Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:29]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1cnn(CCc2ccccc2)c1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cnn(CCc5ccccc5)c4)ncnc3[nH]2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (110 mg, 0.33 mmol) and 4-amino-1-phenethyl-1H-pyrazole (74 mg, 0.39 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the desired product and some de-Boc product (ca. 1:1 ratio). After the mixture was cooled to rt, it was diluted with methylene chloride (3 mL), then N,N-diisopropylethylamine (0.11 mL, 0.66 mmol) and di-tert-butyldicarbonate (72 mg, 0.33 mmol) were added, the resulting mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc (30 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized with EtOAc to give the title compound as an off-white solid. LC-MS (ES, Pos.): 486 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=1.50 (s, 9H), 2.50 (m, 2H), 3.23 (t, J=7.3 Hz, 2H), 3.66 (m, 2H), 4.17 (m, 2H), 4.38 (t, J=7.3 Hz, 2H), 6.08 (s, 1H), 6.17 (s, 1H), 6.55 (s, 1H), 7.17-7.32 (m, 5H), 7.60 (s, 1H), 7.80 (s, 1H), 8.37 (s, 1H), 10.99 (br s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5]N1C2=C3C(=CC=C2)CCCN3S1.[NH:18]1[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[S:19]1(=[O:31])=[O:30].[H-].[Na+].BrCCCCCl>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:18]1[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[S:19]1(=[O:30])=[O:31]
Reactant: ClCCCCN1SN2CCCc3cccc1c32
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Agent: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)N(CCCCCl)c2cccc3c2N1CCC3
Reaction time: 0.5 h

