Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22][NH2:23])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22][NH:23][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CCN)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 45 parts of benzoyl chloride in 149 parts of chloroform is added portionwise over a 30 minute period to a solution of 78 parts of 3-benzyloxy-4-methoxyphenethylamine in 72 parts of triethylamine and 596 parts of chloroform. The mixture is stirred at room temperature for an additional 90 minutes. It is then washed twice with water and once with dilute aqueous sodium bicarbonate solution, dried over anhydrous calcium sulfate and stripped to a low volume under reduced pressure. Addition of n-hexane results in crystallization of N-(3-benzyloxy-4-methoxyphenethyl)benzamide. That product melts at about 136°-138°C.
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[C:12]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][N:33]=1>>[ClH:30].[ClH:1].[CH:2]([C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:26]=[N:27][N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][N:33]=3)[CH:29]=2)[C:12]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3ccccc32)cn1
Reactant: COc1ccc(CCl)nc1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4ccccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 73.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 334 using N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.95 g) and 2-chloromethyl-5-methoxypyridine (0.83 g) as starting materials, N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.97 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][O:13][CH3:14])[C:3]=1[CH3:9]
Reactant: Cc1c(O)cccc1Br
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc(Br)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.9 g (74 mmol) of 3-bromo-2-methylphenol are dissolved in 120 mL of dimethylformamide and the mixture is cooled to 0° C. 3.6 g (90 mmol) of 60% sodium hydride are then added portionwise and the medium is stirred for 1 hour. 6.8 mL (90 mmol) of methoxymethyl chloride are then added slowly and the medium is warmed to room temperature and then stirred for 1 hour. After the usual treatment, the residue is purified by chromatography on silica gel (eluent: 80 heptane/20 ethyl acetate). The desired product is obtained in the form of a colourless oil (m=16.2 g; Y=95%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:25])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20](OCC)=[O:21])[CH2:16][CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:25])[CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][OH:21])[CH2:18][CH2:19]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(CC(C)Cc2ccc(C(C)(C)C)cc2)CC1
Solvent: CCOCC
Solvent: O
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCC(CO)CC1
Yield: 57.8 %

Procedure:
A solution of 41.4 g of N-[3-(4-tert.-butylphenyl)-2-methyl-propyl]-4-carbethoxy-piperidine in 100 ml of absolute diethyl ether is added dropwise to a suspension of 10 g of LiALH4 in 100 ml of absolute ether. An exothermic reaction ensues and the ether refluxes. When the reaction has subsided, the mixture is heated under reflux for 4 hours. 100 ml of water are then slowly added dropwise, with ice cooling. 500 ml of diethyl ether are added, the top layer is decanted and the smeary residue is triturated twice more with ether. The combined ether phases are washed with water, dried over Na2SO4 and concentrated. Distillation of the residue gives 21 g of N-[3-(4-tert.-butylphenyl)-2-methyl-propyl]-4-hydroxymethylpiperidine [B]. Boiling point 175°-178° C./0.2 mbar.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]([OH:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[OH:31][C:28]([C:27]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=2[CH:7]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(O)c1ccncc1Br
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(-c3cnccc3C(C)(C)O)cc21
Temperature: 100 °C
Yield: 0.5 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (304 mg, 1.1 mmol), 2-(3-Bromo-pyridin-4-yl)-propan-2-ol (217 mg, 1.0 mmol), Na2CO3 (2 M in water, 1.5 mL, 3.0 mmol) and PdCl2(PPh3)2 (56 mg, 0.08 mmol) in DMF (6 mL) was heated at 100° C. for 4 hrs. After concentration, the residue was diluted with DCM and saturated NH4Cl solution. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-3.5%) to give the title compound (1.4 mg, 0.5%); ESI-MS m/z: 285 [M+1]+, Retention time 0.98 min; 1H-NMR (CDCl3, 400 MHz) δ 1.51 (s, 6H), 3.43 (s, 3H), 6.95 (d, J=1.6 Hz, 1H), 7.04 (dd, J=8.4, 1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 8.11 (d, J=6.0 Hz, 1H), 8.40 (s, 1H), 8.65 (d. J=6.0 Hz, 1H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:25]=2[CH:43]=1>CC(N(C)C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:25]=2[CH:43]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-chloro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4-H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC[O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]([C:33](=O)[CH:34]([CH3:36])[CH3:35])[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[CH:17][CH:16]=1.C(OCC)C.