Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([C:21]([C:23]3[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:25][C:24]=3[CH3:41])=[O:22])[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:42])[C:14]=3[NH:13][C:12]=2[CH:43]=1>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([C:21]([C:23]3[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:34][CH2:33]4)=[CH:25][C:24]=3[CH3:41])=[O:22])[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:42])[C:14]=3[NH:13][C:12]=2[CH:43]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(CNC(=O)CCC2CCNCC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCC(CCC(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of propionyl chloride (0.46 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=577.4
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:27][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:27]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C

Procedure:
In a solution of 1.4 g of 2-chloro-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]benzaldehyde in 50 mL of diethyl ether under nitrogen atmosphere, 6.6 mL of a solution (0.87 mol/L) of methyl magnesium bromide in tetrahydrofuran was added dropwise with stirring at room temperature. After the completion of the addition dropwise, the mixture was continued to stir under reflux with heating further for 30 minutes. After the completion of the reaction, 5 mL of ammonium chloride aqueous solution was added in the reaction mixture under cooling with ice and with stirring, the mixture was extracted with ethyl acetate (50 mL×1), the organic phase was washed with water (30 mL×2), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and then the solvent was distilled off under reduced pressure to obtain 1.5 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].C(O)(=O)C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]=O)=[CH:20][CH:19]=1>C(O)C>[CH2:1]([N:3]1[C:7]2[CH2:8][CH2:9][NH:10][CH:26]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:19][CH:20]=3)[C:6]=2[C:5]([CH3:11])=[N:4]1)[CH3:2]
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: CCn1nc(C)cc1CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCn1nc(C)c2c1CCNC2CCc1ccc(C(F)(F)F)cc1
Yield: 34.5 %

Procedure:
2-(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-ethylamine (148 mg, 0.97 mmol) was dissolved in ethanol (3 ml) and acetic acid (116.5 mg. 1.94 mmol) was added followed by the addition of 3-(4-trifluoromethyl-phenyl)-propionaldehyde (197 mg, 0.97 mmol). The mixture was sealed and put in the microwave oven (100 Watts; 130° C., 14 bar, 6 minutes). The solvents were removed under reduced pressure and the residue was purified by prep. HPLC to give 113 mg (34.5%) of 1-ethyl-3-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. LC-MS: tR=0.75 min; [M+H]+=338.22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([C@@](O)([C@@H](O)[C@H](O)[C@H](O)CO)C(N)=O)=[CH:16][CH:15]=1.BrCC(C1C=C([NH:43]C(=O)C)C=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:43])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc([C@](O)(C(N)=O)[C@@H](O)[C@H](O)[C@H](O)CO)cc2)C1
Reactant: CC(=O)Nc1cccc(C(=O)CBr)c1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
Starting from 2,4-dichlorobenzylmethylamine (Example 1, intermediate 1) and N-[3-(2-bromoacetyl)phenyl]acetamide (cf. Example 1, intermediate 2), the aniline derivative 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (cf. Example 1, intermediate 6) was prepared in a similar manner to the synthetic route described in Example 1.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:15]=2[C:16]([OH:18])=O)=[C:11]([CH3:29])[CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:57][CH:56]=1>CN(C=O)C>[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:15]=2[C:16]([NH:54][C:55]2[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])=[CH:57][CH:56]=2)=[O:18])=[C:11]([CH3:29])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Triethylamine (177.4 ml, 1.27 mmol) was added to a solution of 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoic acid (100 mg, 0.32 mmol), HATU (121 mg, 0.32 mmol) and tert-butyl 4-aminobenzoate (61.49 mg, 0.32 mmol) in DMF (1 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and purified by reverse phase LC-MS using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield tert-butyl 4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoate (43.8 mg, 28%). ESI-MS m/z calc. 489.16. found 490.3 (M+1)+; Retention time: 2.46 minutes (3 minutes run).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-phenoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (86%, white crystals). HPLC-MS m/z=320.1 (M+1), Rt: 5.13 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: OC1CCNCC1
Reactant: N#CNc1ccccc1-c1ccccc1F
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: N=C(Nc1ccccc1-c1ccccc1F)N1CCC(O)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.5 g) and 4-hydroxypiperidine (1.4 g) in ethanol (30 ml) was heated at reflux on a steam bath for 2 hours gave a yellow foamy solid which was reacted with fumaric acid (1.3 g) in methanol (10 ml) to give N-(2'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine fumarate as a colourless solid (m.p. 214°-215° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1[CH:28]=[CH:27][C:20]([CH2:21][CH:22]([C:24]([OH:26])=[O:25])[NH2:23])=[CH:19][CH:18]=1>>[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]([NH:23][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:24]([OH:26])=[O:25])=[CH:27][CH:28]=1
Reactant: Nc1ccc(CC(N)C(=O)O)cc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: Nc1ccc(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-amino-DL-phenylalanine and crude product is separated by flash chromatography on SiO2 to provide the title compound in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:29])([F:31])[F:30])[C:9]=5[CH:17]=4)=[CH:26][CH:25]=3)=[O:24])[CH2:40][CH2:39]2)=[CH:35][CH:34]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorobenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=639.99 (M+H+); retention time=0.69 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:28]=[C:27]([F:29])[C:26]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)=[C:25]([F:42])[CH:24]=2)=[CH:4][C:3]=1[N+:43]([O-:45])=[O:44].[C:46]([C@@H:49]1[CH2:53][CH2:52][CH2:51][N:50]1[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])(=[O:48])[NH2:47].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:10]2[N:9]([C:23]3[CH:24]=[C:25]([F:42])[C:26]([N:30]4[CH2:35][CH2:34][CH:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:32][CH2:31]4)=[C:27]([F:29])[CH:28]=3)[C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:47][C:46]([C@@H:49]4[CH2:53][CH2:52][CH2:51][N:50]4[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[O:48])=[C:3]([N+:43]([O-:45])=[O:44])[CH:4]=3)[CH2:12][CH2:11]2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2c2cc(F)c(N3CCC(c4ccccc4)CC3)c(F)c2)ccc1Cl
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)C(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2c2cc(F)c(N3CCC(c4ccccc4)CC3)c(F)c2)cc1[N+](=O)[O-])C(C)C
Temperature: 100 °C
Yield: 43.4 %

