Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.C(Cl)(=O)C.[Br:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:7][N:5]([CH2:4][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:17][C:16]1[CH:27]=[CH:28][C:13]([Br:12])=[CH:14][CH:15]=1)=[CH:26][CH:25]=2)[CH3:6]
Reactant: Brc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)CN(C)C
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CN(C)Cc1cc2cc(Oc3ccc(Br)cc3)ccc2[nH]1

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.186 g, 0.25 mL, 1.83 mmol) in CH2Cl2 (10 mL) with acetyl chloride (0.143 g, 0.13 mL, 1.83 mmol) followed by a solution of 5-(4-bromophenoxy)indole (0.394 g, 1.37 mmol) in CH2Cl2 (5 mL), gave after work-up 2-(N,N-dimethylaminomethyl)-5-(4-bromophenoxy)indole as a brown gum. This was treated with finely ground potassium cyanide (0.34 g, 5.21 mmol) and methyl iodide (0.77 g, 0.34 mL, 5.44 mmol) in DMF (30 mL) for 16 hr, and after appropriate work-up, 3-cyanomethyl-5-(4-bromophenoxy)indole was obtained as a brown gum 0.29 g, (ca 65%; carried through to next stage without further purification).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxybenzaldehyde (10.0 g, 81.8 mmol), 1-bromooctane (15.8 g, 81.8 mmol), and K2CO3 (34.0 g, 0.25 mol) in DMF (150 mL) was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was subsequently diluted in toluene. The organic layer was washed with HCl (10%), brine, and water. The solvent was concentrated in vacuo and the oil was purified by short silica gel plug (dichloromethane (DCM) in n-hexane, 10%). Solvent was dried in vacuo to afford the product 4-octyloxy benzaldehyde as a slightly colored oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][CH2:13][S:14][C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1>C(Cl)(Cl)Cl>[Cl:12][CH2:13][S:14]([C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCSc1ncc(Cl)cn1
Solvent: ClC(Cl)Cl
Product: O=S(CCl)c1ncc(Cl)cn1
Temperature: -5 °C
Yield: 73 %

Procedure:
90% m-chloroperbenzoic acid (4.2 mmol) in chloroform (7 ml) was added dropwise over 40 min to a solution of 2-(chloromethyl)thio-5-chloropyrimidine (3.9 mmol) in chloroform (6 ml) with stirring at -5° C. The mixture was allowed to reach room temperature and stirred overnight, washed with 1 M K2CO3, the dried (MgSO4) chloroform solution evaporated and the residue recrystallized from benzene/petroleum ether (60°-80° C.); yield 73%, m.p. 90° C. 1H NMR (CDCl3): δ4.70 and 5.00 (2H-CO2SO, Jgem 10 Hz), 8.84 (H-4, H-6).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.CSC1C2C(=CN=CC=2)NN=1.[CH3:31][S:32]([C:35]1[C:43]2[C:38](=[CH:39][N:40]=[CH:41][CH:42]=2)[NH:37][N:36]=1)(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]3)[C:7]([CH2:9][N:37]3[C:38]4=[CH:39][N:40]=[CH:41][CH:42]=[C:43]4[C:35]([S:32]([CH3:31])(=[O:33])=[O:34])=[N:36]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C1CC(n2c(CCl)nc3cc(Cl)ccc32)CCN1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: CSc1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC(=O)C2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 4-(5-chloro-2-(chloromethyl)-1H-benzo[d]imidazol-1-yl)piperidin-2-one and 3-(methylthio)-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[N:8][N:7]([CH3:11])[C:6]=2[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]([OH:19])[CH3:18])[C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:26](=[N:27][N:28]([CH3:31])[N:29]=2)[C:25](=[O:32])[N:24]([CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([OH:39])[CH3:38])[C:23]1=[O:40].C(O[C@@H](C)CCCCCl)(=O)C>>[CH3:1][N:2]1[C:10]2[N:9]=[N:8][N:7]([CH3:11])[C:6]=2[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([OH:19])[CH3:18])[C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:26](=[N:27][N:28]([CH3:31])[N:29]=2)[C:25](=[O:32])[N:24]([CH2:33][CH2:34][CH2:35][CH2:36][C@@H:37]([OH:39])[CH3:38])[C:23]1=[O:40]
Reactant: C[C@@H](O)CCCCn1c(=O)c2nn(C)nc2n(C)c1=O
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Agent: CC(=O)O[C@@H](C)CCCCCl
Product: C[C@H](O)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Product: C[C@H](O)CCCCn1c(=O)c2nn(C)nc2n(C)c1=O

