Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[N:14]=[C:15]([NH:18][C:19](=[O:22])[CH2:20][Cl:21])[S:16][CH:17]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[C:29]1([CH:35]([O:42][C:43]([C:45]2[N:50]3[C:51](=[O:54])[C@@H:52]([NH2:53])[C@H:49]3[S:48][CH2:47][C:46]=2[CH:55]([S:57][C:58]2[NH:62][N:61]=[N:60][N:59]=2)[CH3:56])=[O:44])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1>C(Cl)Cl>[C:29]1([CH:35]([O:42][C:43]([C:45]2[N:50]3[C:51](=[O:54])[C@@H:52]([NH:53][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]4[N:14]=[C:15]([NH:18][C:19](=[O:22])[CH2:20][Cl:21])[S:16][CH:17]=4)[C@H:49]3[S:48][CH2:47][C:46]=2[CH:55]([S:57][C:58]2[NH:62][N:61]=[N:60][N:59]=2)[CH3:56])=[O:44])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(NC(=O)OC(C)(C)C)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a suspension of 349 mg of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl)acetic acid in 5 ml of methylene chloride is added 249 mg of phosphorous pentachloride, and the mixture is stirred at room temperature. The mixture is added dropwise under stirring to the solution of 494 mg of 7β-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester dissolved in 5 ml of methylene chloride, followed by the addition of 474 mg of pyridine. After that, the stirring is continued for further 1 hour at room temperature. The reaction solution is washed with 0.5N hydrochloric acid and then with water, and dried. The oily product obtained by the distillation of the solvent is purified by a column chromatography packed with silica gel. The procedure gives 513 mg of 7β-{α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl ]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=[O:9].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10][C:13]1[CH:14]=[C:15]([Cl:19])[C:16]([Cl:18])=[CH:17][C:12]=1[Cl:11])=[O:9]
Reactant: O=C(O)CN1CCCC1=O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CN1CCCC1=O)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
84.8 g of 2-oxo-1-pyrrolidineacetic acid and 128.5 g of 2,4,5-trichlorophenol are dissolved in 1,500 ml of methylene chloride, 138.75 g of dicyclohexylcarbodiimide are slowly added at 0° C. and the mixture is stirred at 20° C. for three hours. The urea which has precipitated is then filtered off, the solvent is evaporated off and the residue is recrystallised from ethyl acetate.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[CH2:17]([N:24]1[CH2:29][C@@H:28]2[CH2:30][C@H:25]1[CH2:26][NH:27]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[OH-]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH:28]2[CH2:30][CH:25]1[CH2:26][N:27]2[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CC2CN3C2=Nc3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 11-oxo-dibenz[b,f][1,4]oxazepine (Aldrich) (0.149 g, 0.0007 mol) in dry toluene (10 mL), was added (1S,4S)-2-benzyl-2,5-diazabicyclo(2.2.1)heptane (0.54 g, 0.003 mol) and TiCl4 (0.75 mL, 0.0008 mol) via syringe. The mixture was stirred at room temperature for 30 min then refluxed for 5 hrs. The reaction mixture was cooled and dumped into conc. NH4OH and extracted with CHCl3. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed (hexane:EtOAc, 1:1) to give 11-(2-benzyl-2,5-diazabicyclo(2.2.1) hept-5-yl)-dibenz[b,f][1,4]oxazepine (yield 0.1319, mp 70°-72° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])[CH:21]=[CH:22][C:23]=1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([Br:17])[CH:19]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.33 mmol, 1.07 g) in THF at room temperature, NaH (100 mg, 4.5 mmol) was added and stirring continued for 30 min then 4-(3-Bromo-4-cyclohexyloxy-phenyl)-3-butyl-6-chloro-pyridazine (3.50 mmol, 1.5 g) was added. The resulting mixture was stirred at 50° C. for over night, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10-20% ethyl acetate in hexanes to provide 4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (1.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:11][C:12](N)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]=O.[BH3-][C:30]#[N:31].