Procedure:
1-(4-((2R,5R)-2,5-Bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine (0.745 g, 1.14 mmol) was dissolved in dioxane (12 mL) in a tube and treated with methyl(S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.309 g, 1.14 mmol), cesium carbonate (0.409 g, 1.25 mmol), Xantphos (0.066 g, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol). Nitrogen was bubbled through this mixture for 15 minutes, then the tube was sealed and heated at 100° C. for 2 hours. The mixture was diluted with water, extracted into dichloromethane, concentrated, and purified by chromatography, eluting with 0-5% methanol in dichloromethane to give 0.44 g (43%) of a dark yellow solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([F:30])([F:29])[C:8]([N:10]1[CH2:28][CH2:27][C:13]2([C:18]3=[C:19]([CH3:22])[CH:20]=[CH:21][N:17]3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)[CH2:12][CH2:11]1)=[O:9].[OH-].[Na+].CN([CH:36]=[O:37])C>>[CH3:22][C:19]1[CH:20]=[C:21]([CH:36]=[O:37])[N:17]2[C:18]=1[C:13]1([CH2:27][CH2:28][N:10]([C:8](=[O:9])[C:7]([F:6])([F:29])[F:30])[CH2:11][CH2:12]1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]2=1
Reactant: Cc1ccn2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Reaction time: 0.5 h
Yield: 24 %

