Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].Cl([O-])(=O)(=O)=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:15]=4[O+]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1.O>C(O)(C)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:28])([CH3:29])[CH2:23][C:15]=4[N:2]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1
Reactant: Cc1[o+]c2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Reactant: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Yield: 50 %

Procedure:
Aqueous ammonium hydroxide solution (3 mL) was added to a suspension of 9-fluoro-3,3,6-trimethyl-1-oxo-2,3,4,7-tetrahydro-1H-5-oxonia-7-aza-benzo[c]fluorene perchlorate of Example 3b (0.72 g, 1.88 mmol) in isopropanol (2 mL). The reaction mixture was refluxed for 1 h, cooled, and water (5 mL) was added. Aqueous ammonium hydroxide solution was added to the mixture to pH 9. The precipitate was filtered off, washed with water and dried. The crude product was dissolved in acetone, and 37% aqueous hydrochloric acid (0.2 mL) was added. The precipitate was filtered off, suspended in hot water, and the mixture was basicified with ammonium hydroxide to pH 9. The product was filtered off, washed with water, dried and crystallized from toluene to give 0.26 g (50%) of colorless crystals; m.p. 244-246° C.
Reaction SMILES: [O:1]([C:19]1[CH:26]=[C:25]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][C:20]=1[CH:21]=O)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:36]([C:38]1[C:39](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:40][C:41]([CH3:45])([CH3:44])[C:42]=1[CH3:43])#[N:37]>C(O)C>[O:1]([C:19]1[CH:26]=[C:25]([N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=[CH:23][C:20]=1[CH:21]=[CH:43][C:42]1[C:41]([CH3:44])([CH3:45])[O:40][C:39](=[C:46]([C:47]#[N:48])[C:49]#[N:50])[C:38]=1[C:36]#[N:37])[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 60 °C
Yield: 72.6 %

Procedure:
In 5 ml of ethanol were dissolved 200 mg (0.41 mmol) of 2-(tert-butyldiphenylsiloxy)-4-dibutylaminobenzaldehyde and mg (0.45 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 60° C. for 3 hours, the precipitate was separated by filtration and washed with methanol. The crystal was purified by silica gel column chromatography and washed with methanol to give 199 mg of a dark brown crystal having a mp of 220-221° C. (yield: 72.6%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][O:23][C:24]5[CH:28]=[CH:27][O:26][N:25]=5)[O:19][C:18]4=[O:29])=[CH:13][C:12]=3[F:30])[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C.O>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][O:23][C:24]4[CH:28]=[CH:27][O:26][N:25]=4)[O:19][C:18]3=[O:29])=[CH:13][C:12]=2[F:30])[CH2:9][CH2:10]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 88.8 %

Procedure:
3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (3.58 g, 8.52 mmol) was dissolved in a mixture of glacial acetic acid (50 ml) and water (50 ml), and heated at 50° for 12 hours. Solvent was evaporated, the residue azeotroped with toluene (50 ml), then partitioned between EtOAc (150 ml) and water (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×100 ml), water (100 ml), dried (magnesium sulfate) and evaporated. The residue was purified by chromatography on a 90 g silica Biotage column eluting with a gradient from 5:1 EtOAc to isohexane to EtOAc. Relevant fractions were combined to give the desired product (2.84 g).
Reaction SMILES: C[Al](C)C.C([O:7][C:8]([C:10]1[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[C:17]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=2)=[CH:18][CH:19]=1)=O)C.[CH2:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=2)[CH2:34][CH2:33]1)[CH3:31].O>C1(C)C=CC=CC=1>[CH2:30]([N:32]1[CH2:33][CH2:34][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:8]([C:10]3[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]([C:20]4[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=4)=[CH:18][CH:19]=3)=[O:7])=[N:43][CH:44]=2)[CH2:36][CH2:37]1)[CH3:31]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(OC)cc(OC)c4)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Trimethyl aluminum (2 M in toluene, 0.37 mL, 0.74 mmol, 2.5 equiv) was added to a mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) and 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by column chromatography) (78 mg, 0.36 mmol, 1.2 equiv) in toluene (2 mL). The reaction mixture was stirred for 1 h at rt, heated to reflux, stirred for 3 h, allowed to cool, poured onto EtOAc and H2O, and filtered through a pad of celite. The filtrate was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by reverse-phase preparative HPLC to afford 54 mg of the title compound as a pale yellow solid. Title compound: ESI-MS: 513.2 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [N:1]1([C:7]([C:9]2([CH2:21][NH2:22])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35]([NH:22][CH2:21][C:9]1([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=[O:36]
Reactant: CCCS(=O)(=O)N1CCC(CN)(C(=O)N2CCOCC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of {[4-(morpholin-4-ylcarbonyl)-1-(propylsulfonyl)piperidin-4-yl]methyl}amine (I-5) (33 mg, 0.10 mmole), DIEA (35 μL, 0.20 mmole), and 2,4-dichlorobenzoyl chloride (23 mg, 0.11 mmole) in DCM (2 mL) was shaken 1 h at room temperature. After this time, LCMS indicated that the reaction was completion. DCM was removed by nitrogen gas flow and the residue was purified by LCMS to afford the title compound (I-6) as a white solid. Analytical LCMS: single peak (214 nm), 2.867 min. 1H NMR (600 MHz, CD3CN): δ 7.52 (dd, J=0.9, 1.5 Hz, 2H), 7.39 (m, 2H), 6.98 (t, J=5.9 Hz, 1H), 3.63 (m, 10H), 3.49 (m, 2H), 3.05 (m, 2H), 2.89 (t, J=7.8 Hz, 2H), 2.30 (m, 2H), 1.74 (m, 2H), 1.62 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); HRMS: calc'd for C21H29Cl2N3O5S [M+H], 506.1278; found 506.1248.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.C(N(CC)CC)C.[N-]=C=O>ClCCl.CCOC(C)=O>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:18]([NH2:20])=[O:19])=[C:8]2[S:5]([NH:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:31])(=[O:6])=[O:7]
Reactant: NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Reactant: COc1ccc(N=C=O)cc1
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)NCCNS(=O)(=O)c2c(C(N)=O)[nH]c3ccc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 63 (50 mg) was combined with 4-methoxyphenyl isocyanate (21 mg) and triethylamine (58 μL) in 2 mL of dichloromethane and stirred at room temperature for 3 hours. An additional 18 μL of the isocyanate were added and the reaction stirred for 3 hours more, then diluted with EtOAc and washed with saturated NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative reversed-phase HPLC followed by triteration with Et2O/hexane to give the titled product. ESI+ MS: 510 [M+H]+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[S:13]1[C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]1=2>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:18]([C:17]2[S:13][C:14]3[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=3[CH:16]=2)(=[O:20])=[O:19])=[C:5]([NH:10][S:18]([C:17]2[S:13][C:14]3[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=3[CH:16]=2)(=[O:19])=[O:20])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: O=S(=O)(Nc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Yield: 53.3 %

