Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CCN(CC)CC.[C:38]([O:43]CC)(=O)[C:39]([NH2:41])=[O:40].[CH2:46](N)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:38](=[O:43])[C:39]([NH:41][CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:40])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CCN(C)CC1
Reactant: CCOC(=O)C(N)=O
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a 0° C. solution of 3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenylamine (66 mg, 0.13 mmol) and Et3N (0.34 mL) in CH2Cl2 (6 mL) was added slowly ethyl oxalyl chloride (98 mg). The reaction mixture was stirred at rt for 30 min, then diluted with CH2Cl2 and washed with sat. aqueous NaHCO3. After dried over MgSO4 and concentrated, the crude ethyl oxamate was reacted with phenethylamine (80 mg, 0.64 mmol) at 80° C. for 2 h. Purification by HPLC gave product, N-{3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide (52 mg, 68% yield). 1H NMR (400 MHz) δ 9.38 (br s, 1H), 8.48 (d, J=5.2 Hz, 1H), 7.83 (dd, J=11.7, 2.6 Hz, 1H), 7.59 (t, J=6.2 Hz, 1H), 7.55 (s, 1H), 7.40-7.20 (8H), 6.39 (d, J=5.3 Hz, 1H), 4.06 (d, J=6.6 Hz, 2H), 4.04 (s, 3H), 3.67 (q, J=6.8 Hz, 2H), 2.98 (br d, J=11.5 Hz, 2H), 2.92 (t, J=7.0 Hz, 2H), 2.34 (s, 3H), 2.10-1.80 (m, 5H), 1.60-1.54 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.C(N(C(C)C)C=O)(C)C.[CH3:30][CH:31]([NH2:34])[CH2:32][CH3:33]>O>[Cl:18][C:9]1[N:8]=[C:7]([NH:34][CH:31]([CH3:30])[CH2:32][CH3:33])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(C)N
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Agent: CC(C)N(C=O)C(C)C
Solvent: O
Product: CCC(C)Nc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To 250 mg (1.21 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 1.23 ml (12.10 mmol) of 1-methylpropylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 234 mg (68.9%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:14]([NH2:16])=O>>[OH:13][CH2:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:16][CH:14]=[N:1]2)=[CH:8][CH:9]=1
Reactant: NC=O
Reactant: COC(=O)c1ccc(CO)cc1N
Product: O=c1[nH]cnc2cc(CO)ccc12
Temperature: 180 °C

Procedure:
A mixture of 2.0 g (19.1 mmole) of methyl 2-amino-4-hydroxymethlybenzoate in 4 ml of formamide is heated in an oil bath of 180° C. for three hours. The mixture is cooled and triturated with 70 ml of boiling ethyl acetate. The ethyl acetate is then decanted from the dark oil and cooled in a freezer overnight to precipitate 0.7 g 205-12° C. mp; 40% yield. 1H NMR (d6-DMSO, 300 MHz) δ 8.08 (s, 1H), 8.06 (d, 1H), 7.60 (s, 1H), 7.45 (d, 1H), 5.48 (bs, 1H), 4.65 (s, 2H), 3.35 (bs, 1H). EI MS, [M]+=176.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCN(CC1)CC2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:35]([CH2:36][OH:37])=[CH:34][C:33]2[C:28](=[C:29]([CH3:38])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.[H-].[Na+]>CS(C)=O.O>[N:10]1[C:2]([O:37][CH2:36][C:35]2[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:38])=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: Cc1cccc2cc(CO)c(-c3ccccc3Cl)nc12
Reactant: Clc1ncnc2nc[nH]c12
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2cc(COc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared according to procedure L A mixture of 6-chloropurine (75 mg, 0.49 mmol) and 1,4-diazabicyclo[2.2.2]octane (109 mg, 0.97 mmol) in DMSO (0.5 mL) was stirred at rt for 5 h and was then added via cannula to a mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanol (69 mg, 0.24 mmol) and sodium hydride, 60% dispersion in mineral oil (39 mg, 0.97 mmol) in DMSO (0.5 mL) that had been stirred at rt for 15 min prior to the addition. The mixture was stirred at rt for 3.5 h, cooled to 0° C., and H2O (5 mL) was added carefully. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel (deactivated with 2M NH3 in MeOH), and purified by flash chromatography (Biotage® Si 25+M) eluting with 2M NH3 in MeOH/CH2Cl2 (5%) to provide a white solid [PI3Kδ IC50=25 nM]. MS (ESI+) m/z=402.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])[CH3:10].C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:15][CH2:14][CH2:12][CH:11]([CH3:17])[CH3:9].[Cl:1][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCc1ccccc1N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)C
Product: CCc1ccccc1Nc1ccnc(Cl)n1
Temperature: 100 °C

