Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23][O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: C[O-]
Reactant: COC1=CC2=CC[C@@H]3C(=CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)C3=CC[C@]2(C)C1=O
Reaction time: 1 h

Procedure:
3-Methoxyandrosta-3,5,9(11)-trien-17-one (IAa, 20 g) in THF (220 ml) was combined with dimethyloxylate (11.8 g) and sodium methoxide (25%, 18.4 ml) at 0° under nitrogen. After the reactants were combined, the ice was removed. After one hour, TLC shows the reaction has gone cleanly. Triethylamine (7.0 ml), acetic acid (1.0 ml), paraformaldehyde (3 g), and methanol (28 ml) were added and the mixture stirred overnight at 20°-25°. TLC showed the reaction had gone to completion. The reaction mixture was washed with phosphate buffer (121 ml) and water (202 ml). The mixture was extracted with methylene chloride (48 ml) and again with methylene chloride (40 ml). The methylene chloride extracts were combined and back-extracted with water (80 ml) and saline (10 ml). The organic mixture was concentrated under reduced presure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9]([N:12]3[CH:16]=NC=N3)[C:10]=2[N:11]=1.N1C[CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9]([N:12]3[CH2:16][CH2:22][O:21][CH2:20][CH2:19]3)[C:10]=2[N:11]=1
Reactant: C1COCCN1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Solvent: ClCCl
Product: Nc1nc(N2CCOCC2)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 244.6 %

Procedure:
A suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (0.1 g, 0.4 mmol) and morpholine (0.07 mL, 0.8 mmol) in DCM (10 mL) was stirred at room temperature for 48 hours. After the removal of solvent, the residue was purified by flash chromatography (using 5% i-PrOH/DCM as the eluent), providing the title compound (0.26 g, 99% yield) as a yellow solid which was characterised as follows: MS (m/z) 266.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][N:41]1[CH2:45][CH3:46]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:45]([N:41]1[CH2:42][CH2:43][CH2:44][CH:40]1[CH2:39][NH:38][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:46]
Reactant: CCN1CCCC1CN
Reactant: COc1ccc(C(=O)O)cc1OC/C=C(\C)CCC=C(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1ccc(OC)c(OC/C=C(\C)CCC=C(C)C)c1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
3-geranyloxy-4-methoxybenzoic acid(1.52 g) was dissolved in chloroform (50 ml) and triethylamine (1.4 ml), and then diphenylphosphinic chloride(1.0 ml) was added thereto while being cooled with ice. After being stirred for 15 minutes, the mixture, with 2-aminomethyl-1-ethylpyrrolidine(0.7 ml) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1), thereby yielding 1.47 g(71%) of the aimed compound.
Reaction SMILES: C(N1C[C@H](OCC)[C@H](NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)C1)(=O)C.[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:58][CH3:59])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH2:56][F:57])[CH2:52][NH:51][CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47].Cl[C:61]([O:63][CH3:64])=[O:62]>>[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:58][CH3:59])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH2:56][F:57])[CH2:52][N:51]([C:61]([O:63][CH3:64])=[O:62])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47]
Reactant: COC(=O)Cl
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CNC[C@@H]1OCCF
Agent: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OC)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (DMSO-d6) δ) 1.08, 1.15, 2.37, 2.65, 3.54, 3.60, 3.71, 3.82, 4.25, 4.43, 4.54, 5.93, 6.98, 7.10, 7.26; IR (liq.) 2972, 2068 (w), 1996 (w), 1707 (s), 1607, 1566, 1484 (s), 1454 (s), 1393 (s), 1287, 1230, 1197, 1175, 1128, 1104, cm−1 HRMS (FAB) calcd for C23H31ClN4O4+H 463.2112, found 463.2104.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[NH:37][NH2:38]>>[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:38]1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=468.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12].C(N(CC)CC)C.[CH2:27]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([OH:13])=[O:12])=[O:40])=[CH:42][CH:43]=1)/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)c1ccccc1Sc1ccccc1N
Reactant: CCCC/C=C/COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(=O)O)cc1
Yield: 79 %

Procedure:
In 30 ml of methylene chloride were dissolved 2.1 g of ethyl 2-(2-aminophenylthio)benzoate and 1.8 g of triethylamine, followed by dropwise addition of 2.2 g of (E)-4-(2-heptenyloxy)benzoyl chloride with ice-cooling and stirring. The mixture was stirred at room temperature for 10 hours, and then the methylene chloride was distilled off. The residue was diluted with water and extracted with ether. The ether layer was washed with diluted hydrochloric acid and saturated sodium hydrogen carbonate solution and dried and the ether was distilled off. The oily residue was dissolved in 50 ml of ethanol followed by addition of 7 ml of 10% aqueous sodium hydroxide solution, and the mixture was heated on a water bath for 40 minutes. After cooling, the reaction mixture was acidified with hydrochloric acid and diluted with water and the crystals separated out therefrom were collected by filtration and washed with water and aqueous ethanol in that order to give 2.8 g of the title compound as white crystals.
