Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1C=CC=[CH:4][CH:3]=1.C(=O)(O[CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)OC.N1CCCC1>C1COCC1>[C:16]1([CH:15]([N:8]2[CH2:1][CH2:2][CH2:3][CH2:4]2)[CH:14]=[CH2:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)OCC=Cc1ccccc1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)N1CCCC1
Reaction time: 16 h
Yield: 61 %

Procedure:
A stock solution containing [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) and L1 (10.8 mg, 0.0200 mmol) in 1.0 mL of THF was prepared. By the procedure for reaction of benzylamine with methyl cinnamyl carbonate, the reaction of pyrrolidine (85.0 mg, 1.19 mmol) and methyl cinnamyl carbonate (201.5 mg, 1.049 mmol) was conducted at room temperature for 16 h. 1H NMR analysis of the crude mixture showed the ratio of branched to linear product to be 99/1. After purification, 121 mg of the title compound (61%) was isolated and HPLC analysis as described above indicated that the enantiomeric excess of the major product was 97%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:17](=[O:18])[CH2:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: O=C(Cl)CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Yield: 99 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (4.3 g) and cyclopentylacetyl chloride (3.46 g) were mixed in acetonitrile (50 mL) and tetrahydrofuran (20 mL) and the reaction mixture was heated to reflux for 1 hour. Potassium carbonate (4.5 g) was added and the reaction mixture was refluxed for 1 hour and then poured onto crushed ice and saturated aqueous potassium carbonate (50 mL). The product was collected by filtration and washed with water (100 mL) to furnish 6.6 g (100% yield) of the title compound as a solid. LC-MS (m/z) 311 (MH+); tR=3.07, (UV, ELSD) 100%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.11 (s, 6H), 2.25 (m, 1H), 2.31 (d, 2H), 7.27 (s, 2H), 9.23 (s, 1H).
Reaction SMILES: C(=O)(O)[O-].[K+].COP([CH2:12][C:13](=[O:21])[CH2:14][P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])(OC)=O.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[O:34]>O.C(O)(C)(C)C>[CH3:20][O:19][P:15]([CH2:14][C:13](=[O:21])[CH:12]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[O:34])([O:17][CH3:18])=[O:16]
Reactant: O=CCCCCCCCCCCC=O
Reactant: COP(=O)(CC(=O)CP(=O)(OC)OC)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COP(=O)(CC(=O)C=CCCCCCCCCCCC=O)OC
Reaction time: 2 h

Procedure:
A solution of 5 g of potassium bicarbonate in 150 ml of water was added to a mixture of 8.22 g (30 mMole) of 1,3-bis(dimethylphosphono)propan-2-one and 5.94 g (80 mMole) of dodecan-1,12-dial in 150 ml of t-butanol. After 21/2 h stirring at 27° under nitrogen water was added and the mixture was extracted with ether. The organic layer was separated, washed with brine, dried over sodium sulphate and evaporated. The residue was chromatographed on 150 g of silica gel. Hexane-ethyl acetate 1:1 eluted 2.68 g of unreacted dodecan-1,12-dial and ether eluted 4.38 g (42%, resp. 75% when based on recovered dial) of the title compound as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=2[CH2:9][C@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][NH:7]2.C(=O)(O)[O-].[Na+].[CH3:23][C:24](=[CH2:27])[CH2:25]Cl>CN(C)C=O>[CH3:25][C:24](=[CH2:23])[CH2:27][N:7]1[C@@H:8]2[C@@H:3]([C:2]([CH3:17])([CH3:1])[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[CH2:9]2)[CH2:4][CH2:5][CH2:6]1
Reactant: C=C(C)CCl
Reactant: CC1(C)c2cc(O)ccc2C[C@@H]2NCCC[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN1CCC[C@H]2[C@@H]1Cc1ccc(O)cc1C2(C)C

