Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.B.[CH:7]1([NH:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[CH:16]=[C:15]3[C:22](=O)[CH2:23][CH2:24][O:25][CH3:26])[CH2:9][CH2:8]1.[OH-].[Na+].CO>O1CCCC1>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH2:11][NH:10][CH:7]3[CH2:8][CH2:9]3)[CH:13]=2)[N:17]([CH3:21])[CH:16]=1
Reactant: COCCC(=O)c1cn(C)c2ccc(CNC3CC3)cc12
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCc1cn(C)c2ccc(CNC3CC3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
A 1M tetrahydrofuran-solution of borane tetrahydrofuran (2.62 ml) was added dropwise to a solution of 1-{5-[(cyclopropylamino)methyl]-1-methyl-1H-indol-3-yl}-3-methoxy propan-1-one (150 mg) in tetrahydrofuran (2.5 ml) under ice-cooling and the mixture was stirred at room temperature for 15 hours. A 5N aqueous solution of sodium hydroxide (2.5 ml) and methanol (1.25 ml) were added to the reaction mixture and it was stirred at 50° C. for 24 hours. The reaction mixture was cooled to room temperature, extracted with diethyl ether. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform to chloroform/methanol=5/1) to give N-{[3-(3-methoxypropyl)-1-methyl-1H-indol-5-yl]methyl}cyclopropanamine (107 mg) as a colorless oil.
Reaction SMILES: C1C2C3C=CC=CC=3SC=2C=CC=1.BrBr.O.S([O-])([O-])=O.[Na+].[Na+].Br[C:24]1[CH:37]=[CH:36][C:27]2[S:28][C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=3[C:26]=2[CH:25]=1>C(Cl)(Cl)Cl>[Br:35][C:32]1[CH:33]=[CH:34][C:29]2[S:28][C:27]3[CH:36]=[CH:37][CH:24]=[CH:25][C:26]=3[C:30]=2[CH:31]=1
Reactant: Brc1ccc2sc3ccc(Br)cc3c2c1
Agent: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
15 g (79.9 mmol) dibenzothiophene was dissolved in 1.5 L chloroform. To the solution, 12.76 g (79.9 mmol) bromine was added dropwise. The reaction mixture was vigorously stirred for 2 days at room temperature and then treated with sodium sulfite water solution. The organic phase was evaporated to give a white solid which has 48% unreacted dibenzothiophene, 50% 2-bromodibenbzothiophene and ˜less 2% 2,8-dibromodibenzothiophene based on GC-MS and HPLC results. The mixture was repeatedly recrystallized with ethyl acetate to get pure 2-bromodibenzothiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=O.CN(C)C=O.[O:17]1[CH2:22][CH2:21][NH:20][C:19]2[CH:23]=[N:24][CH:25]=[CH:26][C:18]1=2.N1C=CC=CC=1>S(Cl)(Cl)=O.CN(C)C(=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][O:17][C:18]3[CH:26]=[CH:25][N:24]=[CH:23][C:19]2=3)=[O:7])[CH:3]=[C:2]([Cl:1])[N:10]=1
Reactant: c1cc2c(cn1)NCCO2
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(c1cc(Cl)nc(Cl)c1)N1CCOc2ccncc21
Reaction time: 4 h
Yield: 71.9 %

Procedure:
In a 25 ml flask, 2,6-dichloro-isonicotinic acid (100 mg, 0.52 mmol) was dissolved in thionylchloride (0.76 ml), and a catalytic amount of N,N-dimethyl formamide was added thereto and then stirred for 4 hours under reflux. Thionyl chloride was removed under reduced pressure, and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (78 mg, 0.57 mmol) and pyridine (0.13 ml) were added to the reaction flask and dissolved in N,N-dimethyl acetamide (2.6 ml) and then stirred at room temperature for 18 hours. The reaction mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous magnesium sulfate (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=2:1. The fractions containing the product were collected and evaporated to obtain the target compound 31 as yellow solid (116 mg, 72%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]([OH:23])=O)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.CO[CH:39]1[CH2:44][CH2:43][NH:42][CH2:41]C1>CN(C=O)C.CO>[N:42]1([C:21]([C:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)[CH:12]=3)[N:17]=2)=[O:23])[CH2:41][CH:39]=[CH:44][CH2:43]1
Reactant: CC(C)N1CCC(Oc2ccc3nc(C(=O)O)ccc3c2)CC1
Reactant: COC1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3nc(C(=O)N4CC=CC4)ccc3c2)CC1
Yield: 14 %

Procedure:
6-(1-Isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1 hydrochloride (30 mg, 0.086 mmol, see intermediate 2) was dissolved in DMF (0.300 ml). 1,1′-Carbonyl-diimidazole (17 mg, 0.10 mmol) was added and the mixture was stirred for half an hour. 4-Methoxy-piperidine was added (6 mg, 0.014 mmol) and the mixture was stirred overnight. The mixture was diluted with 0.4 ml methanol and subjected to preparative HPLC purification on reversed phase material eluting with a gradient of acetonitrile/water/triethylamine. The product fractions were evaporated to dryness to yield 4.7 mg (14%) of the title compound as light brown solid. MS (m/e): 412.4 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:26])[NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: COCCN
Product: COCCNC(=O)Cc1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12

Procedure:
As described in Example 1, 60 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with 2-methoxy-ethylamine to give 40 mg of {6,7-dimethoxy-4-[(2-methoxy-ethylcarbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. H1-NMR (CDCl3): δ, d 8.21 (s, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 6.17 (br s, 1H), 5.74 (br s, 1H), 4.89 (d, J=4.7 Hz, 2H), 4.03 (s, 6H), 3.89 (s, 2H), 3.36 (m, 4H), 3.17 (s, 3H), 1.51 (s, 9H); MS: APCI (M+H) calc'd for C22H31N3O6+H 434.5; found 434.0.