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:11][C:12]([N:31]([CH3:30])[CH3:27])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCc1nc(N(C)C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 305 mg (0.86 mmol) of 5-(benzyloxy)-4-decyl-6-methylpyrimidin-2-amine in 3 mL of methanol were added 3 mL of 35% aq. formaldehyde followed by 271 mg (4.30 mmol) of NaCNBH3. The reaction mixture was stirred at 23° C. for 3 h. The reaction mixture was quenched with acetic acid until bubbling ceased then poured into 20 mL of water and extracted with two 40-mL portions of ethyl acetate. The combined organic layer was washed with one 40-mL portion of saturated aq. NaHCO3 and one 40-mL portion of brine. The organic solution was dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (8×3 cm). Elution with 2:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 154 mg (46%); silica gel TLC Rf 0.8 (2:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 0.87 (t, 3H, J=6.4 Hz), 1.33 (m, 14H), 1.69 (quint, 2H, J=7.2 Hz), 2.32 (s, 3H), 2.61 (dd, 2H, J=7.6, 7.6 Hz), 3.14 (s, 6H), 4.70 (s, 2H) and 7.33-7.44 (m, 5H); 13C NMR (CDCl3) δ 14.07, 19.29, 22.65, 27.85, 29.30, 29.50, 29.55, 29.59, 29.62, 31.71, 31.89, 37.21, 37.21, 75.72, 127.91, 128.11, 128.11, 128.54, 128.54, 137.17, 141.27, 158.60, 159.01 and 163.49; mass spectrum (APCI), m/z 384.3003 (M+H)+ (C24H38N3O requires 384.3015).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:12][CH:11]=1.[CH3:27][OH:28]>>[CH3:27][O:28][C:10]1([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13](=[N:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH:14]=[CH:15]1
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccccc4s3)cc2)cc1
Product: COC1(c2nc3ccccc3s2)C=CC(=NS(=O)(=O)c2ccc(C)cc2)C=C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To the the sulfonamide (0.1 g) dissolved in methanol (2 mL) was added BTIB (1.1 eq.) in one portion as a solid. The resulting suspension was stirred at room temperature for 5 hours. The precipitate formed was collected on a filter, washed with ice cold methanol (2 mL) and dried under vacuum to give the title compound.
Reaction SMILES: [O:1]1[CH:8]2[CH:9]=[CH:10][CH:2]1[CH:3]1[CH:7]2[C:6](=[O:11])O[C:4]1=[O:12].[CH2:13]([CH2:15][NH2:16])[OH:14]>CO>[OH:14][CH2:13][CH2:15][N:16]1[C:6](=[O:11])[CH:7]2[CH:3]([CH:2]3[O:1][CH:8]2[CH:9]=[CH:10]3)[C:4]1=[O:12]
Reactant: O=C1OC(=O)C2C3C=CC(O3)C12
Reactant: NCCO
Solvent: CO
Product: O=C1C2C3C=CC(O3)C2C(=O)N1CCO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The adduct 1 (10.0 g, 60.0 mmol) was suspended in methanol (150 mL) and the mixture cooled to 0° C. A solution of ethanolamine (3.6 mL, 60 mmol) in 30 mL of methanol was added dropwise (10 min) to the reaction mixture, and the resulting solution was stirred for 5 min at 0° C., then 30 min at ambient temperature, and finally refluxed for 6 h. After cooling the mixture to ambient temperature, solvent was removed under reduced pressure, and residue was dissolved in 150 mL of CH2Cl2 and washed with 3×100 mL of water. The organic layer was separated, dried over Na2SO4 and filtered. Removal of the solvent under reduced pressure gave white-off solid which was further purified by flash chromatography eluting with ethylacetate (EtOAc) to give the product, 2-(2-hydroxyethyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione (2), as a white solid. Yield: 3.3 g (27%). 1H NMR (500 MHz, CDCl3, δ): 6.53 (s, 2H, CH═CH, bridge protons), 5.29 (s, 2H, —CHO, bridge-head protons), 3.79-3.70 (m, 4H, NCH2CH2OH), 2.90 (s, 2H, CH—CH, bridge protons). 13C NMR (500 MHz, CDCl3, δ): 176.8, 136.5, 80.9, 60.1, 47.5, 41.7.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][S-:32].[Na+]>CS(C)=O.C(OCC)(=O)C.O>[OH:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([S:32][CH3:31])[CH:7]=2)=[CH:10][C:11]=1[C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[OH:30])=[O:22]
Reactant: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccnc(Cl)c2)c2ccccc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(O)c3ccccc23)ccn1
Temperature: 100 °C

Procedure:
To a solution of 4-[(2-chloropyridin-4-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide (0.050 g, 0.12 mmol) in 1 mL of DMSO was added sodium thiomethoxide (0.025 g, 0.35 mmol). The mixture was heated in a sealed tube at 100° C. for 18 hours, then cooled to room temperature. Additional sodium thiomethoxide (0.025 g, 0.35 mmol) was added, and the reaction was heated to 120° C. for 3 hours, then recooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was extracted 3× with ethyl acetate and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-hydroxy-N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[2-(methylthio)pyridin-4-yl]methyl}-2-naphthamide that gave a mass ion (ES+) of 423.0 for [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.CO[C:16]([CH2:18][NH2:19])=O.Cl.O.[CH3:22][N:23](C)C=O>>[Cl:1][C:2]1[C:7]([C:8]([N:19]2[CH:18]=[CH:16][N:23]=[CH:22]2)=[O:10])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12