[Cl-].[NH4+]>CS(C)=O.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:10][C:11](=[O:12])[O:13]3)[C:33]([CH:34]([CH3:36])[CH3:35])=[C:23]([C:24]([NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[C:22]=2[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:19][CH:20]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCC[C@@H]1C[C@H](CC(=O)O)OCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@H]1C[C@H](O)CC(=O)O1
Reaction time: 18 h
Yield: 23.1 %

Procedure:
A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2- aminoethyl)-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) of (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide in 5 mL of dimethyl sulfoxide is heated at 105° C. for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100 mL--to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1/H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.15 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two crops.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28]>C([O-])(=O)C.[Na+].CO>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[O:1])[CH:11]=[CH:10][C:9]=1[NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:28])[F:29]
Reactant: O=S([O-])OO
Reactant: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Oxone (1.47 g) as a solution in 1M sodium acetate solution (12 ml) was added to a mixture of (R)-N-[2-chloro-4-(4-carboxyphenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 291) (1 g) in methanol (25 ml) and stirred for 2 hours. The reaction mixture was filtered and the solid washed with water and dried under vacuum to give the title compound as a solid (1.02 g) containing 9% of the corresponding sulphone. NMR: 1.6 (s, 3H), 7.75 (d, 1H), 7.8-7.9 (m, 3H), 7.95 (d, 1H), 8.0-8.05 (m, 3H), 8.15 (d, 1H), 9.8 (s, 1H); MS (ESP−); 434.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH3:22])=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.O.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:8][C@H:12]([CH2:11][OH:10])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:19][CH:20]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)c1ccc(CC[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C(=O)c1ccc(Cl)cc1)c1ccc(CC[C@H](N)CO)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 122.7 %

Procedure:
(S)-4-(2-{4-[(4-Chloro-benzoyl)-methyl-amino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (110 mg) was dissolved in acetonitrile (1 ml) and water (2 ml) at room temperature before addition of trifluoroacetic acid (140 μl). The reaction mixture was heated to 80° C. and then stirred for 3 hours. After cooling to room temperature, ethyl acetate (4 ml) was added and the solution basified to pH 14 by addition of 2M aqueous sodium hydroxide. The mixture was stirred for 5 minutes and then extracted four times with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo to afford N-[4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-4-chloro-N-methyl-benzamide (95 mg) as a light yellow viscous oil. MS (ISP): 333.4 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:4]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:4]=1)=[O:1]
Reactant: CC(=O)NCCc1cc(CO)c2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCCc1cc(C=O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of N-{2-[4-(hydroxymethyl)-2-naphthalenyl]ethyl}acetamide (1 eq.) from the previous step and sodium bicarbonate (1.2 eq.) in dichloromethane (0.09 M) was added DMP (1.1 eq.) at 0° C. The resulting mixture was stirred at RT for 18 h before it was quenched with sat. aq. NaHSO3 and then extracted with Et2O. The combined organic extracts were washed further with 10% aq. HCl, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 19:1 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=1.CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.Cl.C(O[Pd]OC(=O)C)(=O)C.CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: Clc1cncc(Br)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1cncc(Cl)c1)c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