Procedure:
A mixture of 6.92 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g]quinolin-7-ol, 2.52 g. of sodium bicarbonate, 2.98 g. of 2-methyl-2-propenyl chloride, and 60 ml. of N,N-dimethylformamide was stirred and refluxed for 1 hour. The reaction mixture was worked up in a manner similar to that described above in Example 11 to yield crude cis-1,2,3,4,4a,5,10,10a-octahydro-1-(2-methyl-2-propenyl)-5,5-dimethylbenzo[g]quinolin-7-ol. A 1.7 g. portion of the partially purified base was chromatographed on 170 g. of alumina (6% water) using diethyl ether as eluant, and the resulting syrupy product (1.3 g.) was recrystallized from hexane to yield 1.0 g. of the pure base as an off-white solid melting at 129°-131°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[N:12]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2nc(Cl)ccc12
Product: Clc1ccc2c(Cl)ncnc2n1
Yield: 73 %

Procedure:
A mixture of Example 140C (1 g, 5.5 mmol) in phosphorus oxychloride (40 mL) was refluxed for 2 h then cooled and evaporated. The residue was taken into ethyl acetate (75 ml), washed with saturated sodium bicarbonate (50 ml) water (50 ml) and brine (50 ml). The ethyl acetate was evaporated to yield 0.8 g of product (73%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCc1ccc(OCCO)cc1
Reaction time: 48 h

Procedure:
5 g p-hydroxyphenylacetonitrile were dissolved in 250 ml methylethylketone. 7 g of 2-bromoethanol and 23 g potassium carbonate were added thereto. The mixture was stirred for 48 hours under reflux. At the end of the reaction the potassium carbonate and the produced potassium bromide were filtered. The precipitates were washed with acetone and the acetone wash was added to the reaction mixture. The clear solution was reduced to about 10-15 ml. It was then taken up in ether and shaken with 1/100 N sodium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:29])=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.9 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) and commercially available cyclopentanecarboxylic acid (66 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (110 mg) was added, and the admixture was stirred at room temperature for 17 hours. The reaction mixture was purified in the same manner as described in Example 51 to obtain 35 mg of the title compound (yield: 50%).
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:5].B(Br)(Br)Br>C(Cl)CCl>[F:1][C:2]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: COc1ccc(C(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: O=C(c1ccc(O)cc1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A solution of 5.6 g of 2,3,4,5,6-pentafluoro-4'-methoxy-benzophenone in 100 ml of ethylene chloride was added dropwise at -7° under argon to a solution of 23.23 g of boron tribromide in 100 ml of ethylene chloride. The reaction mixture was warmed to room temperature and stirred at this temperature for 5 hours. The reaction mixture was poured into 200 ml of ice-cold water and extracted three times with 150 ml of methylene chloride each time. The combined extracts were washed with 200 ml of water and dried over magnesium sulphate. After evaporation of the solvent the residue was chromatographed on 900 g of silica gel with methylene chloride. There were obtained 3.87 g (72%) of 2,3,4,5,6-pentafluoro-4'-hydroxybenzophenone: m.p. 138°-140°.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:30][CH3:31])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[NH:8][N:7]=1)(=[O:5])[CH3:4]>CCO>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[NH:8][N:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:10]=3)=[O:12])[CH2:30][CH3:31])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)=O)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)O)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a cooled (0° C.) solution of sodium borohydride (12 mg, 0.32 mmol) in 2 ml of dry EtOH was added (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide of Example 99 (66 mg, 0.16 mmol) as a solution in 3 ml of dry EtOH. Reaction mixture was stirred at RT overnight before being quenched by adding some water and 0.5 M HCl until pH was acidic. Solvents were evaporated and the evaporation residual was taken up in 5% MeOH in DCM, washed with 1 M NaHCO3 solution and water. Organic phase was dried over Na2SO4, filtered and evaporated to yield 64 mg (96%) of the title compound. 1H-NMR (400 MHz; CDCl3/MeOD): δ 1.00 (t, 3H), 1.48-1.65 (m, 5H), 4.29-4.43 (m, 3H), 4.94 (q, 1H), 6.59-6.62 (m, 2H), 7.52 (d, 1H), 7.67-7.72 (m, 1H), 7.78-7.82 (m, 1H), 7.99-8.01 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](OC(OCC)OCC)C.C1CCN2C(=NCCC2)CC1>ClCCCl>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: CCOC(OCC)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1cc(-n2cnc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide [Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5 ml) and treated with triethylorthoformate [Aldrich] (2 ml) then heated to reflux for 12 h. The mixture was cooled and DBU (0.1 ml) introduced. The solvent was evaporated then the residue purified by flash chromatography on silica gel (eluting with ammonia-methanol-dichloromethane) to obtain the title compound;
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([CH:12]([CH3:14])[CH3:13])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10].[O-:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+].O>O1CCCC1>[CH:12]([C:6]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:3]([CH2:2][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:8]([CH:9]([CH3:10])[CH3:11])[N:7]=1)([CH3:13])[CH3:14]
Reactant: [O-]c1ccccc1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CCl)c1-c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COc2ccccc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
3.22 g (9.1 mmol) of the compound from Example 86 dissolved in 50 ml of absolute tetrahydrofuran are added dropwise at 0° C. to a solution of 2.11 g (18.2 mmol) of sodium phenoxide in 50 ml of absolute tetrahydrofuran and the mixture is heated to reflux for 4 days. After cooling to room temperature, the mixture is diluted using 150 ml of water and extracted several times using ether. The combined organic phases are dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using petroleum ether/ethyl acetate 95.5).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=O)(C)(C)C>>[CH:14]1([N:8]2[C:6]3[N:7]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([N:29]5[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]5)=[CH:33][N:34]=4)[N:3]=[CH:4][C:5]=3[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)c1cn(C2CCCC2)c2nc(Cl)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: CC(C)c1cn(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cn3)ncc12