Procedure:
POCl3 (38 μL, 0.41 mmol) was added dropwise at 0° C. under N2 to DMF (32 μL, 0.41 mmol). The reaction was stirred for 30 min at this temperature and a white solid formed, to which was slowly added a solution of 2,2,2-trifluoro-1-(3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone (95 mg, 0.27 mmol) in dry DMF (0.7 mL). The reaction stirred for 4 h, poured onto ice, 0.8 ml of 1M NaOH was added and the product was extracted with dichloromethane (3×5 mL). The organic phases were combined, washed with brine, dried, filtered and concentrated and the residue was purified by silica-gel column chromatography eluting with 5-40% EtOAc in hexanes to yield 3-methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (25 mg, 24%). ESI-MS m/z calc. 378.1. found 379.3 (M+1)+; Retention time 1.83 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([CH3:14])[CH2:8][O:9][N:10]=C(C)C)=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:14])[CH2:8][O:9][NH2:10])=[CH:15][CH:16]=1
Reactant: CC(C)=NOCC(C)Oc1ccc(Cl)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: O
Product: CC(CON)Oc1ccc(Cl)cc1
Temperature: 78 °C
Yield: 720.4 %

Procedure:
A mixture of 10 g (4.13 mmol) of acetone O-[2-(4-chlorophenoxy)-propyl]-oxime (compound 28 in Table 1) and 44 g of 30% strength by weight aqueous trichloroacetic acid solution was heated for 10 hours at 78° C. and a reduced pressure of 450 mbar in a stirred apparatus having an attached 30 cm column, 110 g of water being continuously added dropwise to the reaction mixture and the resulting water/acetone mixture being continuously distilled off. The reacted mixture was worked up by rendering it alkaline with 10% strength by weight sodium hydroxide solution and extracting it with toluene. 6 g of 2-(4-chlorophenoxy)-propoxyamine were isolated. Yield: 72%.
Reaction SMILES: [N:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][N:5]=1)=[N+]=[N-].CP(C)C.[N-]=[N+]=[N-]>O1CCCC1.O>[C:18]1([CH2:17][CH2:16][CH2:15][NH:14][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:1])[C:9]=2[C:10]([F:13])([F:11])[F:12])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=Nc1nccc(NCCCc2ccccc2)c1C(F)(F)F
Agent: CP(C)C
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nccc(NCCCc2ccccc2)c1C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 2-azido-N-(3-phenylpropyl)-3-(trifluoromethyl)pyridin-4-amine (125 mg, 0.389 mmol) in tetrahydrofuran (4.0 mL) and water (0.066 mL, 3.69 mmol was added trimethylphosphine (1.0 M in tetrahydrofuran; 0.443 mL, 0.443 mmol. After four hours starting material remained and an additional 500 μL of trimethylphosphine was added. After 21 hours, LC/MS showed a 6.7:1 ratio of desired:starting material. An additional 200 μL of trimethylphosphine was added. After 25 hours the ratio by LC/MS was 12:1 product:starting material. After 27 hours the mixture was concentrated. This material was purified on silica gel (12 g) equilibrated in hexane, loaded in dichloromethane and eluted using hexane (96 mL), 20% EtOAc/hexane (250 mL), 20 to 50% EtOAc/hexane (320 mL, linear gradient). Fractions 39-50 gave 84.5 mg of an off white crystalline solid. This was consistent with desired product by 1H NMR containing 10% of the starting azide. The material was used as is. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.79 (d, J=6.0 Hz, 1H), 7.39-7.29 (m, 2H), 7.25-7.15 (m, 3H), 5.98 (d, J=6.0 Hz, 1H), 4.96 (br. s., 3H), 3.25-3.12 (m, 2H), 2.73 (t, J=7.5 Hz, 2H), 1.98 (quin, J=7.3 Hz, 2H).
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:20]=[CH:19][C:10]2[C@H:11]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][O:13][C:9]=2[CH:8]=1)(=O)=O.[CH3:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=[C:26]([CH3:38])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CN(C)C=O.O>[CH3:38][C:26]1[CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:29]=[C:24]([CH3:23])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:6][C:7]2[CH:20]=[CH:19][C:10]3[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][O:13][C:9]=3[CH:8]=2)[CH:40]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a solution of methyl(S)-2-(6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (4.88 g) and (2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methanol (5.00 g) in N,N-dimethylformamide (15 mL) was added tripotassium phosphate (4.57 g), and the mixture was stirred at 70° C. for 3 hr. The mixture was allowed to cool to room temperature, toluene (60 mL) and water (60 mL) were added, and an extraction operation was performed. The organic layer was washed with water (60 mL) and 10% brine (60 mL), and concentrated. The obtained oil was dissolved in dimethyl sulfoxide (30 mL), and 2N sodium hydroxide (8 mL) was added at room temperature. The mixture was stirred at 70° C. for 1 hr, and allowed to cool to room temperature. Ethyl acetate (60 mL) and water (60 mL) were added, and the mixture was partitioned. The aqueous layer was acidified with 6N hydrochloric acid to pH 1, ethyl acetate (60 mL) was added, and an extraction operation was performed. The organic layer was washed with water (60 mL), and concentrated. The crude product was recrystallized from acetone (30 mL)-water (60 mL), and the obtained solid was dried at 60° C. under reduced pressure to give the title compound (4.91 g) as white crystals. Yield 65%.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]([C:14]1[CH:39]=[CH:38][C:17]([CH:18]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[C:23](=[O:28])[N:22]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[C:21]3=[O:37])[OH:19])=[CH:16][CH:15]=1)#[N:13]>C(Cl)Cl>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[C:23](=[O:28])[N:22]([C:29]2[CH:30]=[C:31]([Cl:36])[CH:32]=[C:33]([Cl:35])[CH:34]=2)[C:21]3=[O:37])=[O:19])=[CH:38][CH:39]=1)#[N:13]
Reactant: N#Cc1ccc(C(O)C23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)C23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.8 %