1-(4-chlorophenyl)ethanone (17.22 ml, 133 mmol) was added to an ice cold solution of 3-bromo-5-chloropyridine (24.3 g, 126 mmol) and sodium 2-methylpropan-2-olate (30.3 g, 316 mmol) in THF (158 ml) under an argon atmosphere. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.731 g, 1.263 mmol) and diacetoxypalladium (0.283 g, 1.263 mmol) were then added and the solution was heated to 70° C. for 1.5 hours. The solution was cooled to rt and diluted with ice, 2N HCl (95 mL) followed by EtOAc (300 ml). The layers were partitioned and the aqueous layer was washed with EtOAc (2×100 ml). The organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue obtained was enriched on a silica gel column. The fractions containing the product were combined and concentrated. To the residue obtained was added 130 ml of Et2O and the suspension was heated to a reflux in a water bath. The suspension was then cooled in an ice bath. The solids were collected by filtration to provide the title compound.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:2]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([N:3]3[C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:9]=4[N:1]=[CH:2]3)=[CH:11][CH:12]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(-n2cnc3ccncc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2cnc3ccncc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
The 4-(imidazo[4,5-c]pyridin-3-yl)aniline prepared in Step A was dissolved in 10 mL of dichloromethane, and 14.2 mg (0.064 mmol) of 4-chloro-3-(trifluoromethyl)phenyl isocyanate was added thereto and the mixture solution was stirred at room temperature for three hours. The solvent was distilled under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate to obtain 20.2 mg (73%) of 1-(4-chloro-3-(trifluoromethyl)-phenyl)-3-(4-imidazo[4,5-c]pyridin-3-ylphenyl)urea (Table 1, Compound No. 2) as a colorless crystal.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](O)=[O:19])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:55]([NH:57][CH2:58][CH3:59])[CH3:56].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:6][CH:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](=[O:19])[N:57]([CH2:58][CH3:59])[CH2:55][CH3:56])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNCC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)CSc1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Reaction time: 20 h

Procedure:
To a solution of {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetic acid (33 mg, 70.4 mmol) in DMF (0.5 mL) was added 3-hydroxy-1,2,3-benzotriazin-4-(3H)-one (12 mg, 73.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14 mg, 73 mmol). The reaction mixture was stirred at room temperature for 2 hours after which diethyl amine (10 μL, 96.3 mmol) and DIPEA (12 μL, 70.3 mmol) were added. Stirring was continued for 20 hours. The reaction mixture was purified by HPLC (C18, gradient 25%-100% acetonitrile) to give 3-cyclopentyl-N-(5-diethylcarbamoylmethylsulfanyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)propionamide as an oil. Yield: 15 mg (42%). 1H-NMR (CDCl3): δ 7.91 (d, 2H), 7.62 (d, 2H), 7.45 (s, 1H), 3.93 (t, 1H), 3.63 (s, 3H), 3.38 (q, 2H), 3.31 (q, 2H), 3.05 (s, 3H), 2.28-2.21 (m, 1H), 1.97-1.90 (m, 1H), 1.75-1.47 (m, 7H), 1.23-1.11 (m, 8H); HPLC-MS: m/z: 525 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c([C@@H]3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC[C@@H](c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-[(3R)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (107 mg, 0.25 mmol), N,N-dimethylglycine (31 mg, 0.30 mmol), EDCl (53 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), and N,N-diisopropylethylamine (132 μL, 0.76 mmol) in DMF (2.3 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 35 mg (27%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.27-7.39 (m, 5 H), 7.14 (d, 1 H), 6.64 (d, 1 H), 5.65 (s, 2 H), 3.95-4.97(m, 2 H), 2.62-3.32 (m, 5 H), 2.03-2.23 (m, 7 H), 1.68-1.91 (m, 2 H), 1.37-1.64 (m, 1 H); ES-MS m/z 509.15 [M+H]+, HPLC RT (min) 2.22.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C3C=CC(C(OCC4C=CC=CC=4)=O)=CC=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:8]3[CH:7]=[CH:6][CH:11]=[CH:10][C:9]=3[C:12]([OH:14])=[O:13])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(C(=O)Oc3ccccc3C(=O)O)cc21
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 580 mg (1.34) of benzyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate in 12 ml of methylene chloride at -10° C. under nitrogen was added slowly 1.24 ml of a 1.0M (1.24 mmol) solution of boron tribromide in methylene chloride. The reaction mixture was stirred at -10° C. for a further 2 h and then was quenched by the addition of ice. The organic layer was separated and the aqueous layer extracted with 2×25 ml methylene chloride. The organic extracts were combined and then washed with water and dried (MgSO4). The solution was then filtered and the solvent removed in-vacuo. The resultant residue was purified by flash chromatography (silica; 20% ethyl acetate in hexane followed by 100% ethyl acetate) and then recrystallization from a mixture of ethyl acetate and ethanol to give the title compound as a white solid. PMR (CDCl3): δ1.39 (6H, s), 2.10 (2H, m), 3.10 (2 H, m), 7.21 (1H, d, J~8.4 Hz), 7.28 (2H, d, J~8.7 Hz), 7.82 (1H, dd, J~8.4, 2.1 Hz), 8.14 (2H, d, J~8.7 Hz), 8.16 (1H, d, J~2.1 Hz).