Procedure:
1-(4-Chlorobutyl)-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline can be prepared as follows: a solution of 5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4 g) in dry N,N-dimethylformamide (20 cc) is added dropwise to a suspension of sodium hydride (0.69 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 30 minutes' stirring, a solution of 1-bromo-4-chlorobutane (3.93 g) in N,N-dimethylformamide (20 cc) is added. The reaction mixture is stirred at 20° C. for 2 hours and then diluted in a mixture of water (200 cc) and ethyl acetate (200 cc). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 50-cm height) and eluted at a pressure of 0.7 bars of nitrogen with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 125-cc fractions being collected. Fractions 3 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(4-chlorobutyl)-5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4.5 g).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[CH2:13]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1)[CH3:14]>>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:14][CH2:13][N:15]=[C:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:17]1
Reactant: CCNc1cc(C)ccn1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: CCN=C1CC(C)CCN1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-(ethylamino)-4-methylpyridine to the title compound except platinum oxide was used as the catalyst. The analysis of the product, obtained as an oil, was found to be consistent with the proposed structure. MH+=141; 1H NMR (D2O): 3.40-3.10 (m, 2H); 3.00 (q, J=6 Hz, 2H); 2.50-2.40 (m, 1H); 2.10-1.90 (m, 1H); 1.83 (s, 3H); 1.80-1.65 (m, 4H); 1.40-1.20 (m 1H); 1.02 (t, J=6 Hz, 3H); 0.83 (d, J=6 Hz, 3H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]1([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1ccccc1-c1ccccc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1-c1ccccc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-phenylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:23]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH3:38])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH3:38])=[CH:28][CH:27]=3)=[CH:23][C:6]=2[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:10]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Reactant: CCOCCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g), 4-(3-ethoxypropoxy)phenyl borate (0.62 g), 1M potassium carbonate solution (8 ml), ethanol (8 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.2 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[N:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][NH2:12]
Reactant: Cc1cc2[nH]ncc2cc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc2[nH]ncc2cc1CN
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 6-methyl-1H-indazole-5-carbonitrile (preparation 32) (230 mg, 1.47 mmol) in THF (10 ml) under nitrogen was treated with a solution of lithium aluminium hydride (1N, 3.66 ml, 3.66 mmol) in THF at 0° C. The resultant mixture was stirred for 16 hr warming to room temperature, then treated with MeOH (12 ml), H2O (0.8 ml), NaOH (4N, 2 ml) and H2O (4 ml). The resultant precipitate was removed by filtration, washed with THF and purified by chromatography (SiO2, eluting with 90:10:1 CH2Cl2:MeOH:NH3) to give the desired product (71 mg, 30%). 1H NMR (CD3OD) δ 2.40 (s, 3H), 3.95 (s, 2H), 7.35 (s, 1H), 7.70 (s, 1H), 7.95 (s, 1H), LRMS m/z=162.0 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][CH2:13][CH:15]2[CH2:16][O:17]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1ccc(CO)cc1
Product: CC(C)(C)c1ccc(COCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(tert-butyl)-benzyl alcohol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CCCNC(=O)OC(C)(C)C
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF was added EDCI (123 mmol, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and tert-butyl 4-amino-4-methylpentylcarbamate (139 mg, 0.64 mmol) in one portion at room temperature and the mixture stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered, the filter cake washed with petroleum ether then dried to give crude tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpentylcarbamate (75 mg, 46%) as a yellow solid. MS: (M+H)+=510.2.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:22][CH2:23][CH2:24]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(CN2CCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)c(F)c1
Reaction time: 5 h
Yield: 97.7 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (33 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and then 10% palladium carbon (17 mg) was added thereto, followed by stirring under a hydrogen atmosphere for 5 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to give a crude product of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (30 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15]N(CC(NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1.CCN(C(C)C)C(C)C.[O:48]([CH:55]1CCNCC1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(C)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][CH:55]([O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:15][CH2:16]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCC(Oc3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 84 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (162 mg, 0.64 mmol), DIPEA (3.5 eq, 2.24 mmol, 0.39 mL), isopropanol (3 mL) and 4-phenoxypiperidine (1.1 eq, 0.70 mmol, 125 mg). Concentration in vacuo to half volume after 18 h gave a bright yellow solid, which was filtered and washed with cold water (2×2 mL) to give the product (212 mg, 84%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.74-1.81 (m, 2H, 2× piperidine CHAHB), 2.04-2.08 (m, br, 2H, 2× piperidine CHAHB), 2.98-3.03 (m, 2H, 2× piperidine NCHAHA), 3.24-3.27 (m, 2H, 2× piperidine NCHAHA), 4.63 (quintet, J=3.9 Hz, 1H, piperidine CH), 6.92 (t, J=7.4 Hz, 1H, phenyl H-6), 6.98 (s, br, 2H, NH2), 6.99 (d, J=7.8 Hz, 2H, phenyl H-2 & H-4), 7.28 (dd, J=8.6, 7.8 Hz, 2H, phenyl H-3 & H-5), 8.17 (s, 1H, pyridine H-6);
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1.Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([OH:15])[CH2:10][CH2:11][N:12]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([F:29])([F:31])[F:30])=[N:26][N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:6]=[N:7][CH:8]=1
Reactant: OC1(c2cncc(C(F)(F)F)c2)CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: OC1(c2cncc(C(F)(F)F)c2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 75 %

Procedure:
A mixture of 4-[5-(trifluoromethyl)pyridin-3-yl]piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-[5-(trifluoromethyl)pyridin-3-yl]-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 75% yield.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:18]=[CH:17][C:10]([CH:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])=[CH:9][CH:8]=1)=[N+:2]=[N-:3].[C:19]([CH2:21][C:22]([NH2:24])=[S:23])#[N:20]>C(O)C>[NH2:16][C:15]1[C:12]([C:13]#[N:14])=[C:11]([C:10]2[CH:17]=[CH:18][C:7]([O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[CH:8][CH:9]=2)[C:21]([C:19]#[N:20])=[C:22]([SH:23])[N:24]=1
Reactant: N#CCC(N)=S
Reactant: N#CC(C#N)=Cc1ccc(OCCN=[N+]=[N-])cc1
Solvent: CCO
Product: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCN=[N+]=[N-])cc1
Temperature: 25 °C

Procedure:
A solution of 2.39 g (9.98 mmol) of the compound from Example 37A and 2.50 g (24.92 mmol) of cyanothioacetamide in 100 ml of ethanol is stirred at +78° C. for 6 h. After cooling to RT and a further 12 h of standing without stirring, the reaction mixture is concentrated using a rotary evaporator. The residue is recrystallized from about 30 ml of ethanol. The resulting precipitate is filtered off with suction and washed twice with in each case 10 ml of methyl tert-butyl ether.
Reaction SMILES: I[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C)C=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)c(C)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C)cc1C
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2, 9.2 g, 31.71 mmol, 1.00 equiv), Zn(CN)2 (4.46 g, 38.12 mmol, 1.20 equiv), and Pd(PPh3)4 (2.93 g, 2.54 mmol, 0.08 equiv) in N,N-dimethylformamide (120 mL) was stirred under a nitrogen atmosphere at 100° C. overnight. After cooling to room temperature, the reaction was then quenched by careful addition of 100 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 2×20 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to yield 6.2 g (93%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2[Cl:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2cc(OCc3ccccc3)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)c2cc(OCc3ccccc3)ccc2n1
Temperature: 0 °C