Reaction SMILES: O.Cl.[O:3]=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(OCC)C.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17].[OH-].[Na+]>O>[Cl:20][CH2:19][O:18][C:16]([N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)=[O:17]
Reactant: O=C(Cl)OCCl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C1CCN(C(=O)OCCl)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 1 g of 4-oxopiperidine hydrochloride monohydrate in 0.7 ml of water was added 2.2 ml of diethyl ether, and the mixture was stirred at 0° C. Chloromethyl chloroformate (0.3 ml) was added dropwise, and the mixture was stirred at 0° C. for 5 minutes. Next, 0.8 ml of a 17N aqueous sodium hydroxide solution and 0.3 ml of chloromethyl chloroformate were divided into three portions and alternately added dropwise, and the resulting mixture was stirred at 0° C. for additional 20 minutes. The reaction mixture was diluted with 5 ml of a saturated aqueous saline, and extracted three times with 5 ml of diethyl ether. The organic layer thus obtained was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 1.7 g (100%) of 1-chloromethoxycarbonyl-4-oxopiperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:32])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([C:36]1[C:37]([N:43]=[CH:44][N:45]([CH3:47])C)=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1)#N>>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:30])(=[O:31])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:32][C:47]2[C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:37]=3[N:43]=[CH:44][N:45]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2N)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
The product from Example 458D was reacted with the product from Example 9B using the procedure described in Example 458E substituting the product from Example 9B for the product from Example 8E to provide {4-[4-(4-Bromo-phenylsulfamoyl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester which was deprotected according to the procedure described in Example 458F, followed by silica gel chromatography provided the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3 H), 6.64 (d, J=8.46 Hz, 2 H), 6.89 (d, J=8.09 Hz, 1 H), 7.05 (d, J=9.19 Hz, 2 H), 7.12 (d, J=8.82 Hz, 2 H), 7.44 (d, J=8.82 Hz, 2 H), 7.63 (dd, J=7.72, 0.74 Hz, 1 H), 7.74 (s, 1 H), 7.79 (dd, J=7.72, 1.10 Hz, 1 H), 8.70-8.83 (m, 1 H), 8.88 (d, J=8.09 Hz, 1 H), 10.55 (s, 1 H); MS (ESI+) m/z 593/595 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH2:29][N:30]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:59])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:38]=4)[CH3:31])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]([CH2:32][C:33]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]6)[CH:40]=5)[C:36]([F:59])=[CH:35][CH:34]=4)[CH3:31])[CH:24]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 20 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-phenyl}methyl)(methyl)amino]-methyl}-2′-fluoro-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.386 g, 0.463 mmol) in DCM (3.6 mL) was added TFA (1.8 mL) and this mixture was stirred at room temperature for 100 min before being quenched with NaHCO3 (sat. aq.). This mixture was extracted with DCM, concentrated, purified using a Gilson HPLC (with TFA). Product was basified with an amine cartridge to afford 0.068 g (20%) of the title compound. LC-MS m/z 733 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.65 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.79-1.92 (m, 2 H) 2.05-2.14 (m, 2 H) 2.74 (s, 3 H) 3.18 (q, J=7.61 Hz, 2 H) 3.43-3.58 (m, 8 H) 3.63-3.72 (m, 2 H) 3.99-4.07 (m, 2 H) 4.30-4.62 (m, 9 H) 4.72 (s, 2 H) 7.34 (dd, J=10.42, 8.66 Hz, 1 H) 7.54-7.65 (m, 4 H) 7.67-7.78 (m, 4 H) 8.02 (d, J=8.03 Hz, 1 H) 8.12 (s, 1 H) 8.29 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([Cl:10])[S:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4].B(Cl)([C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1)[C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1.[K].[OH-].[Na+]>COC(C)(C)C.O1CCCC1.C(OCC)C>[Cl:10][C:8]1[S:7][C:6]2[S:11](=[O:13])(=[O:12])[NH:14][CH2:2][C@@H:3]([OH:4])[C:5]=2[CH:9]=1
