Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](#[N:19])[CH2:16][CH2:17][CH3:18].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[O:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:15](=[NH:19])[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:11]1
Reactant: CCCC#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCCC(=N)Nc1ccccc1N1CCOCC1
Temperature: 170 °C

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (7.5 g) and n-butyronitrile (20 ml) was heated at 170° C. in a sealed stainless steel pressure vessel for 60 hours. Excess n-butyronitrile was removed and the residue dissolved in water, basified with 10% aqueous sodium hydroxide solution to pH 12 and extracted with dichloromethane. The extract was washed with water and then brine, dried and the solvent removed. The residue was purified by chromatography on a neutral alumina column. Elution with a 1:1 mixture of dichloromethane and hexane removed unreacted starting material and then elution with a 1:99 mixture of methanol and dichloromethane yielded a solid which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give N-(2-morpholinophenyl)butyramidine monofumarate (m.p. 168°-170° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][CH2:28][OH:29].[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCO)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCOS(C)(=O)=O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 1.5 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-(2-hydroxyethoxy)pregna-1,4-diene-3,20-dione in 25 ml of pyridine is cooled to 0°C and 0.6 ml of methanesulfonyl chloride is added. After 2 hours the mixture is poured into cold dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to 2.0 g of crude mesylate.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)[C@H](C)O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A167) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.Cl.[F:24][C:25]1[C:34]2[C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=[CH:30][C:29]=2[CH:28]=[N:27][CH:26]=1>C(#N)C>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[S:35]([N:8]2[CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][C@@H:2]2[CH3:1])(=[O:36])=[O:37])[CH:28]=[N:27][CH:26]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1
Reactant: O=S(=O)(Cl)c1cccc2cncc(F)c12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1cccc2cncc(F)c12
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (2.76 kg, 12.9 mol) and triethylamine (2.97 kg, 29.3 mol) in acetonitrile (45.2 kg) was added 4-fluoroisoquinoline-5-sulfonyl chloride hydrochloride (3.30 kg, 11.7 mol) and washed well with acetonitrile (6.45 kg) while ice cooling under an argon atmosphere. The resulting mixture was stirred for two hours while ice cooling. After confirming the disappearance of the starting materials by high-performance liquid chromatography (HPLC), the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate (74.3 kg) and a 5% sodium bicarbonate solution (66.0 kg) for extraction. The resulting organic layer was washed with water (66.0 kg) and a 20% aqueous solution of sodium chloride (33.0 kg), and then dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to give the target product as a yellow amorphous product (5.18 kg, quantitative).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl.O>[CH2:7]([O:6][C:1](=[O:5])[C@@H:2]([O:3][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[CH3:4])[CH3:8]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)-(−)-ethyl lactate (37.4 g, 0.32 mol) in DCM (200 mL) was added imidazole (25.75 g, 0.38 mol) and TBSCl (50 g, 0.33 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with water and extracted with DCM (2×50 mL), the combined organic extracts washed with brine dried (MgSO4) and concentrated in vacuo to give the title product as a colourless oil (100%). 1H NMR (CDCl3, 400 MHz) 4.21 (1 H, q, J=6.73 Hz), 4.14-4.01 (2H, m), 1.29 (3H, d, J=6.79 Hz), 1.18 (3H, t, J=7.09 Hz), 0.80 (9H, s), −0.01 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:6]=2[CH:34]=1.C(O)(=O)C>ClCCl.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][NH:8][CH:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:6]=2[CH:34]=1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2ccccc2F)=NC3)cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2ccccc2F)NC3)cc1OC
Temperature: 0 °C
Yield: 67.1 %