Procedure:
6-Benzyloxy-4-hydroxy-2-methylquinoline (2.6 g; see step (ii) above) in phosphorus oxychloride (40 mL) was heated at reflux for 3.5 hours. The mixture was then added carefully to ice/water and solid sodium carbonate added until the solution reached pH 8.0. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The resulting solid was triturated with diethyl ether to give the title compound (6.4 g) as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)OCC)C.[CH2:16]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccn1Cc1ccccc1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 960 mg, 24 mmol) in DMF (20 ml) was added dropwise at an ice bath temperature a solution of diethyl(methoxycarbonylmethyl)phosphonate (5.04 g, 24 mmol) in DMF (1 ml). The mixture was stirred for 15 minutes at room temperature and cooled again. To the mixture was added dropwise a solution of 1-benzyl-2-formylpyrrole (3.7 g, 20 mmol) in DMF (2 ml). The reaction mixture was stirred for 4 hours at room temperature and poured into ice-water and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated. The obtained white crystal was washed with isopropylether to give 1-benzyl-2-(2-methoxycarbonylvinyl)pyrrole (3.14 g). Yield: 65%.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>CO>[CH2:1]([NH:19][CH2:20][CH:21]([OH:22])[CH2:23][OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNCC(O)CO
Temperature: 60 °C
Yield: 95.9 %

Procedure:
Octadecylamine (18 g) was dissolved in 200 ml methanol and heated to 60° C. Glycidol (4.95 g) was added dropwise under constant stirring over one and half hours. The reaction mixture was kept under reflux for one additional hour, and then cooled to room temperature, and evaporated to dryness, resulting in 22 g white solid material. This was then recrystallized from hexane, to yield ODP, mp 81°-83° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][C@H:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][C@H:12]1[CH2:13][O:14][C:27]([CH3:32])([CH3:28])[N:15]1[C:16]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](COCc1ccccc1)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 3.51 g of tert-butyl (3(S)-benzyloxymethyl-1(S)-hydroxymethyl-4-methyl-pentyl)carbamate in 20 ml of dichloromethane is cooled to 0° C. and admixed successively with 0.076 g of p-toluenesulphonic acid monohydrate and 2.6 ml of 2-methoxypropene. The reaction mixture is stirred at room temperature for another 16 hours and subsequently poured onto 1M sodium hydrogencarbonate solution, extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellowish oil. Rf=0.42 (1:4 EtOAc-heptane); Rt=6.20 (gradient I).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[OH:12]O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: OO
Reactant: OB(O)c1cccc(F)c1F
Solvent: ClCCl
Product: Oc1cccc(F)c1F
Yield: 93 %

Procedure:
Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25° C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C1(C)CCC(C(C)C)[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]3C(C(C)C)CCC(C)C3)[C:16]=2[OH:31])C1>>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH3:8])[C:16]=1[O:31][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: CC1CCC(C(C)C)C(c2cccc(C3CC(C)CCC3C(C)C)c2O)C1
Product: CC(=O)COc1c(C)cccc1C
Yield: 84 %

Procedure:
Prepared by 1-chloro-propan-2-one (50 mmol) and 2,6-dimenthylphenol (60 mmol); purified by silica gel/hexane:ethyl acetate (5:1) column chromatography as a colorless oil; yield 84% (7.5 g); H NMR (400 MHz, CDCl3): d 2.34 (s, 6H, CH3), 2.42 (s, 3H, CH3), 4.40 (s, 2H, OCH2), 7.02-7.10 (m, 3H, Ar); CNMR (100 MHz, CDCl3): δ 16.3, 26.6, 76.8, 124.5, 129.1, 130.6, 155.0, 205.4; GC-MS m/z 178.1 (M+).