Reactant: NS(=O)(=O)c1sc(Cl)cc1C(=O)CBr
Agent: C[C@H]1C2CC(C[C@@H]1B(Cl)[C@H]1CC3CC([C@@H]1C)C3(C)C)C2(C)C
Agent: [K]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S1(=O)NC[C@@H](O)c2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In the fourth step of the process, 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (4) is reduced with an appropriate reagent to provide initially an (S)-bromohydrin, which upon subsequent treatment with aqueous sodium hydroxide cyclizes to (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5). The preferred reducing agent is (+)-β-chlorodiisopinocampheylborane, which is well known to provide bromohydrins in high enantiomeric excess from prochiral α-bromo ketones [H. C. Brown, W. S. Park, B. T. Cho, and P. V. Ramachandran J. Org. Chem. 52, 5406 (1987) and H. C. Brown U.S. Pat. No. 4,918,246 (1990)]. Several different reaction solvents can be used for the reduction of (4), including diethyl ether, tetrahydrofuran, and t-butyl methyl ether. The reduction is typically carried out using 1.2 to 2.2 equivalents of (+)-β-chlorodiisopinocampheylborane at a temperature of -40° to 0° C. for 6 to 24 hours. A higher enantiomeric excess is obtained at the lower temperature; however, the reaction rate is slower. The preferred conditions utilize t-butyl methyl ether at a temperature of -25° to -15° C. After the reduction is complete, aqueous potassium or sodium hydroxide is added and the mixture is stirred at ambient temperature for a period of 1 to 5 hours to accomplish cyclization. The product is isolated by phase separation, acidification of the aqueous phase, extraction, solvent removal, and trituration. The enantiomeric excess of the (5) produced is typically greater than 96%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[C:32]6[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=6)[N:26]=[C:25]([CH3:34])[N:24]=5)[CH2:18][C:17]=4[CH:35]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:2].[CH2:36](I)[CH3:37]>>[CH2:1]([NH:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[C:32]6[C:27](=[CH:28][C:29]([O:33][CH2:36][CH3:37])=[CH:30][CH:31]=6)[N:26]=[C:25]([CH3:34])[N:24]=5)[CH2:18][C:17]=4[CH:35]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(O)ccc35)CCO4)cc2[nH]1
Reactant: CCI
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(OCC)ccc35)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 10 using 4-{7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl}-2-methylquinazolin-7-ol (example 11) and ethyl iodide in step 2. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.91-7.82 (m, 1H), 7.63 (dd, 1H), 7.52-7.36 (m, 2H), 7.26-7.13 (m, 2H), 6.99 (dd, 1H), 6.94-6.86 (m, 2H), 6.70 (q, 1H), 4.96 (s, 2H), 4.45-4.35 (m, 2H), 4.16-3.98 (m, 4H), 3.46-3.36 (m, 2H), 2.44-2.37 (m, 3H), 1.28-1.17 (m, 6H); MS (EI) for C29H30N6O2: 495 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Ni].C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc3ccccn3c2)cc1
Agent: [Ni]
Solvent: CCO
Product: c1ccc(-c2cc3n(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
Raney nickel (6 g) was slurried in ethanol (100 mL) and a solution of 2-phenylindolizine (48 g, 0.24 mol) in ethanol (1 L) was added. The reaction mixture was stirred under hydrogen at room temperature and 50-60 psi overnight. The mixture was filtered through Celite then the solvent was evaporated under vacuum to yield 2-phenyl-5,6,7,8-tetrahydro-indolizine (32 g, 65%) as a white solid.
