Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (318 mg) in CH2Cl2 (10 mL) containing Et3N (91 mg) was added methanesulfonyl chloride (70 μL) and the mixture was stirred at room temperature for 1 hour. The solution was washed with water, with brine and dried over Na2SO4, filtered and evaporated. The solid obtained was recrystallized from CH3CN to give the title compound (170 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]#[N:20])[C:7]=2[CH:21]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+]>C(OC(=O)C)(=O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][CH2:19][NH:20][C:22](=[O:24])[CH3:23])[C:7]=2[CH:21]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)N(CC#N)C(c1ccccc1)CO2
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)N(CCNC(C)=O)C(c1ccccc1)CO2
Reaction time: 36 h

Procedure:
The compound obtained in Step C (200 mg; 0.71 mmol) is dissolved in a Parr reactor with acetic anhydride. Raney nickel (30% by weight, 60 mg) and sodium acetate (1.5 eq.; 1.07 mmol; 88 mg) are then added. The mixture is left at 50° C. for 36 hours under a hydrogen pressure of 40 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The crude reaction product is purified by flash chromatography on silica gel (eluant: AcOEt). The title product is obtained in the form of white crystals, which are recrystallised from an Et2O/i-PrOH mixture.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[C:31]1(=O)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:23][CH2:24]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Reactant: O=C1CCCC1
Agent: Cl
Product: O=C(N[C@@H](COCC1CCN(C2CCCC2)CC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using alkylation method A, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide hydrochloride (150 mg, 0.33 mmol) and cyclopentanone (0.5 mL, 5.7 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 78 mg (49%) of the title compound.
Reaction SMILES: [C:1]1([CH:13]2[CH:18]([CH3:19])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.[ClH:27]>O1CCOCC1.CCOCC>[ClH:27].[CH3:19][CH:18]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:1]1[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1c1ncc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1CCNCC1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (12.2 g, 34.3 mmol) in 1,4-dioxane (100 mL) was added 4N HCl (4N in 1,4-dioxane, 25.7 mL, 103 mmol). The reaction mixture was heated at about 60° C. for about 2 h. The mixture was allowed to cool to ambient temperature and was diluted with Et2O (100 mL). The mixture was triturated and filtered, and the precipitate was washed with Et2O (100 mL) to give 1-(4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (10 g, 98% yield) as a tan solid: LC/MS (Table 2, Method a) Rt=1.05 min; MS m/z: 256 (M+H)+.
Reaction SMILES: [CH3:1]CCCCC.C([Li])(C)(C)C.[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH:28]=O)=[CH:19]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH:28]=[CH2:1])=[CH:19]2
Reactant: CCCCCC
Reactant: COc1cc2cc(C=O)ccc2c(OC)c1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (2.8 g) was suspended in dry THF (10 mL) under an argon atmosphere, and a 1.7 M hexane solution (3.3 mL) of tert-butyllithium was added to the suspension at −20° C. After stirring the mixture at room temperature for 1 hour, the reaction mixture was cooled again to −20° C., a solution of 5,6,7-trimethoxynaphthalene-2-carboaldehyde (1.26 g) in dry THF (30 mL) was added dropwise thereto, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH2:12])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H]1c1ccc(F)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@@H]1C[C@H]1c1ccc(F)cc1
Yield: 66 %

Procedure:
2-{[trans-2-(4-Fluorophenyl)cyclopropyl]methyl}isoindoline-1,3-dione (974 mg, 3.30 mmol) in ethanol (50 mL) was stirred with hydrazine monohydrate (825 mg, 16.5 mmol) at 100° C. for 30 minutes. The reaction mixture was concentrated to give the title compound as a colorless oil (360 mg, yield 66%).
