Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>CN(C=O)C.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:25]([C:28]#[C:29][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1)([CH3:27])[CH3:26]
Reactant: C#C[Si](C)(C)C
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNC(=O)Nc1nc2ccc(C#C[Si](C)(C)C)cc2s1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea (0.100 g, 0.33 mmol), Pd(PPh3)2Cl2 (0.012 g, 0.017 mmol, 0.05 eq), and triethylamine (0.20 mL, 1.42 mmol, 4.3 eq) in 1 mL of anhydrous DMF was bubbled with nitrogen gas for about 5 minutes, followed by the addition of trimethylsilyl acetylene (0.23 mL, 1.65 mmol, 5.0 eq). The mixture was heated at about 80° C. with stirring in a sealed tube for about 15 hours. The mixture was cooled down, taken up in 10 mL MeOH, and evaporated to dryness. Purification by HPLC gave pure desired compound 0.093 g (89%). LC/MS 318 (M+1); LC retention time 3.77 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH:11]3[O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][O:17][CH:13]2[CH:11]3[O:12][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[O:9][CH:10]3[CH2:16][CH2:15][CH2:14]2)[CH2:23][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: COc1cccc2c1OC1CCCC(O)C1O2
Agent: Cl
Product: COc1cccc2c1OC1CCCC(OCCN3CCOCC3)C1O2
Yield: 55.7 %

Procedure:
In an analogous manner as described in Example 3, but starting with 10 g (0.042 mole) of the alcohol of Example 2 and 9 g (0.038 mole) of 4-(2-chloroethyl)morpholine hydrochloride, there were obtained 7.4 g of the title-compound of boiling point 192°-195° C. at a pressure of 65 Pa, having the elementary analysis:
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].CO[C:12](OC)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:14])[O:2][C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4]1
Reactant: Oc1cccc(O)c1O
Reactant: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cccc(O)c2O1
Yield: 16.9 %

Procedure:
A mixture of 9.0 g of pyrogallol, 7.5 g of 2,2-dimethoxypropane and 100 ml of toluene was refluxed for 4.5 hours. After cooling, the reaction mixture was worked up in a customary manner and purified by column chromatography to give 2.0 g (yield 17%) of the desired product as a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2]1.C(O[CH2:16][C:17]([CH2:19][Si](C)(C)C)=[CH2:18])(=O)C>C1COCC1.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.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]=[C:17]1[CH2:19][C@@H:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:18]1
Reactant: COC(=O)C=Cc1ccsc1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccsc2)C1
Yield: 86.2 %

Procedure:
A mixture of methyl 3-(3-thienyl)acrylate (10.0 g, 59.5 mmol), tetrakis(triphenylphosphine)palladium(0) (5.15 g, 5.6 mmol), 1,2-bis(diphenylphosphino)ethane (1.35 g, 3.4 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (20 g, 107 mmol) in THF (125 mL) under argon was heated to reflux for 24 h. The volatiles were then removed in vacuo and the residue was purified by FC (5% ethyl acetate in hexanes) to afford the title compound (11.4 g).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:13].C1C=CC=CC=1>O>[C:9]1(=[N:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])=[CH:21][CH:20]=2)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCCc2ccccc21
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(N=C2CCCc3ccccc32)cc1

Procedure:
A solution of α-tetralone (40 ml), ethyl-p-amino-benzoate (42 g) and benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with the continuous removal of water. The crude product was crystallized from ethanol to give N-(1,2,3,4-tetrahydonaphthylidene)-p-carbethoxyaniline (XXVIII). XXVIII had a.m.p. of 108.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 2-(piperazin-1-yl)ethanamine (32.3 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 66.6 mg, (70% yield) MS (ES+): 379.2, (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:5]2.B([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1)(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:11])[N:6]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:5]4)[CH:21]=2)=[CH:27][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: O=C(O)c1cc(-c2cccc(B(O)O)c2)ccc1Cl
Reactant: O=C1c2ccc(Br)cc2CN1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2cccc(-c3ccc4c(c3)CN(C3CCCC3)C4=O)c2)ccc1Cl
Temperature: 75 °C
Yield: 12.3 %