Reaction SMILES: C([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH-:36])=O)CCCCCCCCCCCCCCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[OH-].[Na+]>CCOCC>[CH2:32]([NH:36][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]/[CH:26]=[CH:25]\[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCC/C=C\CCCCCCCC([NH-])=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCNCCCCCCCCCCCCCCCC
Yield: 85 %

Procedure:
20 ml 1M LiAlH4 in ether are provided under argon inert gas in a 250 ml three-neck flask having a dropping funnel and a reflux condenser and subsequently a solution of 7.59 g (15 mmol) palmityloleoylamide in 80 ml THE added dropwise within 20 minutes. The mixture is refluxed for 2.5 hours, then another 5 ml 1 M LiAlH4 in ether is added and refluxed for another 2.5 hours. Excess hydride is decomposed using 6 M NaOH under ice bath cooling and the precipitate is filtered off. The precipitate is extracted twice with 40 ml of hot MtBE each, the combined organic phases dried over Na2SO4 and the solvent removed using a rotary evaporator. The residue is crystallised from 100 ml MtBE at −20° C. 6.23 g (12.7 mmol) corresponding to a yield of 85% of a colourless crystalline solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[S:16]([O:8][C:7]1[C:2]([NH:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[CH:3][C:4]([CH3:9])=[CH:5][CH:6]=1)([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(O)c(N)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(C)ccc2OS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-amino-p-cresol (12.3 g, 0.10 mol) in 125 ml of pyridine was added p-toluenesulfonyl chloride (38.1 g, 0.20 mol) in one portion. Stirring was continued overnight at ambient temperature. TLC now indicated no starting material, but there were two products. Another 7.6 g (20 percent excess) of p-toluenesulfonyl chloride was added and stirring continued for 6 hours. The reaction was poured into excess hydrochloric acid and stirred until completely solidified. The tan solid precipitate was filtered, washed with water and nearly dried. The damp filter cake was dissolved in one liter of boiling ethanol and let stand overnight at ambient temperature. Yield 33.0 g (76 percent) of crystals. NMR was consistent for the product.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C@H:14]1[CH2:18][C@@H:17]([C:19]([O:21][CH3:22])=[O:20])[N:16](C)[CH2:15]1)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C@H:14]1[CH2:18][C@@H:17]([C:19]([O:21][CH3:22])=[O:20])[NH:16][CH2:15]1)=[O:12]
Reactant: COC(=O)[C@@H]1C[C@H](OC(=O)N2CCc3ccccc3C2)CN1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(=O)N2CCc3ccccc3C2)CN1
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Compound 6 (1.45 g, 3.6 mmol) dissolved in DCM (20 ml) was treated with TFA (10 ml) at 0° C. After 2 hr, volatiles are evaporated. The residue is treated with sat. sodium bicarbonate aqueous solution and extracted with DCM. Compound 7 (0.86 g, 79%) is obtained as a pale yellow powder after the evaporation of solvent.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][S:12][C:13](=[NH:15])[CH3:14])=[CH:6][CH:5]=1>CO.C([O-])(O)=O.[Na+].[Cl-].[Zn+2].[Cl-]>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:13]([CH3:14])[S:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=O)CSC(C)=N)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(-c2csc(C)n2)cc1
Yield: 92.4 %

Procedure:
Heat a mixture of thioacetimidic acid 2-(4-methoxyphenyl)-2-oxoethyl ester hydrobromide (10.0 g, 32.9 mmol) and zinc (II) chloride (4.50 g, 33.0 mmol) in methanol (80 mL) at reflux under nitrogen protection for 6.5 hours. Cool the mixture, slowly dilute with saturated NaHCO3 (300 mL), and extract with methylene chloride (400 mL×2). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the crude product by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to provide 4-(4-methoxyphenyl)-2-methylthiazole (6.24 g, 92%): APCI mass spectrum m/z 206 [C11H11NOS+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′,6′-dihydroxyacetophenone (4 g) and potassium carbonate (3.82 g) in acetone (40 mL) was added benzyl bromide (3.13 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were washed with water and n-hexane, and dried under reduced pressure to give the title compound (3.67 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1Br.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1.[OH-].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1[O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][O:13][CH3:12])=[CH:23][CH:22]=1
Reactant: COCOc1ccc(CO)cc1
Reactant: CCn1ncc(Br)c(Br)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc(OCc2ccc(OCOC)cc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 1.2 g of 4,5-dibromo-2-ethyl-3(2H)-pyridazinone and 0.88 g of 4-methoxymethoxybenzyl alcohol, and 0.34 g of powdery potassium hydroxide was added thereto. The reaction mixture was stirred overnight at room temperature, poured into water and extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate and freed of the benzene by distillation under reduced pressure. The resulting oil was purified by means of TLC [eluting with benzene/ethyl acetate (12/1)] and recrystallization (from benzene/n-hexane) to obtain 450 mg of the aimed compound, m.p. 104°~106.0° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[N:10]=[CH:9][C:8]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[N:10]=[CH:9][C:8]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnc(C(C)C)cc1NCCCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCNc1cc(C(C)C)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 126.8 %

Procedure:
To a solution of ethyl 4-[(3-methoxypropyl)amino]-6-(1-methylethyl)pyridine-3-carboxylate (263 mg) in ethanol (5 ml) was added 2 M aqueous sodium hydroxide solution (0.94 ml) and the mixture was stirred at room temperature for 15 hr. The reaction mixture was adjusted to pH 7 with 1 M hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol, and the precipitated inorganic salt was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (300 mg) as a mixture of inorganic salts.