Procedure:
2,4-Dichloropyrimidine (596 mg, 4 mmol), 2-ethylaniline (494 ml, 4 mmol) and N,N-diisopropylethylamine (695 ml, 4 mmol) were dissolved in n-butanol (20 ml) with stirring. The reaction mixture was heated to 100° C. for 18 hours, allowed to cool to ambient temperature and evaporated onto silica (3 ml). The residue was purified by column chromatography eluting with EtOAc (0–20%): isohexane to give the title product as a colourless solid on evaporation (215 mg, 23%). NMR (CDCl3, 300 MHz): 1.20 (t, 3H), 2.61 (q, 2H), 6.26 (d, 1H), 6.80 (br, 1H) 7.31 (m, 4H), 8.04 (d, 1H); m/z: (ES−) 234.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(NCc2ccc(Cl)cc2)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Cl)cc1)C1CCC(=O)CC1
Reaction time: 8 h

Procedure:
8.4 g (35 mMol) of 4-[N-(4-chloro-benzyl)-amino]-cyclohexanone are dissolved in 50 ml of absolute dimethylformamide and, after the addition of 2.6 g (18.7 mMol) of potassium carbonate, 5.0 g (35 mMol) of methyliodide are added dropwise at 25°-30° C. After standing overnight the mixture is concentrated, mixed with water and extracted with chloroform. The extracts are dried and concentrated.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:45][CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-Boc-3-aminopiperidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.95 (m., 14 H) 2.52 (t, J=7.38 Hz, 2 H) 2.92 (br. d., 1 H) 3.07 (br. d., 1 H) 3.39 (s, 3 H) 3.81 (br. s., 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.64 Hz, 2 H) 4.45 (m, 1 H) 7.34-7.55 (m, 2 H) 7.90 (s, 1 H) 8.03 (d, J=7.58 Hz, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H). [M+H] calculated for C27H35F2N7O3, 544; found 544.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([OH:17])[C:13]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:12]=3[C:11]=2C(CCl)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(O)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=O)=O.O.C1C(=O)N([I:45])C(=O)C1>C1COCC1.CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:15]=[C:14]([O:17][CH2:33][C:32]2[CH:34]=[CH:35][CH:29]=[CH:30][CH:31]=2)[C:13]2[C:12](=[CH:21][C:20]([C:22]#[N:23])=[CH:19][CH:18]=2)[C:11]=1[I:45])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ccc(C#N)cc21
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1I
Temperature: -40 °C
Reaction time: 1 h
Yield: 437.2 %

Procedure:
A solution of 23 (250 mg, 0.67 mmol) in 10 mL of THF-CH3OH (1:1) at -40° C. was treated with a catalytic amount of TsOH-H2O (20 mg) and NIS (180 mg, 0.80 mmol, 1.2 equiv) in 2 mL of THF. The reaction mixture was stirred under Ar at -40° C. for 1 h, and then warmed to 0° C. Additional TsOH-H2O (10 mg) and NIS (75 mg, 0.5 equiv) were added. After the reaction mixture was stirred for 1 h at 25° C., it was quenched with the addition of 5 mL of saturated aqueous NaHCO3 and extracted with Et2O (4×15 mL). The combined organic layer was washed with saturated aqueous Nacl and dried (Na2SO4). PCTLC (2 mm SiO2, 0-10% EtOAc-hexane gradient) afforded 27 (230 mg, 338 mg theoretical, 68%) as a solid: mp 177° C. dec (needles, EtOAc-hexane); 1H NMR (CDCl3, 400 MHz) δ8.38 (d, 1H, J=1.5 Hz), 8.26 (d, 1H, J=8.6 Hz), 8.21 (s, 1H), 7.52 (dd, 2H, J=1.0, 7.8 Hz), 7.47 (dd, 1H, J=1.5, 8.6 Hz), 7.45-7.35 (m, 3H), 7.33 (br s, 1H), 5.26 (s, 2H), 1.59 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ155.4, 152.5, 140.2, 137.0, 135.9, 134.2, 128.7, 128.4, 127.9, 125.1, 125.0, 124.3, 119.0, 112.2, 102.2, 81.8, 78.8, 70.7, 28.3; IR (film) vmax 3383, 2978, 2228, 1732, 1600, 1563, 1495, 1397, 1366, 1331, 1230, 1154, 987, 879, 735 cm-1 ; FABHRMS (NBA-CsI) m/z 632.9674 (M+ +Cs, C23H21IN2O3 requires 632.9651).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.C([O:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21])C.[O:35]1CCO[CH2:37][CH2:36]1>C(Cl)Cl.Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]1[C:4]2[C:13](=[CH:12][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([C:36](=[O:35])[CH3:37])[CH:10]=3)[CH:14]=[CH:15][C:2]=1[C:20](=[O:19])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C1COCCO1
Reactant: Brc1ccc2cc3cc(Br)ccc3cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1ccc2cc3cc(C(C)=O)ccc3cc2c1
Temperature: 100 °C