Procedure:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine (I-71, 49 mg, 0.10 mmol) was dissolved in dichloromethane (1.8 mL). Acetic acid (0.43 mL) was added and the solution was stirred and cooled to 0° C. Zinc dust (20 mg, 0.31 mmol) was then added and the mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stir for 4 hours. Additional zinc dust (10 mg, 0.15 mmol) and acetic acid (0.22 mL) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane. The organic layer was separated and washed with 1N NaOH, brine and then dried over magnesium sulfate, filtered and concentrated in vacuo. The yellow powder was purified by column chromatography (silica gel, ethyl acetate) to afford [9-Chloro-7-(2-fluoro-phenyl)-6,7-dihydro-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine (I-72) as an orange solid (32 mg, 65%): MS m/z=477.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([S:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH2:4]([S:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]#[N:1])[CH:16]=[CH:17][CH:18]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#CBr
Reactant: Nc1cccc(SCc2ccccc2)c1
Solvent: CCOCC
Product: N#CNc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
A solution of cyanogen bromide (1.42 g, 13.4 mmol) in anhydrous diethyl ether (10 ml) was added slowly to a stirred solution of 3-(benzylthio)aniline (4.6 g, 21.4 mmol) in anhydrous diethyl ether (25 ml) at 0-4° C. After the addition, the reaction mixture was stirred at room temperature for 12 hours and became a brown solution with a white precipitate. The precipitate was filtered off and the filtrate was washed with aqueous HCl (1 M, 3×40 ml) and followed by brine (40 ml). The ether solution was dried over MgSO4, filtered, and concentrated in vacuo to yield yellow oil as crude product. It was further purified by flash chromatography (SiO2, CH2Cl2/EtOAc, 0-20%) to afford 3-(benzylthio)phenylcyanamide (2.82 g, 55% yield) as a white solid: TLC: Dichloromethane/EtOAc (93:7), Rf=0.64; 1H-NMR (CDCl3) δ (ppm) 7.2-6.7 (m, 9H, Ar—H), 4.12 (s, 2H, S—CH2). IR(KBr): 3178 cm−1 (secondary N—H), 3023-3085 cm−1 (C—H aromatic stretch), 2227 cm−1 (CN).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[C:39]1([CH2:49][C@H:50]([CH2:54][C:55]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[O:56])[C:51](O)=[O:52])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[C:39]1([CH2:49][C@H:50]([CH2:54][C:55]([N:57]2[CH2:58][CH2:59][O:60][CH2:61][CH2:62]2)=[O:56])[C:51]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:52])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(C)(C)O
Yield: 80.1 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.17 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)], 71 mg (0.22 mmoles) of 2(R)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionic acid, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, obtain 104 mg (yield 75%) of the title compound as an amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (9.0 g, 21.6 mmol) was suspended in THF/water (1:1; 200 mL). Into this solution was added lithium hydroxide monohydrate (5.31 g, 126.5 mmol) and the reaction stirred at ambient temperature overnight. The solution was cooled in an ice-bath and concentrated hydrochloric acid added until the solution reached pH 4. The precipitate was collected, washed with water and dried over P2O5 to yield off-white solid (8.642 g, 99%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].Cl>>[CH2:21]([N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1)[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]
Reactant: ClCCCOc1ccc(-c2nc3ccccc3s2)cc1
Reactant: CCCNCCC
Agent: Cl
Product: CCCN(CCC)CCCOc1ccc(-c2nc3ccccc3s2)cc1
Yield: 19 %

Procedure:
The title compound was prepared as described in Example 43 starting with (I) of Example 43 (2.0 g, 6.3 mmol) and using dipropylamine in place of dibutylamine to produce 0.41 g (19% yield) of the title compound as the HCl salt, mp 142°-143° C. IR(KBr): 3400, 1600 cm-1. MS: 369(MH+). 1H NMR (CDCl3): δ 8.19-6.95 (m, 8H), 4.19 (t, J=5.1 Hz, 2H), 3.01 (m, 6H), 2.64-0.82 (m, 12H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:28]=[N:27]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)Nc1cnc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cnc(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a degassed solution of N-(5-((2-chloropyridin-4-yl)oxy)pyrazin-2-yl)acetamide (0.25 g, 0.945 mmol) in dioxane (6 mL) was added a solution of K2CO3 (0.261 g, 1.889 mmol) in water (1.5 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.255 g, 1.228 mmol), and Pd(PPh3)4 (0.109 g, 0.094 mmol). The mixture was stirred at 80° C. for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×80 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (MeOH/DCM) to afford N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrazin-2-yl)acetamide (240 mg, 82%) product as white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.97 (d, J=1.4 Hz, 1H), 8.43 (dd, J=5.6, 0.5 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H), 8.27 (s, 1H), 7.98 (d, J=0.7 Hz, 1H), 7.40 (m, 1H), 6.92 (dd, J=5.6, 2.4 Hz, 1H), 3.85 (s, 3H), 2.12 (s, 3H); MS (ESI) m/z: 311.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][C:24]([O:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCOC(=O)Cc1ccccc1
Yield: 54 %