Reactant: O=C(O)c1cnc2[nH]ccc2c1Cl
Reactant: CN(C)C=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: O
Product: O=C(c1cnc2[nH]ccc2c1Cl)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (350 mg) in N,N-dimethylformamide (4 ml) were added N,N-carbonyl diimidazole (289 mg) and glycinemethylester hydrochloride (447 mg) successively under ambient temperature. The mixture was stirred at ambient temperature for 2 hours. To the reaction solution was added water. The precipitated solid was filtered, washed with water, and dried to obtain 4-chloro-5-(1H-imidazol-1-ylcarbonyl)-1H-pyrrolo[2,3-b]pyridine (325 mg) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]4[N:31]([CH2:32][CH2:33][O:34]C5CCCCO5)[C:30]5[CH:41]=[CH:42][CH:43]=[CH:44][C:29]=5[N:28]=4)[CH2:15]3)=[O:12])[CH:9]=[CH:10][C:2]1=2.C(O)(=O)C.C1COCC1>O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]4[N:31]([CH2:32][CH2:33][OH:34])[C:30]5[CH:41]=[CH:42][CH:43]=[CH:44][C:29]=5[N:28]=4)[CH2:15]3)=[O:12])[CH:9]=[CH:10][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCO
Temperature: 45 °C

Procedure:
(2R,4R)-tert-butyl 4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (90 mg, 0.15 mmol) was added to a solution of acetic acid (2 mL), THF (1 mL) and water (0.5 mL) (4:2:1), the resulting solution was stirred at 45° C. for over night. The reaction mixture was concentrated to give a yellow oil as title compound (LC-MS: 523.2, t=2.3 min) for the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][CH2:16]CS([O-])(=O)=O)=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>O.CS(C)=O>[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][CH2:16][CH:1]([C:8]#[N:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=S(=O)([O-])CCCc1ccc(Cl)cc1
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: N#CC(CCc1ccc(Cl)cc1)c1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
This product was also obtained by charging a reaction vessel with 58.6 gm of benzylcyanide (0.5 mole), 116.8 gm of 4-chlorophenethylmethanesulfonate (0.5 mole), 500 ml of toluene and 500 ml of dimethylsulfoxide. The mixture was cooled to about 5° C. and 50% sodium hydroxide was added slowly with rapid mixing while maintaining the temperature at about 5°-10° C. After the addition of the sodium hydroxide (about 1.5 hours), the mixture was allowed to warm to room temperature and then stirred for another three hours. One liter of water was added to the mixture and it was transferred to a separatory funnel where it was extracted with ether; the combined ether extracts were sequentially washed with 5% hydrochloric acid, water and brine. The liquid obtained after solvent removal was distilled to obtain 102 gm of 3-(4-chlorophenyl)-1-cyano1-phenylpropane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:4])=[O:3].CS([Cl:18])(=O)=O>[OH-].[Na+]>[ClH:18].[Cl:18][CH2:12][C:7]1[C:6]([CH3:13])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(S(C)(=O)=O)cc[n+]([O-])c1C
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(S(C)(=O)=O)ccnc1CCl
Product: Cl
Temperature: 92.5 °C
Reaction time: 0.75 h

Procedure:
Mixture of 4-Methanesulfonyl-2,3-dimethyl-pyridine 1-oxide (100 g) and methane sulfonyl chloride (300 ml) was heated to 90-95° C. and maintained at the same temperature for 3-4 hrs. 20% sodium hydroxide solution (1500 ml) was cooled to 0-5° C. separately and the above reaction mixture was added to this solution slowly for a period of 2-3 hrs and maintained at the same temperature for 1-2 hrs. The solid was filtered and washed with DM water (200 ml). DM water (400 ml) was added to the wet material and stirred for 30-60 min at 25-35° C. The solid was filtered and washed with DM water (100 ml). Ethylacetate (600 ml) was added to the wet material followed by heating to get clear solution and adding carbon (10 gm) and stirring the reaction mixture for 30 minutes. The resultant reaction mass was filtered through hiflow bed and washed with ethyl acetate (200 ml). The filtrate was dried with sodium sulfate (100 gm). Subsequently, conc. HCl (60 ml) was added, heated to reflux and maintained at the