC(CCc2ccccc2)C(=O)OC(C)(C)C)CCCC1
Reaction time: 18 h

Procedure:
Combine the product of Step 1 (1.50 g, 4.33 mmol) with (S)-methionine ethyl ester hydrochloride (0.92 g, 4.33 mmol), triethylamine (0.65 g, 6.5 mmol), hydroxybenzotriazole (HOBT) (0.66 g, 4.33 mmol), and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (DEC) (0.91 g, 4.8 mmol) in 25 ml dimethylformamide (DMF). Stir 18 h., partition between EtOAc-H20, wash with 1N NaHCO3 and concentrate. Chromatograph the resultant residue on silica, eluting with hexane-ether 1:1 to obtain an oil, [α]D26 =-17.4° (EtOH).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:3]=1.[CH:18]1([O-:21])[CH2:20][CH2:19]1.[Na+]>CS(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([O:21][CH:18]2[CH2:20][CH2:19]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:3]=1
Reactant: [O-]C1CC1
Reactant: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)Nc1nc(C)nc(OC2CC2)c1[N+](=O)[O-]

Procedure:
12.9 g of 2-methyl-4-chloro-5-nitro-6-(3-pentylamino)-pyrimidine (0.05 mole) are reacted in dimethyl sulphoxide (c. 100 ml) with 4.0 g of sodium cyclopropanolate (0.05 mole) to yield 2-methyl-4-cyclopropoxy-5-nitro-6-(3-pentylamino)-pyrimidine.
Reaction SMILES: Cl.[N:2]1([C:6]([C:8]2[CH:42]=[CH:41][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:28]=3)[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=3)=[O:17])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[N:2]1([C:6]([C:8]2[CH:42]=[CH:41][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][OH:32])[CH:28]=3)[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=3)=[O:17])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)nn1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO)c2)nn1C
Reaction time: 0.75 h
Yield: 66.2 %

Procedure:
3.5M Hydrochloric acid (1.0 mL) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(1,5-dimethyl-1H-pyrazol-3-yl)benzamide (232 mg, 0.4 mmol) in methanol (10 mL). The reaction mixture was stirred for 45 minutes then saturated sodium bicarbonate added until the pH was adjusted to 7. The mixture was reduced in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed water (25 mL) and brine (25 mL). Dried (MgSO4) and reduced to a white foam. The crude product was purified by chromatography on silica, eluting with 0-10% methanol in ethyl acetate, to obtain the required product as a white foam (123 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Nc1cncc(Cl)n1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-acetamide I-5a (58.6 mg, 0.34 mmol) and piperazine-1-carboxylic acid tert-butyl ester (636 mg, 3.42 mmol) in ethanol (2 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with 0.1M HCl (3×35 mL), brine, dried (Na2SO4), filtered, and evaporated to dryness. The crude residue was purified by preparative TLC using ethyl acetate as the eluant to afford the title compound I-5b (36.9 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([C:21]1[CH:22]=[CH:23][C:18]([O:24][CH3:25])=[CH:19][CH:20]=1)=[O:9]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: COc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cc(Br)ccc2C)cc1
Reaction time: 6 h
Yield: 87.4 %