Procedure:
To a solution of 2,6-dibromoanthracene (1.2 g, 3.57 mmol) in 1,4-dioxane (20 mL) was added 1-ethoxyvinyltri-n-butyltin (3.65 mL, 10.71 mmol) under N2. Then Pd(PPh3)2Cl2 (0.251 g, 0.357 mmol) was added. The reaction mixture was heated at 100° C. for 16 h then cooled to rt and diluted with DCM and 1.5 N HCl. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over Na2SO4 and concentrated. The crude was purified by Combiflash Isco (Silica gel, 12 g, Redisep, 0.5% MeOH in CHCl3) and the resulting product was washed with petroleum ether to yield 1,1′-(anthracene-2,6-diyl)diethanone (600 mg) as a yellow solid. 1H NMR (CDCl3, δ=7.26 ppm, 400 MHz): δ 8.67 (s, 2H), 8.61 (s, 2H), 8.44-8.04 (m, 4H), 2.78 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[C:7]2[C:9]([O:11]CC2C=CC([N+]([O-])=O)=CC=2)=[O:10])[CH2:3]1.C(=O)(O)[O-].[Na+:37]>O1CCOCC1.O.[Pd]>[O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)=[C:7]2[C:9]([O-:11])=[O:10])[CH2:3]1.[Na+:37]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2cccc(C(F)(F)F)c2)SC2CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C1=C(Oc2cccc(C(F)(F)F)c2)SC2CC(=O)N12

Procedure:
A mixture of a solution of 602 mg of 4-nitrobenzyl 7-oxo-3-(3-trifluoromethylphenoxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 108 mg sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[O:16][N:15]=1>>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]2[C:14]([N:10]3[CH2:9][CH2:8][N:7]4[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]4[CH2:11]3)=[N:15][O:16][C:17]=2[CH:22]=1
Reactant: Clc1ccc2c(Cl)noc2c1
Reactant: OCC1CCC2CNCCN2C1
Product: OCC1CCC2CN(c3noc4cc(Cl)ccc34)CCN2C1
Yield: 53.8 %

Procedure:
By the method of Example 7, the alcohol-amine title product of Example 6 (203 mg, 1.19 mmol) and 3,6-dichlorobenzo[d]isoxazole were converted into present title product (206 mg, 53.8% yield) isolated as a pale yellow amorphous solid. In this product the 7- and 9a-hydrogen substituents are trans. TLC Rf (methylene chloride/methanol=9:1 in volume; potassium permanganate spray): 0.41. 13CNMR (CDCl3) delta 164.2, 160.6, 136.1, 123.3, 122.8, 114.9, 110.8, 65.9, 60.2, 58.7, 54.1, 53.4, 48.0, 39.0, 28.8, 26.7.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[S:18]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:20])(=[O:19])[NH2:21]
Reactant: COC(=N)CCCCc1csc(NC(=N)N)n1
Reactant: NS(N)(=O)=O
Solvent: CO
Product: N=C(N)Nc1nc(CCCCC(=N)NS(N)(=O)=O)cs1
Reaction time: 8 h
Yield: 43 %

Procedure:
1.3 g of methyl 5-(2-guanidinothiazol-4-yl)pentanoimidate and 1.1 g of sulfamide were dissolved in 4.3 g of methanol, and the solution was allowed to stand overnight at room temperature. The solvent was distilled away under reduced pressure and the residue was purified by a silica gel column chromatography using a mixture of acetone and methanol as the developing solvent. The obtained crystals were dissolved in 0.4 ml of acetic acid, 4 ml of ehtanol and 8 ml of water, and the solution was treated with activated charcoal. To the filtrate was added 6.6 ml of N--NaOH, and the precipitated crystals were filtered off to provide 0.70 g of N-sulfamoyl-5-(2-guanidinothiazol-4-yl)pentanoamidine having a melting point of 156°-157° C.
Reaction SMILES: CC1(C)CC(C[N:10]=[C:11]=[O:12])(C)CC(N=C=O)C1.[C:17]([O:21]CCO)(=[O:20])[CH:18]=[CH2:19].CC1C=C(C(C)(C)C)[C:29]([OH:36])=[C:28](C(C)(C)C)C=1.CCCCCCCCCCCC(O[Sn](OC(CCCCCCCCCCC)=O)(CCCC)CCCC)=O>>[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].[NH2:10][C:11]([O:36][CH2:29][CH3:28])=[O:12]
Reactant: C=CC(=O)OCCO
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 1 h