Procedure:
PCC (2.43 g) was added to a solution of the compound from Example 111 (3.90 g) in CH2Cl2 (20 mL) and the reaction mixture stirred at room temperature for 48 hours. The mixture was filtered though a plug of SiO2 (washing with 1:1 CH2Cl2:EtOAc). The solvent was evaporated and the residue was purified by chromatography (SiO2, hexanes to 1:1 hexanes/EtOAc gradient elution) providing the titled compound (1.97 g). MS (m/z) 414 (MH+). mp. 72.1° C.
Reaction SMILES: C(N(CC)CC([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)C)C.C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH:19]1[C:20]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:14][C:15]=2[CH:16]=[CH:17][C:18]=1[C:21](=[S:32])[NH2:22]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of 10-[(2RS)-1-diethylamino-2-propyl]2-phenothiazinecarbonitrile (5.66 g) and triethylamine (2.35 cc) in pyridine (113 cc) is treated with hydrogen sulphide for 1 hour and then stirred for 3 days at a temperature in the region of 20° C. The greenish solution obtained is purged with nitrogen, poured into distilled water (500 cc) and extracted with ethyl acetate (2×500 cc). The combined organic phases are washed successively with distilled water (2×200 cc) and with saturated aqueous sodium chloride solution (200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg, 4 kPa) at 40° C. The residual orange oil (9.1 g) is purified by chromatography on a column (height: 25 cm, diameter: 3 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (750 cc) and collecting 50-cc fractions. The combined fractions 4 to 10 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (6.2 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)#[N:2].C1C(C(OO)=O)=CC=CC=1.[Br:20]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:20][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cn1
Agent: O=C(OO)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1ccc(CBr)nc1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
0.3 g (2.5 mmol) of 5-cyano-2-methylpyridine was dissolved in 15 ml of benzene. 10 mg of perbenzoic acid and 0.49 g (2.8 mmol) of N-bromosuccinimide were added to the obtained solution, and they were stirred at 75° C. for 2 days. The solvent was evaporated and the crude product was purified by the silica gel column chromatography.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH:8]=[CH2:9].[OH-].[K+].Cl>O.CO>[CH2:9]=[CH:8][CH2:7][CH2:6][CH:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1)[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCC(CCC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCCC(CCC=C)OCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 5 h
Yield: 94.4 %

Procedure:
2.3 g of the compound (8) and 1.1 g of potassium hydroxide were dissolved in a solution mixture of 14 ml of water and 6 ml of methanol, and reflux was then carried out for 5 hours. The reaction solution was added into 100 ml of water, and the pH was adjusted approximately to 1 with concentrated hydrochloric acid. The waxen matter generated therein was washed with water and was then dried at 40° C. under reduced pressure, to obtain 2.1 g of the compound (9). (Yield: 93%)