Reaction SMILES: [CH:1]1([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.CN(C)P(N(C)C)(N(C)C)=O.C([N-]C(C)C)(C)C.[Li+].Br[CH2:35][CH2:36][Cl:37]>C1COCC1>[Cl:37][CH2:36][CH2:35][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][CH:1]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: ClCCBr
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CCCl)(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To the above described mixture of crude dimethyl cyclohexane-1,4-dicarboxylate (100 g, 0.5 mol) and hexamethylphosphoramide (360 mL, 2 mol) in anhydrous THF (800 mL) was added the freshly prepared lithium diisopropylamide solution (preparation described above) over 30 min at −40° C. After stirring for 1 h at this temperature, 1-bromo-2-chloroethane (42 mL, 0.5 mol) was added over 1. The mixture was stirred for 3 h at −78° C. and then stirred overnight at room temperature. The reaction was quenched by the addition of aqueous hydrochloric acid solution (3 N, 420 mL). The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (200 mL×3). The combined extracts were washed with brine (2×300 mL) and dried over sodium sulfate. Concentration gave the title compound (116 g, yield 88%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (s, 3H), 3.65 (s. 3H), 3.46-3.42 (m, 2H), 2.33-2.21 (m, 3H), 2.05-1.85 (m, 4H), 1.58-1.42 (m, 2H), 1.25-1.15 (m, 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][S:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[N:25]2)=[CH:18][CH:17]=1)[CH:13]=[CH2:14]>C(OCC)(=O)C.ClCCl>[CH2:12]([O:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][S:21]([CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[N:25]2)=[O:9])=[CH:18][CH:17]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1ccc(CSCCn2ccnn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(CS(=O)CCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of 1.86 g (8.29 mmol) 77% 3-chloroperbenzoic acid in 40 ml ethyl acetate was added at −30° C. within 20 min. to a solution of 1.90 g (6.90 mmol) 1-[2-(4-allyloxy-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 160 ml dichloromethane and stirred for 1 h. The mixture was allowed to warm to room temperature (r.t.) washed with sat. NaHCO3-solution, water and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol 5:1) to give 1.25 g of the title compound as white powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:16]>CO.C(Cl)(Cl)Cl.CCOCC>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc(F)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (2.02 g, 9.71 mmol, Aldrich) in methanol and chloroform (1:1, 32 ml) was added a 2 M TMS-diazomethane in ether (˜7 ml) in portions, over about 2 h, allowing the solution to cool down between additions. The solution was evaporated in vacuo and the residue dissolved in chloroform (˜20 ml). The solution was evaporated in vacuo to give methyl 4-fluoro-2-(trifluoromethyl)benzoate as a slightly yellow-brown liquid (2.07 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@H:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][C@@H:26]4[CH3:38])[CH3:24])[CH:19]=[N:20][C:21]=3[F:22])[CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[CH:10]=2)=[CH:17][C:18]([C@H:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]2[CH3:38])[CH3:24])=[CH:19][N:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNC[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (0.240 g, 0.358 mmol) in CH2Cl2 (5 mL) at 0° C. was treated with TFA (0.53 mL, 7.16 mmol). The reaction was allowed to warm up to RT and stir for 2 hours. The reaction mixture was concentrated, resuspended in CH2Cl2 and treated with aqueous NaHCO3 (sat.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.350 mmol, 98% yield) as a light yellow oil. m/z (ESI, +ve) 571.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J=9.39, 2.35 Hz, 1H); 8.12 (s, 1H); 7.18 (d, J=7.82 Hz, 4H); 6.79-6.89 (m, 5H); 4.74 (br. s., 4H); 4.16 (q, J=6.98 Hz, 1H); 3.79 (s, 6H); 2.80-2.99 (m, 4H); 2.53-2.63 (m, 4H); 2.23-2.41 (m, 2H); 1.47 (s, 3H); 1.08 (d, J=6.26 Hz, 3H).