Procedure:
N,N′-(4-Trifluoromethyl-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (100 mg) was prepared by using 4-trifluoromethyl-benzene-1,2-diamine (0.06 g, 0.33 mmol) and benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol), following procedure as in Example 32.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][NH2:60])=[CH:54][CH:53]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:60][CH2:59][CH2:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][CH3:50])=[CH:53][CH:54]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), EDCI (72.5 mg, 0.378 mmol), and 1-hydroxybenzotriazole (51.1 mg, 0.378 mmol) were dissolved in DCM (Volume: 3.0 ml). The reaction was stirred at room temperature for 10 minutes before Hunig'sBase (0.066 ml, 0.378 mmol) and 2-(4-methoxyphenyl)ethanamine (0.055 ml, 0.378 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude material was triturated with ethyl acetate to obtain product as a white solid. (Yield: 84 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.80, 7.59, 7.51, 7.34-7.27, 7.23-7.14, 7.12-7.02, 6.84-6.78, 6.68, 5.45, 4.48-3.82, 3.67, 3.18, 2.89, 2.60, 2.34-2.26, 1.59, 1.31
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.ClC(O[CH2:11][C:12]1C=CC=[CH:14][CH:13]=1)=O.[C:18](=O)([O-:20])[O-:19].[K+].[K+].CO>C(Cl)Cl>[CH2:5]([NH:4][C:18](=[O:19])[OH:20])[C:6]1[CH:2]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:3]1[CH:2]=[CH:6][CH:5]=[N:4]1
Reactant: Nc1cc[nH]n1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)NCc1ccccc1
Product: c1cn[nH]c1
Reaction time: 24 h
Yield: 177.8 %

