Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[O-]Cl.[Na+].C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[O:10]
Reactant: OCCCCCCCCBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=CCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.6 %

Procedure:
In a 250 mL round bottom flask, 8-bromooctan-1-ol (4.0 g, 19.1 mmol) (available from Sigma-Aldrich Canada) was dissolved in CH2Cl2 (40 mL) at room temperature. 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical (TEMPO) (24.6 mg, 0.16 mmol) (available from Sigma-Aldrich Canada) was added to produce a red-coloured solution. A premix of NaOCl (5.25%, 36.7 g, 25.9 mmol) and saturated NaHCO3 (25.9 mL) was added. The reaction mixture was vigorously stirred for 45 min. at room temperature. The progress of the conversion was monitored by gas chromatography-mass spectrometry (GC-MS) (Varian Saturn 2000 GC-MS). Additional NaOCl was added until complete conversion was obtained. Saturated Na2SO3 (20 mL) was added. The aqueous phase was separated and extracted with CH2Cl2 (2×20 mL). The resulting organic phase was washed with water (20 mL), and dried (Na2SO4). Evaporation of the solvent from the organic phase yielded the 8-bromooctan-1-al as an orange liquid (3.82 g, 96%).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[CH2:5]1)[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:1][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[CH2:5]1)[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](N=[N+]=[N-])C[C@@H]12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](N)C[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.28 g (4.1 mmol) 16β-azido-3-methoxy-estra-1,3,5(10)-triene in 30 ml abs. THF, 10 ml of a 1M lithium aluminum hydride solution in THF (Fluka) is added dropwise under cooling. The mixture is stirred for further 30 min at RT, followed by cautious addition of ether/water at 0° C. and subsequent addition of sodium tartrate solution. After three subsequent extractions of the aqueous phase with ether, the combined organic phases are washed twice with water, dried with sodium sulfate and concentrated. Yield after recrystallization from hexane: 1.05 g (89%), white solid matter with F=90-94° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[N:14]([C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:19][N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.C(Cl)Cl>C1COCC1>[C:21]([C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:13]2=[N:20][CH:19]=1)#[CH:22]
Reactant: C[Si](C)(C)C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
To a solution of N-(4-(methylsulfonyl)phenyl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-8-amine (0.058 g, 0.15 mmol) in 1.5 mL of THF was added 0.23 mL (0.23 mmol) of tetrabutylammonium fluoride (1.0M in THF) at ambient temperature. The solution was stirred for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 100% DCM then 5% MeOH/DCM) to provide a quantitative yield (0.047 g) of product: 312 m/z (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]=[C:5]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=1.[CH:18]1[CH:19]=CC2C(=O)C=CC(=O)[C:22]=2[CH:23]=1.CCN(C(C)C)C(C)C.CI>CN(C=O)C>[CH2:19]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([NH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)(=[O:10])=[O:9])=[CH:16][CH:15]=1)[CH2:18][CH2:23][CH3:22]
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sulfapyridine Naphthoquinone Derivatives (6a, 6b, 6c). (YL1-018-1, YL1-018-2, YL1-018-9). DIPEA (52.9 mg, 0.41 mmol) was added to solution of 4-(3-Chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino-N-pyridin-2-yl-benzenesulfonamide (150 mg, 0.34 mmol) in anhydrous DMF (3 ml) under inert conditions. Methyl iodide (58 mg, 0.41 mmol) was added to the reaction mixture after 5 min. and the reaction was stirred at r.t. for two days. The reaction mixture was dried under reduced pressure and purified by flash chromatography (SiO2, EtOAC in Hexane, gradient elution).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[NH4+].[C:18](O)(=O)[CH3:19]>>[CH2:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]([CH3:1])[CH2:3][CH2:4]1)[CH3:19]
Reactant: CC(=O)O
Reactant: Cc1ccnc2ccccc12
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Product: CCN1CCC(C)c2ccccc21
Temperature: 10 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