Procedure:
To a stirred suspension of 5-bromo-2-methylbenzoic acid (1.29 g, 6 mmol) in 12 mL of CH2Cl2 containing oxalyl chloride (8 mmol) was added 2 drops of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred 6 hr prior to removal of the volatiles using a rotary evaporator. After dissolving the crude 5-bromo-2-methylbenzoyl chloride in 15 ml of CS2, the stirred mixture was cooled to 4° prior to adding anisole (0.7 g, 6.6 mmol) followed by AlCl3 (1.7 g, 12 mmol). The reaction, after warming to 20° over 1 hr, was stirred for 15 hr prior to quenching with 1N HCl. Subsequently, the suspension was diluted with 50 ml H2O and stirred until all solids were in solution. The mixture was extracted 3× with EtOAc. The combined organic extracts were washed 1× with 1N HCl, H2O, aq NaHCO3, and brine prior to drying over Na2SO4. After removal of the volatiles, the resulting tan solid was recrystallized from 95% EtOH to yield 1.6 g of 5-bromo-2-methyl-4′-methoxybenzophenone.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:15])([CH3:14])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:16]([N:18]=[C:19]1[NH:23][CH2:22][CH2:21][S:20]1)#[N:17]>C(N(CC)CC)C>[C:16]([N:18]=[C:19]1[N:23]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:15])([CH3:14])[C@H:2]2[OH:1])[CH2:22][CH2:21][S:20]1)#[N:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: N#CN=C1NCCS1
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
A mixture of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.51 g), 2-cyanoiminothiazolidine (0.64 g), and triethylamine (4.1 ml) was heated at 100° C. for 5 hours. Triethylamine was removed under reduced pressure. To the residue was added a mixture of ethyl acetate (15 ml) and water (15 ml), and the mixture was stirred for 30 minutes. The precipitate was collected by filtration and washed with ethyl acetate to give trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.60 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([F:20])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH2:19])=[N:9]3)[CH:7]=1.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([F:20])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19][C:23](=[O:22])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:9]3)[CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(4aS,5S,7aS)-7a-(5-Bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (620 mg, 1.63 mmol) was dissolved in THF (10 mL). (BOC)2O (0.45 mL, 1.95 mmol) and Et3N (0.27 mL, 1.95 mmol) were added and the reaction was stirred at 100° C. After 1 hour, the solvents were removed in vacuo. The residue was purified using column chromatography (Biotage SNAP 25 g, 20 mL/min eluting with 20-80% EtOAc in n-hexane) to leave the title compound as a foam. (704 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.54 (t, J=1.00 Hz, 1H), 6.86-7.01 (m, 1H), 4.49-4.71 (m, 3H), 4.45 (dd, J=1.22, 8.56 Hz, 1H), 3.68-3.92 (m, 1H), 2.95-3.20 (m, 2H), 2.73 (t, J=1.00 Hz, 1H), 1.46-1.64 (m, 9H)
Reaction SMILES: O/[C:2](=[CH:8]\[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)=O)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:27]=[C:26]([NH2:28])[O:25][N:24]=1>C(O)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:9]2[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:27]3[C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:24][O:25][C:26]=3[N:28]=2)[CH:12]=[N:13][CH:14]=1
Reactant: Nc1cc(-c2cccs2)no1
Reactant: CCOC(=O)/C(O)=C/C(=O)c1cncc(C)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cncc(C)c2)nc2onc(-c3cccs3)c12
Temperature: 25 °C

Procedure:
A mixture of 1-3 (150 mg, 0.638 mmol) and 1-4 (106 mg, 0.638 mmol) in acetic acid (3 mL) was heated at reflux for 3 h. The mixture was cooled to rt and concentrated. The residue was purified by column chromatography (0-100% EtOAc in hexane) to give 1-5 as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.58 (m, 1H), 7.39 (m, 1H), 7.22 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 2.48 (s, 3H), 1.07 (t, J=7.2 Hz, 3H); ESI+ MS [M+H]+ C19H16N3O3S=366.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][NH2:28].Cl>C(#N)C>[CH3:27][NH:28][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 5 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.9 mmol), methanamine (33% in EtOH, 1 ml) and ACN (3 ml). Yield: 0.2 g, 76%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 273° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 79), 79 (bp), 70 (70), 63 (59), 51 (83).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:26]=[CH:25][C:24]=1[OH:37].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:37][C:24]3[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Oc1ccc(CCN2CCOCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(CCN3CCOCC3)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (270 mg, 0.84 mmol) and 2-fluoro-4-(2-morpholin-4-yl-ethyl)-phenol (225 mg, 0.84 mmol) in DMF (5 mL), was K2CO3 (137 mg, 0.84 mmol) added. The reaction mixture was irradiated under microwave for 1 hour at 150° C. The reaction was cooled to room temperature and poured into H2O (50 mL) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over MgSO4, and concentrated under vacuum and purified over SiO2 to afford Compound C146 (380 mg, 90%) as a white solid. 1H NMR (400 Mz, DMSO-d6) δ 8.06 (s, 1H), 7.09˜7.02 (m, 1H), 6.93˜6.91 (m, 2H), 5.12 (m, 1H), 4.61 (m, 1H), 3.46˜3.37 (m, 6H), 3.18˜3.13 (m, 2H), 2.61˜2.57 (m, 2H), 2.38˜2.26 (m, 2H), 2.25 (b, 2H), 1.96 (s, 3H), 1.79˜1.74 (m, 2H), 1.49˜1.45 (m, 2H), 1.03 (d, 6H). LCMS 503.5 [M+1].
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].CN(C1C=CC=CN=1)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>Cl>[C:21]([O:5][C:4]1[C:6]([O:7][CH3:8])=[CH:9][CH:10]=[CH:11][C:3]=1[CH:2]=[O:1])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C=O)c1O
Agent: CN(C)c1ccccn1
Agent: Cl
Product: COc1cccc(C=O)c1OC(C)=O
Reaction time: 8 h

Procedure:
To a solution of o-vanillin (10.1 g) and a catalytic quantity (0.8 g) of dimethylaminopyridine in N-diisopropylethyl amine (23 mL) at 0° C. was added acetic anhydride (8 mL). The solution was stirred overnight, poured into 2N hydrochloric acid (100 mL), extracted with dichloromethane and the solvent removed in vacuo to afford a yellow solid. Recrystallization from ethanol yielded yellow crystals (10.9 g, 85%): m.p. 75.4-76.2° C., lit17 m.p. 76° C.; EIMS m/z 194 (M+), 152, 106, 43.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:57][CH:58]([CH3:60])[CH3:59])[C:7]([F:56])=[C:8]([CH:10]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[N:54]=[C:53]([CH3:55])[O:52][N:51]=3)=[CH:46][CH:45]=2)[C:11]2[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:13]=[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=[O:19])[N:15]=2)[CH:9]=1)[CH3:2].[CH3:61][CH2:62][Mg+].[Br-].CCOC(C)=O.[Na+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:57][CH:58]([CH3:59])[CH3:60])[C:7]([F:56])=[C:8]([CH:10]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[N:54]=[C:53]([CH3:55])[O:52][N:51]=3)=[CH:48][CH:49]=2)[C:11]2[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:13]=[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]([OH:19])[CH2:61][CH3:62])[N:15]=2)[CH:9]=1)[CH3:2]
Reactant: CC[Mg+]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(O)CC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate 122.1 (50 mg, 0.06 mmol) in THF (1 mL) was added EtMgBr dropwise at 0° C. under N2 atmosphere, the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The crude material Intermediate 122.2 was used as is in the following step. LCMS (2 min gradient) RT=2.23 min, 828.4 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:16][NH:17][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: NCC1CC1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: N#Cc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Following the general procedure 2B, 733 mg (4.42 mmol) of 4-fluro-3-nitrobenzonitrile in 80% aqueous ethanol (20 mL) was added cyclopropylmethylamine (377 mg, 5.3 mmol) at room temperature. The mixture was stirred at 60° C. for 3 h before work-up. The crude product (920 mg, 96%) was used for the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.51–8.47 (br, 1H), 7.59 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.22–3.20 (m, 2H), 1.25–1.15 (m, 1H), 0.73–0.59 (m, 2H), 0.42–0.35 (m, 2H). MS (ESI) [2×(M+H)+]: 436.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:11]=3[CH:21]=2)=[N:4][N:3]=[N:2]1.C(Cl)(Cl)Cl.[Br:26]Br>O1CCOCC1>[Br:26][C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]3[NH:1][N:2]=[N:3][N:4]=3)=[CH:21][C:11]=2[C:12]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: c1ccc(-c2coc3ccc(Cc4nnn[nH]4)cc23)cc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Brc1oc2ccc(Cc3nnn[nH]3)cc2c1-c1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of 2.8 g. (0.01 mole) of 5-tetrazolylmethyl-3-phenylbenzofuran in 100 ml. of chloroform and 20 ml. of dioxane is added dropwise 1.6 g. (0.01 mole) of bromine. After 45 minutes the mixture is cooled to 0° C., then the product is separated by filtration and washed with chloroform. Recrystallization from aqueous ethanol provides 2-bromo-3-phenyl-5-(1H-tetrazol-5yl)methylbenzofuran m.p. 215°-217° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:20])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: NC(=S)c1ccc(F)cc1
Temperature: 25 °C
Yield: 146.8 %

Procedure:
4-Fluorobenzamide (5.0 g, 35.9 mmol) in benzene (100 ml) is added Lawesson's reagent (7,27 g, 18.0 mmol) and the resulting solution is heated to reflux for 1 hour. The solution is cooled to room temperature, concentrated and water (150 ml) added. The mixture is heated to reflux for 3 hours, and cooled to room temperature. The precipitate is filtered and dried under vacuum to yield 4-fluorothiobenzamide as a yellow solid (4.1 g, 71%). 1H NMR (CDCl3): δ 7.09 (t, 2H), 7.90(dd, 2H).