Procedure:
To a stirred solution of amino-pyrazole (1.0 g, 5.95 mmol), prepared in step C, in 40 mL of CH2Cl2 at room temperature was added benzyl chloroformate (2.7 mL, 17.97 mmol). Solid potassium carbonate (4.1 g, 29.71 mmol) was added in one portion. After 24 h, methanol (5 mL) was added to the mixture, and stirring was continued for additional 2 h. Insoluble material was removed by filtration, and washed with methanol. The combined filtrate and rinsing were concentrated under reduced pressure to a thick syrup, which was separated by preparative TLC (CH2Cl2-MeOH=30:1). The silica was extracted with MeOH and CH2Cl2, the extracts were filtered and concentrated under reduced pressure to yield 1.16 g (64%) of the pyrazole benzyl carbamate as a solid (MH+=303.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:39]([C@H:35]4[CH2:36][CH2:37][CH2:38][NH:34]4)=[O:40])[C@H:22]([CH3:26])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a stirred solution of the crude 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-indazole (0.078 g, 0.20 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.086 g, 0.40 mmol) in dichloromethane (1 mL) was added HATU (0.15 g, 0.40 mmol) and Et3N (0.10 mL, 0.72 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by the addition with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30% ethyl acetate in hexanes) to afford the desired product (0.034 g, 0.058 mmol, 11% for 2 steps).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 4-tert-butoxycarbonylamino-1-N-(3,3-diphenylpropyl)piperidine (Method J) (10 g, 25 mmol) in DCM (100 ml) was added trifluoroacetic acid (20 ml) dropwise. After 3 h, toluene was added and the reaction mixture was concentrated to give the di-trifluoroacetic acid salt of the title compound as an oil (9.7 g, 19 mmol); MS: 295.
Reaction SMILES: N(OCCC(C)C)=O.[CH2:9]([O:16][C:17]1[CH:44]=[CH:43][CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:26]=[C:25]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])[C:24]([F:40])=[CH:23][C:21]=1N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:21]1[CH:23]=[C:24]([F:40])[C:25]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:26][C:20]=1[O:19][C:18]1[CH:41]=[CH:42][CH:43]=[CH:44][C:17]=1[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
4.46 g of isoamyl nitrite was added dropwise to a mixture of 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 2.45 g of copper (I) chloride, 5.04 g of copper (II) chloride, and 90 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.6 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[O:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A solution of 26.28 g (0.141 mol) of 4-bromobenzyl alcohol and 19.1 g (0.28 mol) of imidazole in 100 mL of methylene chloride was treated dropwise with a solution of 21.18 g (0.14 mol) of t-butyldimethylsilyl chloride in 50 mL of methylene chloride. The reaction mixture was stirred at room temperature for 30 minutes then transferred to a separatory funnel and washed with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum giving 41 g of the product as a colorless, viscous oil. 1H NMR (200 MHz, CDCl3): 0.09 (s, 6H), 0.93 (s, 9H), 4.67 (s, 2H), 7.18 (d, 8 Hz, 2H), 7.43 (d, 8 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[N:19]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C.C1COCC1>CO>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[N:19]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:18]=2)=[O:16])[CH2:9]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: CO
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCNC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 88.4 %

Procedure:
In a round-bottomed flask, (R)-3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (138 mg, 0.22 mmol) was suspended in methanol (2 ml). The reaction was cooled to 0° C. and acetyl chloride (0.30 ml, 4.22 mmol) was added dropwise over 10 min. The resultant bright yellow suspension was stirred at room temperature for 50 min. THF (1 ml) and methanol (1 ml) were added and stirred was continued for 1 h at room temperature then the solvent was evaporated at room temperature. The residue was suspended in dichloromethane and washed with saturated Na2CO3-solution. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 105 mg (90%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-piperidin-3-ylamide as a light yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1.[CH3:14][C:15]([CH3:17])=O.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[CH:15]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1)([CH3:17])[CH3:14]
Reactant: CC(C)=O
Reactant: COc1cccc2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc2c1C[C@@H](NC(C)C)CO2
Reaction time: 72 h

Procedure:
(R)-3-Amino-5-methoxychroman (1.0 g; 6 mmol) and acetone (2.5 g; 40 mmol) were mixed with methanol (820 ml), acetic acid (0.4 g; 6.6 mmol) and NaCNBH3 (1.2 g; 19 mmol), pH was adjusted to 6.0 with acetic acid. Stirring was continued at room temperature for 3 days. The mixture was evaporated and the residue was made alkaline and extracted with CH2Cl2. After drying (Na2SO4) and evaporation the title compound as base was transformed to the HCl-salt. Yield: 1.1 g (83%). Mp: 289° dec. [α]D25 =-29° (C=0.015; MeOH)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:13][O:14][C:15](=[O:24])[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CCOCC.O>[CH3:13][O:14][C:15]([C:16]1[C:4]([C:3]2[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:6][O:7][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: ON=C(Cl)c1c(F)cccc1Cl
Reactant: COC(=O)C#Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1ccccc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of 2-chloro-6-fluorobenzoylchloride oxime (1.04 g, 5.00 mmol) and methyl-3-phenyl-2-propynoate (1.20 g, 7.50 mmol) in Et2O (25 ml) at 0° C. under nitrogen was added a solution of triethyl amine (0.834 ml, 6.00 mmol) in Et2O (3 ml) over 1 h. The reaction was allowed to warm to room temperature overnight (17 h). The mixture was diluted with Et2O and H2O, the layers separated, and the organic fraction was dried (MgSO4). Column chromatography (silica gel, hexane/Et2O gradient) gave the title compound (1.53 g, 92%).
Reaction SMILES: [Sn].[C:2]([O-:5])(=[O:4])[CH3:3].[Sn+2:6].[C:7]([O-:10])(=[O:9])[CH3:8].[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[C:2]([O-:5])(=[O:4])[CH3:3].[Sn+4:6].[C:7]([O-:10])(=[O:9])[CH3:8].[C:11]([O-:14])(=[O:13])[CH3:12].[C:2]([O-:5])(=[O:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: [Sn+2]
Agent: CC(=O)[O-]
Agent: [Sn]
Product: [Sn+4]

Procedure:
Ruf, U.S. Pat. No. 5,068,373, Entitled Method for the Preparation of Anhydrous Tin—(IV)—Carboxylates, issued Nov. 26, 1991, relates to a method of reacting metallic tin or tin (II) acetate with an excess of acetic anhydride to produce tin (IV) acetate. The tin (IV) acetate is separated from the reaction mixture and used as separated or, if desired, is subsequently converted to tin (IV) carboxylate having four or more carbon atoms by reaction with the appropriate carboxylic acid.