4-Methylquinoline (lepidine) (1.43 g, 10 mmol) and 50 ml of glacial acetic acid were added together and cooled to 10° C. Sodium cyanoborohydride (2.64 g, 42 mmol) was added gradually, and the reaction was stirred at 25° for 2 hours, and then heated at 55° for 11/2 hours. After stirring overnight at 25°, the reaction was neutralised with concentrated ammonium hydroxide to pH 10.5, and then the product was extracted into methylene chloride and evaporated. The crude product was purified on a silica gel column eluting with hexane to give 0.55 g (31% yield) of the title compound. MS: 175 (M+), 160 (M+ -Me); NMR: CDCl3 δ 1.22 (tr, J=7 Hz, 3, NCH2Me), 1.30 (d, J=3.5, 3, CHMe), 1.5-2.3 (m, 2, CH2), 2.89 (sextet, 1, CHMe), 3.29 (tr, 2, NCH2), 3.30 (quartet, 2, NCH2Me), 6.59 (m-tr, 2, Ar), 7.10 (m-tr, 2, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12]1)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=N[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N>CN(C=O)C>[C:37]([CH2:38][NH:43][C:16]([CH:13]1[CH2:14][CH2:15][CH:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:12]1)=[O:18])#[N:36]
Reactant: O=C(O)C1CCC(S(=O)(=O)c2ccccc2Cl)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CCC(S(=O)(=O)c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(2-chloro-benzenesulfonyl)-cyclopentanecarboxylic acid (0.25 g, 1.0 eq) in DMF (4.0 mL) was treated with DIPEA (0.22 mL, 1.5 eq) and HATU (0.39 g, 1.2 eq). The mixture was stirred at RT for 15 min, then a solution of aminoacetonitrile hydrochloride (0.12 g, 1.5 eq) and DIPEA (0.22 mL, 1.5 eq) in DMF (1 mL) was added. The resulting solution was stirred at RT overnight and then purified by preparative HPLC. The title compound was obtained as a light yellow gum (0.10 g, 37%). MS (ESI): m/z=327.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:35][CH3:36])[CH:11]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][N:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=45)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:35][CH3:36])[CH:11]=2)[CH2:4]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 85.6 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (0.166 mL, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.227 mL, 1.31 mmol) in DMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. Part purification was achieved by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (443 mg, 86%) as an orange solid; 1H NMR: 1.77-1.88 (1H, m), 2.13-2.20 (1H, m), 2.23 (6H, s), 2.75-2.84 (1H, m), 3.14-3.26 (3H, m), 3.43-3.51 (1H, m), 3.96 (3H, s), 6.58 (1H, s), 7.08 (1H, td), 7.27 (1H, d), 7.34-7.39 (1H, m), 8.24 (1H, s), 8.35 (1H, d), 8.40 (1H, s), 8.49 (1H, d), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 475.31.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:29][CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCc1cccnc1
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3cccnc3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted with 3.0 g of 3-picolyl amine and 5 g of triethyl amine according to Example 76, the solvent was distilled off under reduced pressure and the residue was taken up in 70 ml of water. Three extractions followed with 60 ml of ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue crystallized under diisopropyl ether. Melting point: 152°-153° C.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC.O>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH2:16][Cl:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(CCl)C(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-t-butyl-1-benzoylhydrazine (1 g, 0.005M) in toluene (40 ml) cooled to 5° C. was added 3-chloro-2,2-dimethylpropionylchloride (1.2 g, 0.007M) and 50% aq. sodium hydroxide (0.45 g, 0.0056M) so as to maintain the temperature below 10° C. The mixture was warmed to room temperature and stirred 1 hr. The mixture was diluted with hexane (40 ml) and water (10 ml). The white solid product N'-t-butyl-N-(beta-chloropivaloyl)-N'-benzoylhydrazine was isolated by suction filtration, washed with 50 ml hexane and 50 ml water and dried.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11][CH3:12])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.B1([O-])OO1.[OH2:27].[OH2:28].O.O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11]([CH3:12])(=[O:28])=[O:27])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: C#CCN(C(=O)C(C)SC)c1cn(-c2cccnc2)nc1Cl