Reaction SMILES: Cl[C:2]([C:4]1[N:8]([CH3:9])[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)=[O:3].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC.C1(C)C=CC([Mg]Br)=CC=1>C1CCCCC1>[CH3:9][N:8]1[C:4]([C:2]([C:19]2[CH:20]=[CH:21][C:16]([CH3:22])=[CH:17][CH:18]=2)=[O:3])=[CH:5][CH:6]=[C:7]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cc1ccc(C(=O)Cl)n1C
Reactant: Cc1ccccc1
Agent: Cc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Temperature: -60 °C
Yield: 10 %

Procedure:
To a stirred and chilled (-60°C.) solution of 5.0 g. (0.022 mole) of ethyl 5-chlorocarbonyl-1-methylpyrrole-2-acetate in 300 ml. of dry toluene is added in one portion 0.70 g. (0.0044 mole) of anhydrous FeCl3, weighed under 5 ml. of toluene and dissolved in 2 ml. of ether. The freshly prepared Grignard solution of 0.023 mole of p-tolylmagnesium bromide in 15 ml. ether is added dropwise, under hydrogen, to the above reaction mixture at such a rate so as to maintain the reaction temperature at -60 ± 2°C. The mixture is stirred at that temperature for another hour, then hydrolyzed with ice water and made strongly acidic with 3N HCl-ice. The aqueous layer is washed 3 times with benzene and the combined organic layers are washed sequentially with 3-dimethylaminopropylamine-ice, 3N HCl-ice, and saturated NaHCO3 solution. The organic layer is dried over anhydrous MgSO4, filtered and the solvent evaporated off to give about 2.0 g. (20%) of a solid residue with thin layer chromatography (film, silica, 1:3 EtOAo/cyclohexane) showing two major spots (rf - 0.54, 0.90). Column chromatography on 50 g. of CC-4 silica and sequential elution with hexane, hexane-benzene, benzene and benzene-ether gives the desired product (eluted with 10% Et2O/benzene) as an oil (0.75 g., 12% yield). Crystallization from MeOH gives about 350 mg. of a white solid, ethyl 1-methyl-5-(p-toluoyl)pyrrole-2-acetate, m.p. 68°-70°C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 70 °C

Procedure:
To a solution of Intermediate 96c (100 mg, 0.25 mmol) in 1,4-dioxane (3.00 mL) was added DIPEA (89.0 μL, 0.51 mmol) and Intermediate 39b (133 mg, 0.25 mmol). The reaction was heated to 70° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-8% MeOH in DCM to give the title compound. LCMS (Method 4): Rt 4.09 min, m/z 777 [MH+].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:13]3[CH2:15][CH2:14]3)(O)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:31]3[C:30]4[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=4)[NH:33][CH:32]=3)([CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc2sccc2c1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc4sccc4c3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.75 mmol) of the compound from Example 141A and 0.25 ml (3.30 mmol) of trifluoroacetic acid were added to 487 mg (2.75 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 404 mg (39% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+].I[CH3:32]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][N:11]([CH3:32])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: O=C(NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of N-[2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]benzamide (3.3 g) in dimethyl sulfoxide (20 mL) was added powdered potassium hydroxide (1.6 g), followed by iodomethane (1.0 mL) after 15 minutes. After 1 hour, the mixture was diluted with water (330 mL) and extracted with dichloromethane. The combined organic extracts were dried and evaporated to give the N-methylbenzamide (3.1 g) as an oil; MS: m/z=352[(M+1)-tetrahydropyranyl].