Procedure:
(S)-3,7-Dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT22464) and (S)-3,8-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT22465) were synthesized according to the methods described for (R)-3,7-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT12464) and for (R)-3,8-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT12465) but using (S)-5-acetoxy-1-chlorohexane in place of (R)-5-acetoxy-1-chlorohexane.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][CH2:4][NH:5][C:6](=[O:47])[NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1.O.[OH-].[Li+].Cl.CO>C1COCC1.O>[CH3:48][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:47])[NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 94.8 %

Procedure:
To a cloudy solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.255 g, 0.388 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (0.049 g, 1.16 mmol) in water (1.00 mL). The reaction mixture was heated to 75° C. for 18 h. Then, the reaction was treated with 1N HCl (1 mL) and concentrated in vacuo, absorbed onto silica gel (3.5 g), loaded onto a silica gel column (12 g cartridge) and eluted with 90:10 DCM:MeOH to give the title compound (237 mg, 0.368 mmol, 95% yield) as a white solid. LCMS: m/e 644.4 (M+H)+, 3.95 min (method 8). 1H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.9 (1H, s), 5.3-5.3 (1H, m), 4.8 (1H, d, J=1.8 Hz), 4.6 (1H, s), 3.7-3.8 (1H, m), 3.4-3.6 (2H, m), 3.4 (1H, s), 3.2-3.3 (2H, m), 2.9 (6H, s), 2.7 (1H, td, J=11.1, 5.0 Hz), 2.6 (1H, dd, J=10.2, 3.2 Hz), 2.4 (1H, dd, J=12.1, 8.1 Hz), 2.2 (1H, dd, J=17.4, 6.4 Hz), 1.9-2.0 (2H, m), 1.8 (1H, d, J=13.4 Hz), 1.7 (3H, s), 1.7 (1H, br. s.), 1.7-1.7 (1H, m), 1.6-1.6 (2H, m), 1.5-1.6 (4H, m), 1.4-1.4 (5H, m), 1.3-1.4 (3H, m), 1.2 (3H, s), 1.1-1.1 (1H, m), 1.0-1.1 (6H, m), 1.0 (3H, s), 1.0 (3H, s). 13C NMR (MeOD) δ ppm 14.5, 16.3, 16.8, 19.2, 20.6, 21.3, 22.2, 26.3, 28.2, 29.7, 30.4, 30.5, 34.5, 36.2, 36.4, 37.1, 38.2, 38.4, 41.5, 42.6, 42.8, 43.6, 48.1, 49.0, 49.3, 49.3, 50.4, 50.6, 54.0, 55.6, 59.9, 64.9, 110.3, 111.1, 124.8, 129.3, 130.7, 147.5, 150.9, 160.4.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:12]1([CH2:18][C:19]2[C:6]3[C:5](=[C:4]([O:3][CH3:2])[CH:9]=[CH:8][CH:7]=3)[NH:10][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: COc1ccccc1NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: COc1cccc2c(Cc3ccccc3)c[nH]c12
Temperature: 0 °C