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: C#CCN(C(=O)C(C)S(C)(=O)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 65 °C
Yield: 70 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide (0.10 g, 0.30 mmol) and acetic acid (2.0 ml) was added sodium perborate tetrahydrate (0.11 g, 0.74 mmol) and the vial was heated to 65° C. for 2 h. The reaction mixture was cooled to ambient temperature and neutralized with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (0-20% MeOH/DCM) to afford the title compound as a yellow foam (84 mg, 0.21 mmol, 73%): 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.65 (s, 1H), 8.29 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.54-7.39 (m, 1H), 4.89 (d, J=16.9 Hz, 1H), 4.20-4.08 (m, 1H), 4.07-3.92 (m, 1H), 3.01 (s, 3H), 2.34-2.29 (m, 1H), 1.67 (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.97, 166.90, 148.77, 140.43, 140.24, 135.58, 129.36, 126.64, 124.14, 121.34, 73.80, 60.91, 38.78, 36.29, 13.97; ESIMS m/z 367 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:23][CH2:22][C:21]([NH:27][C:28](=O)[C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:30]=3)([C:24](=[O:26])[NH2:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:9]([CH3:48])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+]>CO>[C:1]([O:5][C:6](=[O:49])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:23][CH2:22][C:21]3([N:27]=[C:28]([C:29]4[CH:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:32]=[C:31]([O:39][CH2:40][C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)[CH:30]=4)[NH:25][C:24]3=[O:26])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[C:9]([CH3:48])[CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC(NC(=O)c2cc(OCc3ccccc3)cc(C(F)(F)F)c2)(C(N)=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCc3ccccc3)cc(C(F)(F)F)c1)NC2=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
4-{2-[4-(3-Benzyloxy-5-trifluoromethyl-benzoylamino)-4-carbamoyl-piperidine-1-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester (1.23 g, 1.75 mmol) was dissolved in methanol (17.5 ml). A 1 M aqueous sodium hydroxide solution (1.75 ml, 1.75 mmol) was added and the mixture was stirred at 60° C. for six hours. After completion of the reaction, the reaction solution was left to cool and an aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saline, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained by concentration was purified by column chromatography (hexane:ethyl acetate) to give 4-{2-[2-(3-benzyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester as a pale yellow amorphous (952.1 mg, yield in two steps: 79.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(Cl)Cl>C1COCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:26][C:25]2[C:20]([O:19][CH3:18])=[N:21][CH:22]=[CH:23][CH:24]=2)[N:7]=1
Reactant: COc1ncccc1N
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ncccc1Nc1ncnc(Cl)n1

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (265.77 mg, 1.77 mmol) in THF (5 mL) was added DIPEA (0.266 mL, 1.61 mmol) followed by 2-methoxypyridin-3-amine (200 mg, 1.61 mmol). The resultant mixture was stirred at RT for 2 hr, then DCM was added and the organics washed with water (×2) and 0.5M aqueous HCl solution. Combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a beige solid: 1H NMR (250 MHz, DMSO) δ 3.88 (3H, s), 7.05 (1H, dd, J=7.54, 4.95 Hz), 7.86 (1H, dd, J=7.61, 1.68 Hz), 8.07 (1H, dd, J=4.95, 1.75 Hz), 8.56 (1H, s), 10.14 (1H, s); =+238.0/239.9 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23].[NH4+].[Cl-].Cl>C1COCC1.CN1C(=O)N(C)CCC1>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(C)CCCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
Under Ar atmosphere at −78° C., to a solution of ethyl isobutyrate (124.0 g, 1.06 mol) and DMPU (5 mL) in THF (160 mL) was added LDA (750 mL, 2M). After 30 min, 1,5-dibromopentane (313 g, 1.32 mol) was added in a single portion. The reaction mixture was allowed to stir overnight, gradually warming to rt. The mixture was hydrolyzed with ice (500 g), saturated NH4Cl (400 mL) and aqueous HCl (6M, 400 mL), and the solution was extracted with Et2O (3×300 mL). The organic layers were washed with half saturated NaCl (2×300 mL), dried (MgSO4) and evaporated in vacuo. The remaining residue was purified by distillation under reduced pressure to give ethyl 7-bromo-2,2-dimethylheptanoate (97.4 g, 32%) as a colorless oil. bp: T=109-110° C. (p=1.5-2 Torr). 