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]1[C:12]([CH2:13][S:14][C:15](=N)N)=[N:11][CH:10]=[CH:9][N:8]=1)=[O:6])[CH3:3].[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:20]=1CBr.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:2]([O:4][C:5]([C:7]1[C:12]([CH2:13][S:14][CH2:15][C:20]2[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:19]=2[Cl:18])=[N:11][CH:10]=[CH:9][N:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1nccnc1CSC(=N)N
Reactant: FC(F)(F)c1ccc(Cl)c(CBr)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1nccnc1CSCc1cc(C(F)(F)F)ccc1Cl
Temperature: 120 °C

Procedure:
To a solution of 3-carbamimidoylsulfanylmethyl-pyrazine-2-carboxylic acid ethyl ester hydrobromide (0.367 g) in acetonitrile (2 ml) was added 2-chloro-5-trifluoromethyl-benzylbromide (commercially available) (0.294 g), potassium carbonate (0.316 g) and water (3 drops). The reaction mixture was heated to 120° C. for 10 minutes in the microwave. The reaction mixture was filtered and the filtrate concentrated. The residue was purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in iso-hexane) to give Compound No. A2 of Table A.
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[C:29]([NH:1][CH:2]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:31])[CH3:30]
Reactant: Cc1nc2cc(OCC(N)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-[2-amino-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazinecarboxylate (260 mg) and 4-dimethylaminopyridine (3 mg) in methylene chloride (6 ml) and triethylamine (178 μl) at 0° C. was added acetic anhydride (160 mg), and the mixture allowed to warm to room temperature. After stirring overnight, the mixture was partitioned between methylene chloride and water, and solvent removed from the organic layer under reduced pressure. The residue was chromatographed on a silica gel column, eluting with 25% ethyl acetate/hexanes followed by 10% methanol/methylene chloride, to provide crude tert-butyl 4-[2-(acetylamino)-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate, which was purified by preparative TLC.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3=[N:9][C:10]([F:13])=[CH:11][CH:12]=[C:7]3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].[Br:16]N1C(=O)CCC1=O>CN(C=O)C>[Br:16][C:6]1[C:7]2[C:8](=[N:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc2ccn(C3CC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(Br)cn(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 1-cyclopropyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (2.03 g, 11.52 mmol) in DMF (38 mL) is added sodium hydroxide (0.506 g, 12.67 mmol), followed by N-bromosuccinimide (2.26 g, 12.67 mmol) portionwise over 5 minutes, resulting in an exothermic reaction (28° C.). The mixture is stirred at room temperature for 15 min., and further sodium hydroxide (46.1 mg, 1.15 mmol) and N-bromosuccinimide (0.205 g, 1.15 mmol) are added. Stirring is continued at room temperature for 30 min. Further sodium hydroxide (46.1 mg, 1.15 mmol) and N-bromosuccinimide (0.205 g, 1.15 mmol) are added. The reaction mixture is stirred at room temperature for 16 h and then poured onto brine (ca. 500 mL) and extracted with CHCl3 (ca. 2×300 mL). The organic layers are combined and dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil, which is purified by column chromatography on silica, eluting with 0 to 100% DCM in isohexane, to give the title compound as a white powder (2.32 g, 9.10 mmol). MS (m/z): 255/257 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([O:4][CH2:3][C@@H:2]([CH3:1])[CH2:5][CH3:6])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](C)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)COS(C)(=O)=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a −25° C. cooled solution of (2S)-2-methylbutan-1-ol (8.8 g) and triethylamine (30 ml) in THF (50 ml), a solution of methanesulfonyl chloride (1.14 