Procedure:
A mixture of 15 gm (0.086 mol) of 2-methoxyphenylhydrazine hydrochloride and 12 mL (0.09 mol) of 3-phenylpropionaldehyde in 300 mL of toluene was refluxed for 1.5 hours with azeotropic removal of water. The suspension was cooled, evaporated in vacuo and the residue dissolved in 500 mL of dichloromethane and stirred with 9 mL (0.09 mol) of phosphorous trichloride for 18 hours. The solution was poured into ice-water, stirred well, and made basic with sodium bicarbonate. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/5-15% ethyl ether to give product, 8.0 gm, 40%, as a viscous oil. 1H NMR (CDCl3) δ: 3.95 (s, 3H), 4.10 (s, 2H), 6.65 (d, 1H), 6.90 (s, 1H), 7.00 (t, 1H), 7.10 (d, 1H), 7.20 (m, 1H), 7.30 (m, 4H), 8.20 (br s, 1H)
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[NH:17][C:18]5[C:23]([C:24]=4[CH:25]=3)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]Cl.Cl>CS(C)=O>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][N:17]1[C:16]2[CH:15]=[CH:14][C:13]([C:10]3[N:11]=[N:12][N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:9]=3)=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: ClCc1cccc(Cl)c1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2nnc(-c3ccc4[nH]c5ccccc5c4c3)n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cccc(Cn2c3ccccc3c3cc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)ccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[2-(Triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole (200 mg, 0.42 mmol) was dissolved in methyl sulfoxide (1.5 mL). Sodium hydride (34 mg, 60%, 0.85 mmol) was added, and the resulting suspension was stirred for 30 min at room temperature. 3-Chlorobenzyl chloride (85 μL, 108 mg, 0.67 mmol) was added, and the stirring was continued at 40° C. for 18 hours. The reaction mixture was cooled to ambient temperature and poured into 0.1 N hydrochloric acid (aq.) (15 mL) The precipitated solid was filtered off and washed with water (3×10 mL) to furnish 9-(3-chlorobenzyl)-3-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole, which was dissolved in a mixture of tetrahydrofuran and 6 N hydrochloric acid (aq.) (9:1) (10 mL) and stirred at room temperature for 18 hours. The reaction mixture was poured into water (100 mL). The solid was filtered off and rinsed with water (3×10 mL) and dichloromethane (3×10 mL) to yield the title compound (127 mg). No further purification was necessary.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:23])[CH:8]([CH3:22])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([NH2:21])=[N:12]1.Br.Br[CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH3:23][N:7]([CH3:6])[CH:8]([CH3:22])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([NH:21][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[N:12]1
Reactant: CC(CCn1nc(N)c2cc(Cl)ccc21)N(C)C
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nn(CCC(C)N(C)C)c2ccc(Cl)cc12
Reaction time: 12 h
Yield: 58.3 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 8.71 g of the 1-(3-dimethylaminobutyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was atirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 7.23 g of 1-(3-dimethylaminobutyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 58 %.
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Cl:9][C:10]1[C:15]2[N:16]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[S:18][C:14]=2[C:13]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[NH:25][C:24]2=O)=[C:12]([F:35])[CH:11]=1>CC(CC)=O>[Cl:9][C:10]1[C:15]2[N:16]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[S:18][C:14]=2[C:13]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:24])[C:3]2=[O:6])=[C:12]([F:35])[CH:11]=1
Reactant: CCCOc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: CCCOc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2s1
Reaction time: 12 h