Procedure:
260.0 g of the polyester A1 (OHN 41) were melted and added in portions at 120° C. with vigorous stirring to a mixture of 83.3 g of a 1:1 adduct of IPDI and hydroxyethyl acrylate, 0.7 g of IONOL CP and 0.2 g of DBTL. After about one hour of stirring, the NCO content was below 0.1% and the hot reaction mixture was poured from the flask onto a sheet. As soon as the reaction mass had solidified and cooled, it was mechanically size-reduced and ground. The Tg of this product was 45° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]([OH:34])[CH2:32][OH:33])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[C:36]1(C)[CH:41]=CC(S(O)(=O)=O)=C[CH:37]=1.COC(OC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]3[CH2:32][O:33][C:36]([CH3:41])([CH3:37])[O:34]3)([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(=O)OC)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: COC(C)(C)OC
Product: CC[C@@H](C(=O)OC)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)butanoate prepared above in Step A (749 mg, 1.47 mmol) in DCM (8.2 mL) was added p-toluenesulfonic acid monohydrate (14.0 mg, 0.074 mmol) and 2,2-dimethoxypropane (8.15 mL, 66.3 mmol). After being stirred at rt for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CCO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc2ccccc12
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CCO
Product: COc1cc2ncnc(Nc3cccc4ccccc34)c2cc1OC
Reaction time: 0.17 h

Procedure:
To a 25 mL flask with 10 ml of abs. EtOH is added 0.137 g of 4-chloro-6,7-dimethoxyquinazoline and 0.087 g of 1-aminonaphthalene. The solution is heated to reflux whereupon the insoluble materials dissolve. After 5 minutes at reflux a precipatate forms. The solution is allowed to stir an additional 10 min before cooling and isolation of the product as the hydrochloride salt by simple filtration. High-vacuum drying of the solid provided analytically pure (6,7-dimethoxy-quinazolin-4-yl)-alpha-naphthalenylamine (0.142 g, white powder, m.p. 271°-273° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>CN(C)C(=O)C>[CH3:14][C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH:17]=[CH:18][N:19]=1
Reactant: Cc1ncc[nH]1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Product: Cc1nccn1-c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 145 °C
Reaction time: 19 h

Procedure:
A mixture of 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH; 17 g, 89 mmol) and 2-methylimidazole (Fluka, Buchs, Switzerland; 22.2 g, 270 mmol) in N,N-dimethylacetamide (80 mL) is stirred at 145° C. for 19 h. The solvent is evaporated off under reduced pressure and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with brine (200 mL), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether—hexane to afford the title compound as yellow crystalline solid, m.p. 132-134° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.O>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)OC(CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1)c1ccccc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-1-phenyl-propyl ester (2 mmol) prepared in Example 84 was dissolved in tetrahydrofuran (25 mL), and potassium carbonate (K2CO3, 2.4 mmol) and benzylbromide (2.4 mmol) were added thereto, and the resulting mixture was stirred at 70° C. for 10 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O.[H][H]>[Cr].[Co].O1CCOCC1>[CH3:10][CH:9]1[CH:5]2[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH:6]2[O:8][CH:12]=[CH:11]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: [H][H]
Agent: [Co]
Agent: [Cr]
Agent: [C]=O
Solvent: C1COCCO1
Product: CC1CCC2C(C)C=COC2C1
Reaction time: 5 h
Yield: 49219.9 %

Procedure:
A 100 ml Hastelloy C autoclave was charged with 15 g of isopulegol, 0.09 g of chlorotristriphenylphosphinerhodium, 0.05 g of triphenylphosphine and 30 ml of dioxane. The autoclave was then charged with equal volumes of carbon monoxide and hydrogen which pressurized the autoclave to 100 kg/cm2. The reaction was carried out at a temperature of 140° C. and at a pressure of 90 to 120 kg/cm2 for a period of 5 hours. After cooling, the pressure was reduced to atmospheric, and the reaction mixture was recovered from the autoclave and distilled for purification which yielded 15.6 g of 4a,5,6,7,8,8a-hexahydro-4,7-dimethyl-4H-1-benzopyran having a boiling point of from 64° to 66° C. at 0.5 mmHg. The IR and NMR spectra of the product had the following absorption characteristics: