Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br>CN(C=O)C.O>[O:15]1[CH2:14][CH:13]1[CH2:11][O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1=CC=CCC1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=CCCC(COCC2CO2)=C1
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
(Compound No. 229) 1,3-Cyclohexadiene-1-methanol (2 g, 0.0182 mol) synthesized in Example 21 was dissolved in DMF (10 ml) and 60% sodium hydride (775 mg, 0.0194 mol) was added at 0° C. The mixture was stirred for 10 minutes and a solution of epibromohydrin (3 g, 0.022 mol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour and at 40° C. for 1 hour and the reaction mixture was poured in water, extracted with ethyl acetate and the combined ethyl acetate layer was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography (silica gel 60 g, ethyl acetate:hexane=1:10) to obtain 1-(2,3-epoxypropoxymethyl)-cyclohexa-1,3-diene (2.31 g, 76%). This compound has the following NMR spectrum.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][CH:49]([S:51](Cl)(=[O:53])=[O:52])[CH3:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([S:51]([CH:49]([CH3:50])[CH3:48])(=[O:53])=[O:52])[CH2:42][CH2:41]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and propane-2-sulfonyl chloride as starting materials in 27% yield. LCMS for C28H34ClN6O3S (M+H)+: m/z=569.2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4c(C(F)(F)F)cccc34)c2c1
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of 2,5-dimethylindole (765 mg) and 4-chloro-8-trifluoromethylquinoline (1.22 g) in NMP (1.5 ml) and 4M HCl in dioxane (0.2 ml) was heated at 140° C. for 1 h. After cooling the mixture was triturated with ether and filtered to give the sub-title compound (1.33 g) as a dark red solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Cl:28])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Cl:28])=[C:11]2[C:7]=1[C:8]([Cl:29])=[N:9][NH:10]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]nc(Cl)c2c1COC(C)=O)C(=O)OCC
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)methyl)succinate (1.12 g, 2.73 mmol) was dissolved in N,N-dimethylformamide (30 ml). Mixture was warmed to 70° C. N-Chlorosuccinimide (400 mg, 3.00 mmol) was added to the solution. Mixture was warmed to 150° C. and held with stirring for 30 minutes. Mixture was cooled to room temperature and then diluted with ethyl acetate. Material was washed twice with 1N sodium thiosulfate and the aqueous phase was discarded. Material was washed successively with water and brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as dark amber oil in quantitative yield. MS (M−H)−=443.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])[CH:3]=3)=[CH:40][CH:39]=2)[CH2:33][CH2:34]1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1)NOC1CCCCO1
Reactant: CN1CCN(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCN(CCOc2ccc(-c3cccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)c3)cc2)CC1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
(E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (7.9 g) and 1-methyl-4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-piperazine (9.0 g) are dissolved in DME (300 mL). Under an inert gas atmosphere there are added (Ph3P)3PdCl2 (2.4 g) and 2M Na2CO3-solution (50 mL) and the mixture is heated to 100° C. for 2 h. The mixture is filtered, evaporated and the residue is treated with ethyl acetate and 5% solution of NaHCO3. The organic phase is dried and evaporated and the crude product is purified by silica gel flash chromatography. 5.7 g of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2].C(O)(=O)C.[ClH:21].OO>O>[Cl:21][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)Nc1c(C)cccc1C(=O)O
Reactant: Cl
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c(C)cc(Cl)cc1C(=O)O
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
A 2-L reactor equipped with overhead stirrer and thermocouple was charged with 150 g (0.672 mol) of 2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid (ca. 98% purity) and acetic acid (500 g). The resulting slurry was heated to 35-40° C. to give a solution, which was cooled to 30° C., and then hydrochloric acid (37%, 150 g, 1.5 mol, 2.2 eq) was added. The mixture was maintained at 30° C. while aqueous hydrogen peroxide (30%, 96 g, 0.85 mol, 1.25 eq) was added over about 1 h. The mixture was then warmed to 35° C. and held at that temperature for about 1 h. About 600 mL of water was metered in over about 30 minutes, while maintaining the temperature at 30-35° C. The mixture was cooled to 10° C., and the product was collected by filtration, and the wet cake was washed with water (3×100 mL); the third wash tested negative with KI-starch paper. The wet cake was dried to constant weight in a vacuum oven at 50° C. The crude yield was about 150 g (about 84% based on an estimated purity of 2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid of 98% and estimated product purity of 95%). A portion of the crude product was first recrystallized from toluene and then recrystallized from aqueous methanol to give an analytical sample melting at 124-126° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH2:17])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:24]([CH3:23])(=[O:26])=[O:25])=[C:11]([C:18]([F:20])([F:21])[F:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1NS(C)(=O)=O
Reaction time: 5 h

Procedure:
(4-Amino-3-trifluoromethyl-5-vinylbenzyl)carbamic acid tert-butyl ester (235.6 mg, 0.75 mmol), Methanesulfonyl chloride (5 eq, 3.73 mmol, 288.40 μl), and triethylamine (3 eq, 2.25 mmol, 313.60 μl) were added to methylene chloride. The reaction mixture was stirred for 5 hr. The reaction mixture was purified according to step 5 of Example 8 to give a title product, yellow syrup (89.3 mg, 30.21%).
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[F:20])=[C:6](/[C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)\CC)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[Cl:19][C:14]1[CH:13]=[C:12]([C@@H:10]2[CH2:11][C@H:9]2/[CH:6]=[C:5](\[F:20])/[CH2:4][OH:3])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)/C(F)=C(\CC)[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OC/C(F)=C/[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 104.6 %

Procedure:
The above ester (4 g) was dissolved in dichloromethane (30 ml) and cooled to -20° under nitrogen. Diisobutylaluminium hydride (26 ml) was added dropwise. After 18 hours at 25° dilate hydrochloric acid was carefully added and the mixture worked up in the usual manner to give (±)-(2Z)-3-[trans-2-(3,4-dichlorophenyl)cyclopropyl]-2-fluoroprop-2-en-1-ol (3.3 g). NMR 1H: 7.32(1H,d), 7.17(1H,d), 6.90(1H,dd), 4.10(2H,dd), 3.60(1H,t), 1.90(2H,m), 1.20(2H,m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@@H:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 88 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl (3R)-3-amino-1-piperidinecarboxylate as in Example 28 gave tert-butyl (3R)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate in 88% yield: 1H NMR (DMSO-d6) (rotamers) δ8.11 and 8.00 (2d, J=8.1, 8.2 Hz, 1H), 7.89 and 7.71 (2t, JHF=53.1 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.95 and 6.94 (2d, J=8.0, 7.8 Hz, 1H), 3.97 (s, 3H), 3.79-3.69 (m, 10H), 3.02-2.80 (m, 2H), 1.97-1.93 (m, 1H), 1.76 (m, 1H), 1.59-1.20 (m, 2H), 1.35 (s, 9H). Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.9; H, 6.1; N, 20.1%.
Reaction SMILES: C(OC(N[C@@H](C(C)C)C(O)=O)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[NH2:32][C@H:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C@H:34]1[OH:42].C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:76][C:77]([C:79]1([NH:84][C:85]([CH:87]2[CH2:91][CH:90]([O:92][C:93]3[C:102]4[C:97](=[CH:98][C:99]([O:103][CH3:104])=[CH:100][CH:101]=4)[N:96]=[C:95]([C:105]4[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=4)[CH:94]=3)[CH2:89][N:88]2[C:111](=[O:131])[NH:112][CH:113]([C:118](=[O:130])NC2C3C(=CC=CC=3)CC2O)[C:114](C)([CH3:116])[CH3:115])=[O:86])[CH2:81][CH:80]1[CH:82]=[CH2:83])=[O:78])C>>[OH:42][C@@H:34]1[CH2:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:33]1[NH:32][C:118]([C@@H:113]([NH:112][C:111]([N:88]1[CH2:89][C@H:90]([O:92][C:93]2[C:102]3[C:97](=[CH:98][C:99]([O:103][CH3:104])=[CH:100][CH:101]=3)[N:96]=[C:95]([C:105]3[CH:106]=[CH:107][CH:108]=[CH:109][CH:110]=3)[CH:94]=2)[CH2:91][C@H:87]1[C:85]([NH:84][C@:79]1([C:77]([OH:78])=[O:76])[CH2:81][C@H:80]1[CH:82]=[CH2:83])=[O:86])=[O:131])[CH:114]([CH3:116])[CH3:115])=[O:130]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)C)C(=O)O
Yield: 22 %