Procedure:
5-Bromo-2-cyclopentylisoindolin-1-one (76 mg, 0.27 mmol), 3′-borono-4-chlorobiphenyl-3-carboxylic acid (90 mg, 0.33 mmol), Cs2CO3 (268 mg, 0.82 mmol) and PdCl2(PPh3)2 (22 mg, 0.03 mmol), were dissolved in a mixture of DME-H2O-EtOH (9.1 mL:3 mL:2.2 mL) and heated at 75° C. for 2 hours. The mixture was filtered through celite washed with water and filtrate was acidified with 2.5 M HCl to form the crude acid as a yellow solid. The crude residue was purified using automated prep-HPLC to yield the desired compound (14.3 mg, 12%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J=2.3 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.78-7.54 (m, 8H), 4.84-4.75 (m, 1H), 4.43 (s, 2H), 2.08-2.00 (m, 2H), 1.83-1.62 (m, 6H). LRMS calcd. for C26H22ClNO3 [M+H]+ 432 found: 432.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: C=CC(=O)O
Reactant: Clc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCc1c[nH]c2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h
Yield: 24.4 %

Procedure:
A mixture of 5-chloro-1H-indole (2.5 g; 16.49 mmol), acrylic acid (2.49 mL; 36.28 mmol) and acetic anhydride (3.09 mL; 32.98 mmol) in acetic acid was stirred at 100° C. for 48 hours, concentrated under reduced pressure and diluted in NaOH 3N (water), the precipitate was filtered off and the solution acidified to pH 2 and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) and (eluent: 15 to 60% of ethyl acetate in heptane) to give 0.900 g (24%) of 3-(5-chloro-1H-indol-3-yl)propanoic acid as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:15][C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18].CSC.B.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(Br)c(NC(=O)C(C)(C)C)c1[N+](=O)[O-]
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CSC
Product: COC(=O)c1ccc(Br)c(NCC(C)(C)C)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
3.76 g (10.47 mmol) of methyl 4-bromo-3-[(2,2-dimethylpropanoyl)amino]-2-nitro-benzoate were suspended in toluene and admixed with 6 ml (11.26 mmol) of borane-dimethyl sulfide (2M in toluene). The mixture was left with stirring under reflux for 15 h and then cooled. Thereafter, 50 ml of saturated NaHCO3 solution were added, stirring was carried out again at RT for 30 min, and then the organic phase was separated off, dried over MgSO4 and concentrated. The product was then subjected to chromatographic separation (silica gel, heptane/ethyl acetate 4:1).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([C:18]3[CH:19]=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([C:18]3[CH:19]=[N:20][C:21]([C:1]#[N:2])=[N:22][CH:23]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccc(-c2cnc(S(C)(=O)=O)nc2)cc1OC1CCCC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(C#N)nc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of potassium cyanide (205 mg) in dry DMF (10 ml) was added the compound of Example 12 (1.0 g) and the reaction mixture stirred at room temperature for 3 hr then at 50° C. for 2 h. The reaction mixture was poured into a saturated NaHCO3 solution (2.5 g Na2CO3 in 120 ml ice). The resulting yellow precipitate was filtered offand washed with water. Recrystallisation from EtOAc/hexane (1:2) gave the title compound (575 mg) as yellow needles (mp 121°-123° C.).Found C, 69.15; H, 5.73; N, 14.13. C17H17N3O2 requires C, 69.14; H, 5.80; N, 14.23%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH:18](F)[F:19])([CH2:14][CH:15]([CH3:17])[CH3:16])C(OCC)=O)=[O:7])(C)(C)[CH3:2]>FC(F)(F)C(O)=O>[CH2:14](/[C:8](=[CH:18]\[F:19])/[C:6]([O:5][CH2:1][CH3:2])=[O:7])[CH:15]([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OC(C)(C)C)C(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C(=C/F)CC(C)C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 2-(tert-butoxycarbonyl)-2-(difluoromethyl)-4-methylvalerate (35.68 g) in trifluoroacetic acid (243 ml) is stirred for 1 hour, then the excess trifluoroacetic acid is removed by evaporation. The residual oil (30.89 g) is dissolved in THF (400 ml) and treated slowly with M NaOH (121 ml) so that the pH does not rise above 7.02. After completion of the addition the solution is stirred for another 15 minutes and the product is extracted into ether. Careful distillation at atmospheric pressure, then at 24mm allows the separation of essentially pure acrylate as a colorless oil (5.72 g), bp 70°-72° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>>[C@H:14]1([NH:13][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1cccnc1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: N[C@@H]1CCc2ccccc21
Product: c1cncc(-c2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)c1

Procedure:
The title compound, MS: m/e=338.4 (M+H+), was prepared in accordance with the general method of example 63 from 5-iodo-2-chloroquinoline, (R)-1-aminoindane and 3-pyridylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][OH:17].NC1C=C(OC(C)C)C(C#N)=CN=1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: OCc1cccs1
Agent: CC(C)Oc1cc(N)ncc1C#N
Product: N#Cc1cnc(N)cc1OCc1cccs1

Procedure:
From intermediate 21 and thiophen-2-ylmethanol, synthesised in an analogous manner to intermediate 97, the title compound was obtained as a pale-yellow solid. (UPLC-MS 3) tR 0.75; ESI-MS 232.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH3:18])[O:9][C:8]2[C:10]([CH3:17])=[C:11]([CH3:16])[C:12]([OH:15])=[C:13]([CH3:14])[C:7]=2[CH2:6][CH2:5]1.[ClH:19].[NH:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[C:21]([NH2:23])=[NH:22].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.CN(C)C=O>[ClH:19].[OH:15][C:12]1[C:11]([CH3:16])=[C:10]([CH3:17])[C:8]2[O:9][C:4]([CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([NH:20][C:21]([NH2:23])=[NH:22])=[CH:32][CH:31]=3)([CH3:18])[CH2:5][CH2:6][C:7]=2[C:13]=1[CH3:14]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN)O2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCNC(=O)c1ccc(NC(=N)N)cc1)O2
Reaction time: 60 h
Yield: 15.3 %

Procedure:
The amine (prepared in reference example 3, 1.0 g) and 4-guanidinobenzoic acid hydrochloride (0.95 g) were dissolved in the mixture of pyridine (5 ml) and dimethylformamide (5 ml). Dicyclohexylcarbodiimide (0.91 g) was added to the solution. The mixture was stirred for 2.5 days. The reaction solution was filtered. The filtrate was evaporated. The residue was dissolved in methanol (10 ml), and 1N hydrochloric acid (6 mi) was added to the solution. The solution was evaporated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=10:1) to give the title compound (275 mg) having the following physical data.
Reaction SMILES: ClC1C=C2C(C(N3CCN(C(NC4C=CC(C(F)(F)F)=CC=4)=O)CC3)=CC=N2)=CC=1.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.[C:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]=[C:67]=[O:68])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]>C(Cl)Cl.CO>[C:57]([C:60]1[CH:65]=[CH:64][C:63]([NH:66][C:67]([N:45]2[CH2:46][CH2:47][N:42]([C:36]3[C:35]4[C:40](=[CH:41][C:32]([Cl:31])=[CH:33][CH:34]=4)[N:39]=[CH:38][CH:37]=3)[CH2:43][CH2:44]2)=[O:68])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (250 mg, 1.01 mmol), diisopropyl(ethyl)amine (261 mg, 2.02 mmol), and 4-acetylphenyl isocyanate (195 mg, 1.21 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[CH2:8]=O.[CH3:10][N:11]1[CH2:23][CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]2=[CH:15][CH:16]=[C:17]3[C:21]([NH:20][CH:19]=[CH:18]3)=[C:13]2[CH2:12]1>C(O)(=O)C>[N:1]1([CH2:8][CH:18]2[C:17]3[C:21](=[C:13]4[CH2:12][N:11]([CH3:10])[CH2:23][CH:22]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:14]4=[CH:15][CH:16]=3)[NH:20][CH2:19]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1Cc2c(ccc3cc[nH]c23)C(c2ccccc2)C1
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: CN1Cc2c(ccc3c2NCC3CN2CCCCC2)C(c2ccccc2)C1
Temperature: 0 °C