Procedure:
A mixture of farnesol (440 mg, 2 mmol) and phenylacetyl chloride (584 mg, 7.8 mmol) was refluxed for 2.5 hours. Extraction with hexane, and purification yielded 368 mg (yield: 54%) of oil having the following physical properties.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:10][CH:11]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>CS(C)=O>[OH:10][CH:11]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:18][CH:17]=1
Reactant: Oc1ccc(CCNCC(O)COc2ccccc2)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc(CCNCC(O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
525 mg of ethyl 4-bromobutyrate were added to a solution of 574 mg of p-[2-[[(RS)-2-hydroxy-3-phenoxypropyl]-amino]ethyl]phenol and 300 mg of potassium t-butylate in 10 ml of dimethylsulfoxide and the mixture was stirred at room temperature under argon for 6 hours. The solvent was evaporated in vacuo and the residue was chromatographed on 75 g of silica gel. Utilizing chloroform/n-propanol/saturate ammonia (500:10:1), there were obtained 600 mg of pure, amorphous ethyl 4-[p-[2-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]butyrate, ε221 =17510.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10](CC3C=CC=CC=3)[C:9]=2[C:8](=[O:21])[N:7]([CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:21])[N:7]([CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CC)c(=O)c2c1ncn2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCn1c(=O)n(CC)c(=O)c2[nH]cnc21
Reaction time: 8 h
Yield: 89 %

Procedure:
3-butyl-1-ethyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione (0.353 g, 1.08 mmol) was dissolved in acetic acid (30 mL), 20% palladium hydroxide on carbon (0.238 g) was added, and the mixture was shaken under hydrogen (at 50 psi) overnight. The catalyst was removed by filtration through Celite® and washed with acetic acid. The filtrate was concentrated under reduced pressure to yield the title compound (0.227 g, 89%); 1H NMR (400 MHz; CDCl3) δ: 0.97 (3H, t), 1.28 (3H, t), 1.38-1.47 (2H, m), 1.74-1.82 (2H, m), 4.12-4.17 (4H, m), 7.80 (1H, s); m/z 237[MH+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[C:15]([CH3:26])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:13]1[C:18]([C:19]([F:20])([F:22])[F:21])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[C:15]([CH3:26])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 72 %

Procedure:
In 50 ml of N,N-dimethylformamide, 3.00 g (19.97 mmol) of 3-tertbutylphenol, 4.35 g (18.16 mmol) of 4-chloro-5-trifluoromethyl-2-methylnitrobenzene and 3.26 g (23.60 mmol) of potassium carbonate are heated at 50° C. for 15 min. The reaction solution is added to water and extracted repeatedly with dichloromethane, the extracts are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. The solid is washed with water and hexane and dried under reduced pressure. (6.6 g, purity 70.0%, yield 72.0%, log P (pH 2.3)=5.68).
Reaction SMILES: S1C=CC(C2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8]C=2)=C1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH:27]=O>C(Cl)Cl.CO>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:8][CH:27]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: O=CCc1ccccc1Cl
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(Nc2ncc(-c3ccccc3Cl)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (2-chlorophenyl)-acetaldehyde. The title compound: ES-MS: 303.0 [M+H]+; single peak at tR=3.59 min (System 2); Rf=0.21 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:36][CH:37]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCOC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCOC2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-[2-[1-(tert-butoxycarbonyl)piperidin-4-yloxy]ethoxycarbonyl]-1,2-benzenediamine (180 mg, 0.362 mmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (0.30 mL). After 0.5 h, the mixture was concentrated in vacuo. The residue was treated with 1 N aqueous sodium hydroxide followed by ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was taken up in methanol and treated with hydrochloric acid (gas,1-2 eq) and concentrated in vacuo yielding the hydrochloride salt of the title compound (270 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1>>[NH2:22][CH2:21][CH2:20][C@H:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)[CH2:14][CH2:15]1)[CH3:23]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: C[C@H](CCN)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Using general procedure A with 4-(trifluoromethyl)aniline (0.19 mL, 1.51 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (302 mg, 1.82 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a pale blue solid (232 mg, 49% over 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][N:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[N:20][N:21]=4)[N:18]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:34]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]5[N:17]([CH:19]=[N:20][N:21]=5)[N:18]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Reactant: O=C(Cl)C1CCCC1
Product: O=C(Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1)C1CCCC1
Yield: 8.7 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 2.00 g (5.37 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo-[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained by the same reaction as in Example 8-2), and using 1.07 g (8.06 mmol) of cyclopentylcarbonyl chloride in place of acetic anhydride to obtain 219 mg of the title compound as a white powder. (Yield: 9%)