Reaction SMILES: I[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[C:26]#[N:27])O1.N>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[C:26]#[N:27])[O:6][N:5]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: Ic1cc(-c2ccccn2)no1
Agent: N
Product: N#Cc1cncc(-c2cc(-c3ccccn3)no2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CC using 5-iodo-3-(pyridin-2-yl)isoxazole (136 mg, 0.5 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (Frontier, 173 mg, 0.750 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (ddd, J=7.3, 4.8, 1.4 Hz, 1H), 7.93 (s, 1H), 8.04 (td, J=7.6, 1.8 Hz, 1H), 8.11 (dt, J=7.9, 1.2 Hz, 1H), 8.78 (ddd, J=2.9, 1.8 Hz, 1H), 8.96 (t, J=2.2 Hz, 1H), 9.16 (d, J=1.6 Hz, 1H), 9.47 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH:57][C:58]2[CH:63]=[CH:62][C:61]([C@@H:64]3[CH2:70][C@@H:69]4[C@H:65]3[CH2:66][N:67]([CH2:71][CH2:72][CH3:73])[CH2:68]4)=[CH:60][CH:59]=2)(=[O:56])=[O:55])=[CH:50][CH:49]=1.[CH3:74][O:75][CH2:76][C@H:77]1[CH2:81][CH2:80][CH2:79][NH:78]1.ClCCl.CO>O1CCCC1>[CH3:74][O:75][CH2:76][C@H:77]1[CH2:81][CH2:80][CH2:79][N:78]1[C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH:57][C:58]2[CH:63]=[CH:62][C:61]([C@@H:64]3[CH2:70][C@@H:69]4[C@H:65]3[CH2:66][N:67]([CH2:71][CH2:72][CH3:73])[CH2:68]4)=[CH:60][CH:59]=2)(=[O:56])=[O:55])=[CH:50][CH:49]=1
Reactant: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(Br)cc4)cc3)[C@@H]2C1
Reactant: COC[C@H]1CCCN1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(N5CCC[C@@H]5COC)cc4)cc3)[C@@H]2C1
Reaction time: 2 h
Yield: 17.5 %

Procedure:
A solution of 0.07 g rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 0.11 mmol) and 0.043 g tri(dibenzylideneacetone)dipalladioum(0) (0.05 mmol) in 5 ml tetrahydrofuran were added dropwise to a solution of 4-bromo-N-[4-((1R,5S,6R)-3-propyl-3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-benzenesulfonamide (0.26 g, 0.59 mmol), (R)-2-(methoxymethyl)pyrrolidine (104 mg, 0.9 mmol), and 0.104 g sodium tert.butylate (1.08 mmol) in 20 ml tetrahydrofuran. The reaction mixture was refluxed for 5½ hours, and, after additional addition of 0.04 ml (R)-2-(methoxymethyl)pyrrolidine, for another 2 hours. After evaporation, the residue was treated with water, extracted twice with diethyl ether and dichloromethane each, and the combined organic layers dried over magnesium sulfate, filtered, and the solvent evaporated. Purification of the thus obtained crude product via silica gel chromatography using a gradient of dichloromethane/methanol 0-12% gave 50 mg (yield 18%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1.[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:21][CH:20]([C:19]3[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=3)[OH:22])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Yield: 11.1 %

Procedure:
2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (400 mg, 2.1 mmol), 4-methylstyrene oxide (2.1 g, 15.7 mmol) and NaH (252 mg, 6.3 mmol) were heated in DMF (5 mL) at 120° C. for 16 h to obtain 75 mg of racemic-2-(1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., inject ion vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.45-13.20 (bs, 1H), 7.40-7.05 (m, 8H), 5.0-4.9 (t, 1H), 4.8-4.6 (t, 1H), 4.25-4.05 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.30 (m, 2H), 3.05 (m, 1H), 3.00-2.91 (m, 3H), 2.3 (s, 3H).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:13])([F:12])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]([F:3])([F:12])[F:13])[CH2:11][CH2:10]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: FC(F)(F)CN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(CC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To as stirred solution of 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride (181.6 mg, 753 μmol) and triethylamine (182 mg, 250 μL, 1.79 mmol) in dichloromethane (5 mL) cooled to 0° C., 2-chloroacetyl chloride (85.1 mg, 60.0 μL, 753 μmol) was added drop-wise over 2 min then stirred for 10 min. The reaction mixture was warmed to 25° C. over 3 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed with water (25 mL) and brine (50 mL), dried over sodium sulfate, and concentrated to give 2-chloro-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethanone (123.3 mg, 504 μmol, 67%) as an orange oil. 1H NMR (DMSO-d6) δ: 4.73 (br. s, 2H), 3.45 (br. s, 4H), 3.23 (q, J=10.3 Hz, 2H), 2.61 (d, J=20.8 Hz, 4H).