Procedure:
(7-Cyclopentyl-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(5-piperazin-1-yl-pyridin-2-yl)-amine is prepared from 2-Chloro-7-cyclopentyl-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidine and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester using a method similar to that for the preparation of Example 202. [MH+] 406.21
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:26])[C:15]([F:25])([F:24])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([C:41]3([C:44]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[O:45])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)O1>>[F:24][C:15]([F:25])(/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([C:41]3([C:44]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[O:45])[CH2:43][CH2:42]3)=[CH:39][CH:40]=2)=[CH:3][CH:4]=1)[OH:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccccc1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(O)C(F)(F)/C=C/c1ccccc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-4-phenyl-but-3-en-1-ol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:32][C:33](ONC(=O)CCC(N)=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C:33]([N:12]1[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:17][CH:16]=2)[CH2:11]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NCC1CCCNC1)c1ccc(O)cc1
Reactant: NC(=O)CCC(=O)NOC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCN(C(=O)OCc2ccccc2)C1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-hydroxy-N-piperidin-3-ylmethyl-benzamide (135 mg, 0.580 mmol) in tetrahydrofuran (5 mL) was added triethylamine (100 μL) and N-benzyloxycarbonyloxysuccinamide (144 mg, 0.580 mmol) and the mixture stirred at rt for 3 h. The reaction was concentrated in vacuo and chromatographed on silica using 50–100% ethyl acetate/hexane to give 3-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester as a foam.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I>C1COCC1.CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[N:23]2[CH3:31])[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1C(=O)OC[C@@]1(C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of (R)-4-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (73 mg, 0.19 mmol) in THF (1 mL) and DMF (1 mL) was added sodium hydride (60% in mineral oil, 12 mg, 0.29 mmol). After the mixture was stirred at room temperature for 2 hrs, methyl iodide (60 μL, 0.96 mmol) was added. The mixture was stirred at room temperature for 3 hrs. LCMS showed about 30% of conversion. Additional sodium hydride (60% in mineral oil, 50 mg) was added. After the mixture was stirred at room temperature overnight, the mixture was partitioned between NH4Cl aq and EtOAc. The organic phase was washed with water, dried over anhydrous MgSO4, filtered, and concentrated to give 80 mg of crude product, 106%. ESI-MS (M+H)+: 396.20, room temperature 2.53 min.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[Br:27][C:28]1C(Cl)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1>C(Cl)Cl>[Br:27][C:28]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[CH2:12][CH2:11]2)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 58.9 %