Procedure:
(2S)-tert-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 followed by reaction with (1S,2R)-1-amino-2-indanol as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (10 mg, 22% yield), Purity by HPLC >90% M+H+748.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:22])=[CH:4][C:5]2[C:6]3[N:7]([C:12](=[O:21])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=3)[CH:8]=[N:9][C:10]=2[CH:11]=1.CS(C)=O.[O-:27][CH2:28][CH3:29].[Na+].C(O)C.[Cl-].[NH4+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH3:22][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]([O:27][CH2:28][CH3:29])=[O:21]
Reactant: CCOC(=O)c1cnc2c3cc(C)c(C)cc3ncn2c1=O
Reactant: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2cc(C)c(C)cc12)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of ethyl 9,10-dimethyl-4-oxo-4H-primido[1,2-c]quinazoline-3-carboxylate (4.46 g) and anhydrous dimethylsulfoxide (17 ml) was stirred at ambient temperature. To the mixture was dropwise 1N sodium-ethoxide-ethanol solution (20 ml) and the reaction mixture was stirred for 3 hours at ambient temperature. To the resultant mixture was added ammonium chloride (2.45 g) and the mixture was stirred for 5 minutes. To the mixture was added water and extracted twice with chloroform. After washing three times with water and with aqueous solution saturated with sodium chloride, the combined chloroform layer was treated with activated charcoal, dried over magnesium sulfate and concentrated under reduced pressure to give a residue, which was dissolved in a mixture of chloroform and ethyl acetate. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure and recrystallized twice from ethyl acetate and from a mixture of chloroform and hexane to give diethyl [(6,7-dimethyl-4-quinazolinylamino)methylene]propanedioate (2.01 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]([NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)=[O:11]>CN(C)C=O>[N:3]1([CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(NC(=O)CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)Cn2ccnc2)cc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a suspension of 2.4 g of 50% sodium hydride in 100 ml of dry dimethylformamide was added slowly 3.4 g of imidazole at room temperature, and the mixture was heated to 80° C. A solution of 12.1 g of ethyl p-chloroacetylaminobenzoate in 45 ml of dry dimethylformamide was added to the mixture over a period of 30 minutes at 80° C., and then the reaction mixture was heated at 100° C. for 1.5 hours. After removal of the solvent under reduced pressure, the residue was dissolved in chloroform and washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residual solid was recrystallized from ethanol-n-hexane to give 10.5 g of ethyl p-(1-imidazolyl)acetylaminobenzoate as colorless needles. M.P.: 185°-187° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].P(Br)(Br)[Br:13]>C1COCC1>[CH2:10]([Br:13])/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])\[CH3:8]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 189.9 %

Procedure:
10.02 g (64.96 mmol) geraniol was dissolved in 120 ml of dry THF. At 0° C., 3.1 ml (8.93 g, 32.98 mmol) PBr3 were added drop wise via septum and syringe and the clear, colorless solution was stirred at 0° C. for 3 h. The reaction was quenched by addition of ice cold water. The layers were separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to give geranyl bromide as a colourless oil (13.59 g, 62.63 mmol, 96%). The crude product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=3)(=[O:27])=[O:28])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2N
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 63.6 %

Procedure:
Starting with (4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester and 3-nitro-benzenesulfonyl chloride using the method analogous to the one described above for example 1-1, [4-(3-nitro-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (519 mg, 63.6%) was obtained as a white solid. MS cald. for C17H20N4O6S 408, obsd. (ESI+) [(M+H)+] 409.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([S:22][CH:23]3[CH2:28][CH2:27][C:26](=[CH:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]3)[N:14]=[C:13]2[CH2:35][CH2:36][CH3:37])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.O1CCCC1>C(O)C>[C:30]([CH:29]=[C:26]1[CH2:25][CH2:24][CH:23]([S:22][C:15]2[N:14]=[C:13]([CH2:35][CH2:36][CH3:37])[N:12]([CH2:11][C:3]3[C:2]([Cl:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)[C:16]=2[C:17]([OH:19])=[O:18])[CH2:28][CH2:27]1)([OH:32])=[O:31]
Reactant: CCCc1nc(SC2CCC(=CC(=O)OCC)CC2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1nc(SC2CCC(=CC(=O)O)CC2)c(C(=O)O)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 24 h
Yield: 62 %

Procedure:
880 mg of the product of Example 9 is introduced into 20 ml of tetrahydrofuran, 50 ml of ethanol and 25 ml of 2N soda are added and the reaction medium is left for 24 hours at ambient temperature. The tetrahydrofuran and the ethanol are evaporated off, then the reaction medium is acidified to pH 1. Extraction is carried out with ethyl acetate, followed by evaporation to dryness and the residue is recrystallized from ethyl acetate. In this way 490 mg of expected product is obtained. M.p.=168° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][NH2:30]>>[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][NH:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC(O)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,3-diaminopropan-2-ol. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=2.0 Hz, 1 H), 7.86 (d, J=1.8 Hz, 1 H), 7.62 (t, J=3.7 Hz, 1 H), 7.57 (s, 1 H), 7.44 (t, J=3.8 Hz, 2 H), 7.30-7.27 (m, J=2.5 Hz, 1 H), 6.09 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.97-3.91 (m, J=5.8 Hz, 2 H), 3.58 (t, J=2.4 Hz, 2 H), 3.66-3.41 (m, J=3.3 Hz, 2 H), 2.90 (dd, J=4.2, 0.90 Hz, 1 H), 2.77 (dd, J=5.2, 0.9 Hz, 1 H), 2.42 (s, 3 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[N:15]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:16]=[N:17][C:18]=2[CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:7]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=O)=[CH:32][CH:31]=1>>[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[N:15]([C:22]3[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=3[Cl:28])[N:16]=[N:17][C:18]=2[CH:19]([CH3:20])[CH3:21])[CH:9]=[CH:8][C:7]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([Cl:3])=[O:38])=[CH:32][CH:31]=1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C(=O)O)cc2)c(Br)c1
Reactant: O=S(Cl)Cl
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C(=O)Cl)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To thionyl chloride (1.5 mL, 20 mmol) is added 2′-bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylic acid (0.074 g, 0.13 mmol). The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure to give 2′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[NH2-].[Na+].Br[CH:12]([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH3:13][CH:12]([CH3:14])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]#[N:8]
Reactant: CC(C)Br
Reactant: N#CCc1cccs1
Agent: [Cl-]
Agent: [NH2-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(C#N)c1cccs1
Reaction time: 0.08 h

Procedure:
2-Thienyl acetonitrile, 15 g 0.12 mol, was dissolved in tetrahydrofuran 125 ml and added dropwise to a suspension of sodium amide 4.75 g 0.12 mol in tetrahydrofuran 250 ml under ice-cooling. After stirring for 5 minutes, a solution of 2-bromopropane 11.4 ml 0.12 mol in tetrahydrofuran 125 ml was added dropwise thereto. Aqueous saturated ammonium chloride was added to the reaction mixture which was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 5.56 g 33.6 mmol, 28.0% was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>Cl>[CH3:13][C:12]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Product: CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 161.0 g of α,α,α-trifluoro-m-toluidine in 500 ml of 2N hydrochloric acid, at room temperature, with vigorous agitation, is added rapidly 102.0 g of acetic anhydride. An exothermic reaction occurs and the temperature is allowed to rise spontaneously to about 50°. Subsequently, the mixture is allowed to cool to room temperature, and then cooled in ice. The crystalline solid is filtered to give 189.3 g of α,α,α-trifluoro-m-acetotoluidide.