g) in THF (10 ml) was drop wise added. After complete addition (15 min) the reaction mixture was further stirred for 2 h at −10° C. then for 30 min at 0° C. It was then filtered over celite and evaporated to dryness to give nearly pure (2S)-2-methylbutyl methanesulfonate as yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([CH:22]=2)[NH2:21])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:21][S:38]([C:32]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=3[F:30])(=[O:40])=[O:39])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3ccc(F)cc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
To a solution of 5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (12 g, 34.4 mmol) in DCM (100 mL) was added pyridine (8.2 g, 103 mmol). The mixture was cooled to 0° C. 2,4-Difluorobenzene-1-sulfonyl chloride (7.32 g, 34.4 mmol) in DCM (30 mL) was added dropwise to the mixture. The reaction was stirred at rt for 4 h. Then the reaction was washed with water (200 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:1) to afford the title compound (9.0 g, 49.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.63-10.70 (br, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.71-7.82 (m, 1H), 7.50-7.57 (m, 1H), 7.41-7.48 (m, 1H), 7.34-7.40 (m, 1H), 7.24-7.32 m, 1H), 7.15-7.23 (m, 1H), 7.08 (d, J=5.3, 1H), 3.27-3.37 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 525 [M+H]+.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].C(N(CC)CC)C.Cl[SiH:15]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.CCCCCC>[CH:16]([SiH:15]([CH:19]([CH3:21])[CH3:20])[O:6][CH2:1][CH2:2][C:3]#[C:4][CH3:5])([CH3:18])[CH3:17]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CC#CCCO
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC#CCCO[SiH](C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 3-pentynol (5.880g, 70.0 mmol, 1.0 equiv), 4-dimethylaminopyridine (DMAP) (840 mg, 7.00 mmol, 0.10 equiv), and triethylamine (TEA) (9.80 ml, 71.0 mmol, 1.01 equiv) in 100 mL of dry hexane was added dropwise chlorodiisopropylsilane (11.0 g, 71.0 mmol, 1.01 equiv) over 20 minutes. The resulting white suspension was allowed to warm to room temperature and was stirred overnight. The reaction mixture was filtered through a short silica pad (10 g) and the solvent was then evaporated in vacuo to give a colorless liquid. Fractional distillation of this liquid afforded 11.2 g (81%) of A-7 as a colorless liquid. An analytical sample (0.48 g) was obtained by redistillation of a 0.50 g sample by Kugelrohr distillation.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:7])=[CH:3]\[C:4](=O)[CH3:5].CO[C:10]1(OC)[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15].C(O[Na])(C)(C)C.CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:10]2=[N:1][C:2]([CH3:7])=[CH:3][C:4]([CH3:5])=[C:14]2[CH2:13][CH2:12]1
Reactant: CC(=O)/C=C(/C)N
Reactant: COC1(OC)CCCN1C
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(n1)N(C)CC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 2.36 g (23.8 mmol) of (Z)-4-aminopent-3-en-2-one in 8 mL of toluene was added 5.88 g (40.5 mmol) of 2,2-dimethoxy-1-methylpyrrolidine. The reaction mixture was heated at reflux and stirred for 2 h, cooled to 90° C., and then treated with 4.65 g (48.4 mmol) of t-BuONa and 4 mL of t-BuOH. The reaction mixture was stirred at 90° C. for another 16 h. The cooled reaction mixture was quenched by the addition of 20 mL of sat aq NH4Cl. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (25 2.6 cm). Elution with 10:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 1.60 g (42%); silica gel TLC Rf 0.15 (4:1 hexanes/ethyl acetate); 1H NMR (CDCl3) δ 2.05 (s, 3H), 2.32 (s, 3H), 2.76 (t, 2H, J=8.4 Hz), 2.86 (s, 3H), 3.34 (t, 2H, J=8.4 Hz) and 6.10 (s, 1H); 13C NMR (CDCl3) δ 17.8, 24.0, 24.3, 33.1, 52.4, 113.1, 118.1, 141.2, 154.5 and 163.7; mass spectrum, m/z 162.1 (M+) (theoretical 162.1).