Procedure:
tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.160 g, 0.56 mmol, 1.0 eq) was dissolved in DCM (1.8 mL) and the reaction mixture cooled in a ice-water bath before the dropwise addition of TFA (1.8 mL). Stirring was continued at this temperature for 1 h, the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.10 g, 0.56 mmol, 1.1 eq) was suspended in iPrOH (0.55 mL) and DIPEA (0.22 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.130 g, 0.51 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.120 g, 55%); 1H-NMR (500 MHz, DMSO-d6): δ 2.58 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.54 (br d, 1H, J=1.2 Hz, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H), 9.04 (d, 1H, J=1.7 Hz, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.83 min—398/400 [(M+H)+, Br isotopic pattern, 100%].
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](O)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:75][C:76]([F:86])([F:85])[C:77]1[N:82]=[CH:81][C:80]([CH2:83][NH2:84])=[CH:79][CH:78]=1>CN(C)C=O>[F:85][C:76]([F:75])([F:86])[C:77]1[N:82]=[CH:81][C:80]([CH2:83][NH:84][C:32]([C:31]2[CH:35]=[CH:36][N:37]=[C:29]([C:18]3[CH:19]=[C:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH:21]=[CH:22][C:17]=3[NH:16][C:14]([C:13]3[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:41])=[O:15])[CH:30]=2)=[O:33])=[CH:79][CH:78]=1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Reactant: NCc1ccc(C(F)(F)F)nc1
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: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Into a 8-mL sealed tube, was placed a solution of 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid 1.1j (90 mg, 0.16 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), HATU (90 mg, 0.24 mmol, 1.51 equiv), N,N-diisopropylethylamine (30.6 mg, 0.24 mmol, 1.52 equiv), and (6-(trifluoromethyl)pyridin-3-yl)methanamine (54 mg, 0.31 mmol, 1.96 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate. The resulting mixture was washed with water and brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 114.7 mg (crude) of tert-butyl 3-(3-((2-(4-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate as red oil.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([CH3:9])([CH3:8])O)([CH3:3])[CH3:2].O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]([CH3:9])([CH3:8])[S:26]1
Reactant: CC(C)NCC(C)(C)O
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C)(C)CN1C(C)C

Procedure:
Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1.C([Li])CCC.C1C[O:22][CH2:21][CH2:20]1>>[CH:1]1[C:13]2[N:12]([CH2:20][CH2:21][OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: C1CCOC1
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Agent: [Li]CCCC
Product: OCCn1c2ccccc2c2ccncc21
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a −30° C. cooled solution of 9H-β-carboline (1.0 g, 5.95 mmol) in dry THF (30 mL) was added butyllithium (4.12 mL, 6.55 mmol) over a 15 min period. After 30 min at −30° C., the reaction mixture was cooled to −50° C. Ethylene oxide (1.6 mL in a cooled measuring cylinder) was then bubbled into the reaction mixture, in a stream of nitrogen. The temperature was slowly raised to −5° C. over a 2 h period, and stirring was continued for 84 h. The mixture was acidified with 1 N HCl (50 mL) and extracted with diclormethane (2×100 mL). The combined extracts were dried (MgSO4), and concentrated in vacuo. The product was chromatographed eluted with dichloromethan/methanol (20:1) to give 660 mg (53%) of 2-β-carbolin-9-yl-ethanol. 1H NMR (300 MHz, CDCl3): δ 3.62 (s, 1H), 4.10 (t, 2H), 4.50 (t, 2H), 7.30 (t, 1H), 7.50-7.65 (m, 2H), 7.80 (d, 1H), 8.10 (d, 1H), 8.22 (d, 1H), 8.78 (s, 1H).