Procedure:
1.7 g of methyl iodide were added dropwise at about 20° C. to a mixture of 200 ml of absolute ethyl methyl ketone, 1.7 g of potassium carbonate and 5.0 g of 3-[4-chloro-6-fluoro-2-propoxybenzothiazol-7-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (compound I.8). Stirring was carried out for 12 hours at room temperature, after which the insoluble components were filtered off. The clear solution obtained was evaporated down. The residue was then taken up in water, after which the solution was neutralized with dilute hydrochloric acid. The product was then extracted with ethyl acetate. The ester phase was finally dried over sodium sulfate and then evaporated down. The purification of the crude product thus obtained was carried out by chromatography over silica gel (eluent: 9:1 cyclohexane/methyl tert-butyl ether). Yield: 1.0 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.F[C:26]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=[CH:28][N:27]=1.O>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:26]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:29]=[CH:28][N:27]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1c(C(F)(F)F)ccnc1F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(C(F)(F)F)ccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of 4-(benzyloxy)aniline (1010 mg), DIEA (1.771 mL) and methyl 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylate (1130 mg) in NMP (10 mL) was stirred at 150° C. for 2 h and at 200° C. for 1 h under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (225 mg).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[CH3:12][NH:13][CH2:14][CH2:15][OH:16].[H][H]>C1COCC1>[CH3:12][NH:13][CH2:14][CH2:15][O:16][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CNCCO
Reactant: [H][H]
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCOc1ccccc1C#N
Temperature: 2 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of sodium hydride (60% w/w, 8.23 g, 205.7 mmol) in dry THF (350 mL) under an inert atmosphere was added 2-fluorobenzonitrile (20.34 g, 164.6 mmol) and the resulting mixture cooled to 2° C. (batch temperature). 2-(Methylamino)ethanol (16.04 mL, 197.5 mmol) was added at a rate commensurate with controlled hydrogen gas evolution. At the end of the addition, the mixture was allowed to warm to ambient temperature and held overnight. The reaction mixture was then concentrated in vacuo to ˜50 mL and partitioned between diethyl ether (200 mL) and water (200 mL). The aqueous phase was adjusted to pH 12 with aq. sodium hydroxide (1 M) and the phases separated. The aqueous fraction was re-extracted with diethyl ether (2×200 mL). Any interfacial gel was removed by filtration of the biphasic mixture through a short Celite pad before the phase separation. The organic fractions were combined, washed with brine (600 mL), dried over sodium sulfate and concentrated in vacuo to afford crude 2-[2-(methylamino)ethoxy]benzonitrile as an orange oil. This was dissolved in THF (195 mL) under an inert atmosphere and triethylamine (51.4 mL, 365 mmol) added. The stirred solution was cooled to 0-5° C. and benzyl chloroformate (37.0 mL, 238 mmol) added over 1 h. At the end of the addition, the mixture was allowed to warm slowly to ambient temperature where it was held overnight. Any residual benzyl chloroformate was then quenched through the addition of diethylamine (20 mL, 497 mmol). The resulting thick slurry was filtered through a short Celite pad, and the filtrate concentrated in vacuo. The residue was partitioned between aq. hydrochloric acid (0.2 M, 200 mL) and TBME (200 mL). The phases were separated and the organic phase washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to ˜120 mL. Isohexane was added slowly until cloudiness was observed whereupon the mixture was left to stir at ambient temperature overnight. The resulting slurry was filtered through 11 μm filter paper. The filter cake was washed with TBME/isohexane (1:1 v/v, 20 mL) and dried overnight (30° C., 400 mbar) to afford benzyl [2-[2-cyanophenoxy)ethyl]methylcarbamate (30.25 g). The mother liquors from the crystallisation and filtrate from the cake wash were combined, concentrated to dryness in vacuo and purified by chromatography on silica gel, eluting with an ethyl acetate/isohexane gradient, to afford further benzyl [2-[2-cyanophenoxy)ethyl]methylcarbamate (13.96 g). The solids were combined to give benzyl [2-(2-cyanophenoxy)ethyl]methylcarbamate (44.21 g, 99.9% w/w). Mp 52° C. (TBME/isohexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Si:19]([O:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:34][NH:35][C:12](=[O:14])[C@H:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:33])=[CH:36][CH:37]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (3 g, 11.16 mmol), 4-((tert-butyldimethylsilyloxy)methyl)benzohydrazide (3.44 g, 12.28 mmol) and anhydrous THF (250 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (1.51 g, 11.16 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (3.21 g, 16.74 mmol) at −15° C. followed by triethylamine (2.33 mL, 16.74 mmol), The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 19 h, the mixture was filtered under vacuum and the residue washed with THF (70 mL). The THF solution was concentrated to ca. 20 mL, whereupon EtOAc (100 mL) was added followed by water (50 mL). The phases were partitioned and the organic phase washed with water (30 mL), brine (30 mL) dried (Na2SO4), filtered and concentrated to furnish a light brown solid (5.82 g). This crude product was not chromatographed. 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.82 (d, J=9 Hz, 2H), 7.42 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 2H), 6.58 (d, J=8 Hz, 1H), 5.42 (d, J=8 Hz, 1 H), 4.75 (s, 3H), 4.31-4.22 (m, 1 H), 3.99-3.97 (m, 1H), 2.24 (s, 3 H), 0.82 (s, 9H) and 0.01 (s, 6H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9]C)=[O:8])[CH2:2]1.CO.[OH-].[Li+].Cl>O.C1COCC1>[S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH2:2]1
Reactant: COC(=O)C1=CCCSC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=CCCSC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate (1.0 g, 6.32 mmol) in 10:1 MeOH:THF (16.5 mL) was added lithium hydroxide (0.30 g, 13 mmol) in water (15 mL). The resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was carefully acidified with 1N aqueous HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:26]3[CH2:27][C:28]4[CH2:29][NH:30][CH2:31][C:24]=4[CH2:25]3)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4=C(CNC4)C3)c(F)c21
Yield: 91.3 %

Procedure:
1-tert-Butyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.32 g), 3,7-diazabicyclo-[3.3.0] oct-1(5)-ene dihydrobromide (0.3 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 0.55 ml) in acetonitrile (12 ml) was refluxed for 5 hours. The produced precipitate was collected by filtration, washed with acetonitrile and methanol to give the title compound (0.38 g, yield 92%)