Procedure:
An ice-cooled solution of 1.51 ml (0.01524 mol) of piperidine and 1.14 ml of H2O in 4.6 ml of acetic acid is added, together with 1.14 ml (0.014 mol) of formalin, all at once, to 2.0 g (0.00762 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole, with stirring and while flushing with nitrogen. The mixture is then rendered alkaline with 2N NaOH and extracted with CH2Cl2. The CH2Cl2 phase is dried over Na2SO4 and the solvent is stripped off on a rotary evaporator. The residue is chromatographed on silica gel (silica gel 60 from e. Merck, Darmstadt) using an eluent mixture of CH2Cl2 /MeOH/N(C2H5)3 (15:6:0.5). The product is dried in a desiccator over P2O5 under a water pump vacuum.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22][CH2:23]Br>C(#N)C>[CH3:20][O:21][CH2:22][CH2:23][N:2]([C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1)[CH3:1]
Reactant: CNc1ccc(OC)cc1
Reactant: COCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCN(C)c1ccc(OC)cc1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a stirred solution of 1.00 g (7.29 mmol) N-methyl-p-anisidine in 15 ml acetonitrile at 0° C. were added dropwise 1.36 ml (8.02 mmol) N-ethyldiisopropylamine and 1.01 g (7.29 mmol) 2-bromoethyl methyl ether. The mixture was heated at 80° C. for 2 days and then concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 1.20 g (84%) (2-methoxy-ethyl)-(4-methoxy-phenyl)-methyl-amine as an orange oil. ES-MS m/e (%): 196 (M+H+, 100).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].CO.Cl>O.C(Cl)Cl>[N+:17]([C:5]1[CH:6]=[C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=1[OH:1])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1O
Temperature: 110 °C
Yield: 25.1 %

Procedure:
Sodium hydroxide (211 mg, 5.28 mmol) was added to a suspension of 1-chloro-2-nitro-4-[(trifluoromethyl)sulfonyl]benzene (297 mg, 1.03 mmol) in H2O (5 mL) at rt, followed by methanol (0.5 mL) to solubilise the starting material, and the reaction was heated at 110° C. for 1 h. The mixture was allowed to cool to rt, diluted with H2O (10 mL) and neutralised with 5 M HCl. DCM was added, the 2 layers were partitioned and the aqueous layer was extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give 2-nitro-4-[(trifluoromethyl)sulfonyl]phenol (D82, 70 mg, 25%) as a colourless oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([CH2:23][OH:24])=[C:21]([CH:25]([CH3:27])[CH3:26])[N:20]=[C:19]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:18]=2)=[CH:13][CH:12]=1.CC1C=CN=C(N)C=1C.[P:43](Cl)([O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44]>ClCCl>[P:43]([O:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([O:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([O:24][CH2:23][C:22]1[C:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[N:18][C:19]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:21]=1[CH:25]([CH3:27])[CH3:26])=[O:44]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Agent: Cc1ccnc(N)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1COP(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Diisopropyl ethyl amine (84.12 g) was slowly added to a mixture of N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide (commercially available; 100 g) and dimethyl aminopyridine (5 g) and diphenyl chlorophosphate (123.2 g) in dichloromethane (500 mL) at 0° C. to 5° C. The reaction mixture was stirred for 30 minutes at the same temperature to give [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl diphenyl phosphate. To this mixture was added 2-mercapto-5-methyl-1,3,4-thiadiazole (41 g) at 0° C. to 5° C. followed by slow addition of diisopropyl ethyl amine (36.5 g). The resultant mixture was stirred for 2 hours at 0° C. to 5° C. After completion of the reaction, the mixture was quenched with de-ionized water (500 mL) and acidified to pH 3.5 using hydrochloric acid (6N). The organic layer was separated and washed with sodium bicarbonate (5%) at room temperature. The organic layer was separated and dichloromethane was recovered at 45° C. to give oily residue. Methanol (300 mL) was added to resulting oily residue and the mixture was stirred at room temperature for one hour to give N-[4-(4-fluorophenyl)-5-{[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide, which was filtered, washed with methanol (100 mL) and dried at 45° C. for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:5]([CH2:6][C:7]2[CH:21]=[CH:20][C:10]([C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=3)=[O:12])=[CH:9][CH:8]=2)=[C:4]([Cl:25])[CH:3]=1.[N:26]([O-])=O.[Na+].Cl[Sn]Cl.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:33](=[N:26][NH:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:20][CH:21]=2)=[C:22]([Cl:24])[CH:23]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)c(Cc2ccc(C(=O)c3ccnc(Cl)c3)cc2)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: O=C(c1ccc(Cc2c(Cl)cc(NN=Cc3ccccc3)cc2Cl)cc1)c1ccnc(Cl)c1
Yield: 92 %

Procedure:
The title compound was prepared as yellow oil at yield of 92.0%, in a similar manner as in Reference Example 13, by the reaction of 4-[4-(4-Amino-2,6-dichlorobenzyl)benzoyl]-2-chloropyridine, NaNO2, SnCl2 and benzaldehyde.