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[OH:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C(N(CC)CC)C.O>C(#N)C>[CH3:6][Si:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][O:2][C:1]([O:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18])=[O:9]
Reactant: O=C1CCC(=O)N1O
Reactant: C[Si](C)(C)CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O

Procedure:
2-Trimethylsilylethyl carbonochloridate (4.8 g, 26.9 mmol) was taken up in dry acetronitrile (50 mL). The solution was cooled to 0° and solid N-hydroxysuccinimide (4.0 g, 34.8 mmol) was added with vigorous stirring followed by a solution of dry triethylamine (3.2 g, 31.6 mmol) in dry acetonitrile (5 mL). The mixture was stirred at low temperature for 15 minutes, then at room temperature overnight. The mixture was poured into water (200 ml) and extracted with ether (4×50 mL). The organic extracts were combined, washed with water (2×60 mL), 1 normal hydrochloric acid (60 mL), again water (60 mL), brine (60 mL), dried with magnesium sulfate and evaporated to dryness. The residue was taken up in boiling hexane (200 mL) and the solution allowed to cool. Crystallization was completed by storage at −15° C. (yield: 1.70 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]4[CH3:26])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.Cl.[C:32]([O:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40])([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH3:40][N:39]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]4[CH3:26])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[CH:5][N:4]=1)[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:41]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CCl)c3)no2)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1C(F)(F)F

Procedure:
A solution of 3-(2-(chloromethyl)pyridin-4-yl)-5-(4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.065 g; 0.15 mmol), sarcosine t-butyl ester hydrochloride (0.031 g; 0.17 mmol) and K2CO3 (0.046 g; 0.34 mmol) in dioxan (2 mL) was heated at 70° C. for 96 hours. DCM and water were added to the reaction mixture. The mixture was poured through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with DCM/MeOH (100% DCM to 10% MeOH/DCM) to afford the title product. 1H NMR (CDCl3, 400 MHz) δ 8.75 (1H, dd, J=5.1, 0.9 Hz), 8.51 (1 H, d, J=2.1 Hz), 8.34 (1 H, dd, J=8.4, 2.1 Hz), 8.21 (1 H, s), 7.91 (1 H, dd, J=5.1, 1.7 Hz), 7.55 (1 H, d, J=8.4 Hz), 3.98 (2 H, s), 3.34 (2 H, s), 3.12-3.01 (2 H, m), 2.59 (1 H, td, J=11.0, 3.0 Hz), 2.48 (3 H, s), 1.87-1.40 (6 H, m), 1.51 (9 H, s), 0.86 (3 H, d, J=6.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28](O)=[O:29])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:65]([O:69][C:70]([N:72]1[CH2:77][CH2:76][N:75]([C:78](=[O:83])[C@@H:79]([NH2:82])[CH2:80][F:81])[CH2:74][CH2:73]1)=[O:71])[CH2:66][CH2:67][CH3:68]>CN(C=O)C>[CH2:65]([O:69][C:70]([N:72]1[CH2:73][CH2:74][N:75]([C:78](=[O:83])[C@@H:79]([NH:82][C:28]([C:19]2[CH:18]=[C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[O:31])[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=2)=[O:29])[CH2:80][F:81])[CH2:76][CH2:77]1)=[O:71])[CH2:66][CH2:67][CH3:68]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Reactant: Cc1ccc2c(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc(C(=O)O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)c2cc(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c3ccc(C)cc3n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 452 mg 4-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 15 ml DMF were added 0.54 ml DIPEA and 400 mg HATU. After 5 minutes 410 mg 4-((R)-2-Amino-3-fluoro-propionyl)-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 24 h. The mixture was concentrated, diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and 0.1 M HCl. The crude product thus obtained after evaporation of the solvent was used in the next step without further purification. Yield: 1.28 g.
Reaction SMILES: [Na].[N:2]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:11][CH2:10][CH2:9][CH2:8][N:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]
Reactant: OCCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Agent: [Na]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Sodium metal (5 equivalents) was added, under nitrogen atmosphere, to a solution of 3-(4-morpholinyl)-1-propanol (4 equivalents) in THF. The obtained suspension was stirred at 20° C. for two hours and was thereafter cannulated, under nitrogen atmosphere, into a solution of 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline. The reaction mixture was refluxed for 18 hours, the solvent was thereafter partially removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. Drying the combined organic extracts, evaporation and silica gel chromatography (using a mixture of 20% MeOH/30% CH2Cl2/50% EtOAc as elute) gave 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitroquinazoline in 72% yield.