same temperature for 30-60 min. The reaction mixture was cooled to 25-30° C., then to 0-5° C. and maintained at the same temperature for 1-2 hrs. The solid was then filtered and washed with ethylacetate (100 ml). The wet compound was dried at 50-60° C. 90 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[N:23]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.CO>[CH3:21][N:22]1[CH2:26][CH2:25][C:24]([C:27]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:28])=[N:23]1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: Cn1ccc(C(=O)O)n1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CN1CCC(C(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (58 mg, 0.21 mmol, example 30, step 1) in DMF (1 mL) was added 1-methyl-1H-pyrazole-3-carboxylic acid (Fluorochem, 34 mg, 0.27 mmol), 1-hydroxybenzo-triazole hydrate (42 mg, 0.27 mmol), and N-((isopropylimino)methylene)propan-2-amine (66 μL, 0.42 mmol). The resulting mixture was then stirred at RT for 16 h. Then, the mixture was filtered and the filtrate was purified by preparative HPLC to give the target compound. The product was dissolved in MeOH and passed through PL-HCO3 MP resin and the resin was washed with MeOH (2×0.3 mL). The combined filtrates were concentrated and dried under vacuum to give the title compound as a light-yellow solid. MS (ESI, positive ion) m/z: 386 (M+H).
Reaction SMILES: CO.C[O-].[Na+].CO.[Br:8][CH2:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([SH:19])[CH:16]=[CH:17][CH:18]=1>O.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([S:19][CH2:10][CH2:9][Br:8])[CH:16]=[CH:17][CH:18]=1
Reactant: BrCCBr
Reactant: Fc1cccc(S)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cccc(SCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 mL of a methanol solution containing 0.83 g of 28% sodium methoxide/methanol, 1.0 mL of 1,2-dibromoethane and 0.50 g of 3-fluorobenzenethiol were added under cooling with ice, the mixture was stirred at the same temperature for 1 hour, at room temperature for 2 hours, and at 50° C. for 1 hour, and then the reaction mixture was refluxed by heating for 5 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane] to obtain 0.62 g of a pale yellow oily substance, 1-(3-fluorophenyl)thio-2-bromoethane.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: O=C(NCCO)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of N-benzyloxycarbonyl-ethanolamine (12.03 g, 61.6 mmol) in dry dichloromethane (50 ml) was added diisopropylethylamine (32.2 ml, 184.9 mmol) and 2-methoxyethoxymethyl chloride (16.9 ml, 147.9 mmol) with stirring. The mixture was allowed to warm to room temperature then stirred for a further 3 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed successively with 1M hydrochloric acid, sat. aq. sodiumhydrogen carbonate and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to porvide the title compound as a orange/yellow oil which was used without further purification. 1H--NMR; δ(CDCI3), 7.35 (5H, m), 5.45 (1H, m), 5.11 (2H, s), 4.72 (2H, s), 3.67 (4H, m), 3.55 (2H, m) and 3.38 (5H, m).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:26])=[C:8]([C:10]2[NH:11][C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:9]=1.[CH3:27][SiH:28]([CH3:30])[CH3:29].[Na+].[Cl-].C1[CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:26])=[C:8]([C:10]2[N:11]([CH2:37][O:36][CH2:35][CH2:34][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:9]=1
Reactant: C1CCOC1
Reactant: C[SiH](C)C
Reactant: CNc1nccc(-c2cc(C(N)=O)c(-c3cc(Cl)ccc3C)[nH]2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: CNc1nccc(-c2cc(C(N)=O)c(-c3cc(Cl)ccc3C)n2COCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
NaH (60% dispersion in mineral oil, 160 mg, 4.0 mmol) was added to a suspension of 2-(5-chloro-2-methyl-phenyl)-5-(2-methylamino-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (1.0 g, 2.92 mmol) in dry THF (15 mL) at 0° C. The reaction was kept at the same temperature for 20 min then 2-(chloromethoxy)ethyl](trimethyl)silane (0.714 mL, 4.0 mmol) was added and the mixture was stirred at room temperature for 2 h. Saturated aqueous NaCl (20 mL) was added at 0° C. and the mixture was extracted with EtOAc (2×30 mL). The separated organic phase was dried over sodium sulfate and the solvent evaporated. The crude was purified by flash chromatography on silica gel (DCM/EtOH 94/6) to afford the title compound (620 mg, 45%).