1H NMR (CDCl3): δ=4.15 (q, J=7.2 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.90-1.83 (m, 2H), 1.55-1.37 (m, 4H), 1.25 (t, J=6.9 Hz, 3H), 1.30-1.22 (m, 2H), 1.16 (s, 6H). 13C NMR (CDCl3): δ=177.9, 60.3, 42.2, 40.5, 33.7, 32.7, 28.6, 25.2, 24.2, 14.3. HRMS calcd for C11H22BrO2 (MH+): 265.0803, found: 265.0816.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[CH3:64][O:65][C:66](C1C=CC(B(O)O)=CC=1)=[O:67]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([C:66]([O:65][CH3:64])=[O:67])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: COC(=O)c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and (4-methoxycarbonylphenyl)boronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 26.35 min.; purity: 90%; MS (m/e): 514 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[CH:14](=O)[CH2:15][CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=C1CCCNc2ccc(Br)cc21
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN1CCCC(=O)c2cc(Br)ccc21
Reaction time: 6 h

Procedure:
To a solution of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-one (5.0 g), propionaldehyde (15 ml) and acetic acid (4.7 ml) in 1,2-dichloroethane (250 ml) was added sodium triacetoxyborohydride (22.0 g) at room temperature, and the mixture was stirred for 6 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4) to give 7-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-one (5.89 g) as yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=2)=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:29][CH:28]2[N:24]([C:25](=[O:30])[CH2:26][CH2:27]2)[CH2:23][CH2:22]1)=[O:14].N1C=CC=CC=1.CO>C1(C)C=CC=CC=1.ClCCl>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=2)=[CH:18][C:19]=1[N:20]([C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9])[CH:21]1[CH2:29][CH:28]2[N:24]([C:25](=[O:30])[CH2:26][CH2:27]2)[CH2:23][CH2:22]1)=[O:14]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1NC1CCN2C(=O)CCC2C1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN2C(=O)CCC2C1

Procedure:
trans-4-Methylcyclohexyl carboxylic acid chloride was added to a solution of 5-cyclohex-1-enyl-3-[(3-oxo-octahydro-indolizin-7-yl)-amino]-thiophene-2-carboxylic acid methyl ester (698 mg, 1.86 mmol) and pyridine (166 μL, 2.05 mmol) in dry toluene (8 mL). The mixture was refluxed for 16 h, then it was brought to room temperature, additional amount of pyridine (0.2 mL) and MeOH (1 mL) were added. The mixture was diluted with dichloromethane, washed with brine; organic phase was dried over Na2SO4, concentrated and purified by column chromatography on silica gel using gradient 0-100% EtOAc in hexane to afford 592 mg (64%) of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(3-oxo-octahydro-indolizin-7-yl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.[Mg].O1CCOC1.[CH3:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>O1CCCC1>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([CH:22]([OH:23])[C:21]([CH3:25])([CH3:24])[CH3:20])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Reactant: CC(C)(C)CO
Agent: [Mg]
Solvent: C1COCO1
Solvent: C1CCOC1
Product: CC1(c2ccc(C(O)C(C)(C)C)cc2)OCCO1
Reaction time: 8 h

Procedure:
In 250 milliliters of tetrahydrofuran, 118 grams of the above dioxolane is dissolved. One quarter of this solution is then added to 12 grams of magnesium, previously washed with chloroform, and refluxed with tetrahydrofuran for 20 minutes; and this mixture is refluxed 4 hours to initiate reaction. Additional dioxolane solution is thereafter added to maintain the refluxing without further heating. After the addition has been completed, 35 grams of 2,2-dimethylpropanol is added and the mixture is refluxed for 2 hours. The reactants are allowed to stand overnight and then poured onto ice-cold ammonium chloride solution. Tetrahydrofuran is added and the two layers formed are allowed to separate. The solvent layer is decanted off and the aqueous layer is extracted twice with 100 milliliters of tetrahydrofuran which are decanted off and combined with the remaining solvent layer. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to yield a yellow oil which is distilled at 120° to 150° C. and recrystallized from pentane/ether to yield 2-methyl-2-(4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)-1,3-dioxolane (m.p. 75°-80° C).