Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH2:12])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.N1C=CC=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][NH:41][C:42](=O)[OH:43])=[O:37])([CH3:34])([CH3:33])[CH3:32].Cl>O1CCCC1>[C:31]([O:35][C:36](=[O:37])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:12][C:10]1[S:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:11]=1)=[O:43])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ncnc2sc(N)nc12
Reactant: CC(C)(C)OC(=O)NCCNC(=O)O
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ncnc2sc(NC(=O)NCCNC(=O)OC(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
A solution of 7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylamine (233 mg, 1.28 mmol) and pyridine (310 μL, 3.53 mmol) in tetrahydrofuran (6 mL) at 25° C. was treated with a solution of triphosgene (190 mg, 0.64 mmol) in tetrahydrofuran (2 mL) followed by (2-tert-butoxycarbonylamino-ethyl)-carbamic acid (225 mg, 1.40 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was treated with a 1N aqueous hydrochloric acid solution and was stirred at 25° C. for an additional 30 min. At this time, the resulting precipitate was collected by filtration and was washed with a 1N aqueous hydrochloric acid solution and diethyl ether to afford {2-[3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-ureido]-ethyl}-carbamic acid tert-butyl ester (170 mg, 36.8%) as a pink solid; LRMS for C14H20N6O4S (M+H)+ at m/z=369.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:5]2[C:6]3[C:7]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:8]=4[N:9]=[C:10]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:11]=3[C:12](=[O:17])[C:13]=2[CH:14]=[CH:15][N:16]=1>ClCCl>[CH3:23][N:21]([CH3:22])[CH2:20][CH2:19][NH:18][C:10]1[C:11]2[C:12](=[O:17])[C:13]3[CH:14]=[CH:15][N:16]=[C:4]([NH:2][CH3:1])[C:5]=3[C:6]=2[C:7]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:8]=2[N:9]=1
Reactant: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccnc(Cl)c1-3
Reactant: CN
Solvent: ClCCl
Product: CNc1nccc2c1-c1c(c(NCCN(C)C)nc3cc(OC)ccc13)C2=O
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of methylamine (1 ml, 40% in methanol) in dichloromethane (1 ml) was added 11-chloro-6-(2-dimethylamino-ethylamino)-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one (Example 27e) (5.7 mg) and the mixture was stirred at 50° C. for 2 days in a sealed tube. The solution was diluted with dichloromethane and washed with saturated ammonium chloride aqueous solution and dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel thin layer chromatography developed by dichloromethane-methanol=4:1. The desired product was obtained as a dark red powder (1.8 mg). ESI−MS: m/z 378 (MH+); 1H-NMR (CDCl3): δ2.44 (6H, s), 2.77 (2H, t, J=6.3 Hz), 3.14 (3H, d, J=4.9 Hz), 3.82 (2H, q-like, J=6.3 Hz), 3.96 (3H, s), 4.85 (1H, brq, J=ca 5 Hz), 6.89-6.95 (2H, m), 7.04 (1H, d, J=2.6 Hz), 7.30 (1H, brt, J=ca 6 Hz), 8.34 (1H, d, J=9.2 Hz), 8.41 (1H, d, J=4.3 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[CH2:2][CH2:3][CH3:4].[CH:12]([CH:14]=[O:15])=[O:13].S(=O)(=O)(O)O>C(O)(C)C>[CH:2]([O:13][CH:12]1[CH:14]([O:15][CH:10]([CH3:11])[CH3:9])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:7])[N:8]1[CH2:9][CH2:10][CH3:11])([CH3:3])[CH3:1]
Reactant: CCCCNC(=O)NCCC
Reactant: O=CC=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCN1C(=O)N(CCC)C(OC(C)C)C1OC(C)C
Yield: 33 %

Procedure:
Example 11 was repeated with 4.21 g of 1-butyl-3-propylurea, 4 ml of 40% aqueous glyoxal, 80 ml of isopropyl alcohol and 1 ml of conc. sulfuric acid. After work up and silica gel chromatography gave 2.6 g (33%) of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[CH2:25][CH2:26][CH:27]([C:29]1[S:33][C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)=[N:31][C:30]=1[CH3:44])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:27]([C:29]2[S:33][C:32]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][CH:35]=3)=[N:31][C:30]=2[CH3:44])[CH2:26][CH2:25][CH:20]2[O:19][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCC1OCCCO1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(CCC2OCCCO2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 3-(4-{3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C([N:16]2[CH2:20][CH2:19][CH:18]3[CH2:21][N:22]([C:24]4[C:25]5[S:33][C:32]6[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=6[C:26]=5[N:27]=[C:28]([NH2:30])[N:29]=4)[CH2:23][CH:17]23)C)C=CC=CC=1>[OH-].[OH-].[Pd+2].CCO>[NH:16]1[CH2:20][CH2:19][C@@H:18]2[CH2:21][N:22]([C:24]3[C:25]4[S:33][C:32]5[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=5[C:26]=4[N:27]=[C:28]([NH2:30])[N:29]=3)[CH2:23][C@H:17]12
Reactant: CC(c1ccccc1)N1CCC2CN(c3nc(N)nc4c5c(sc34)CCCC5)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Nc1nc(N2C[C@H]3CCN[C@H]3C2)c2sc3c(c2n1)CCCC3
Reaction time: 36 h
Yield: 95.1 %

Procedure:
A 90 mL parr shaker was charged with 4-[1-(1-phenyl-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl]-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine trifluoroacetate (synthesized by route described in Example 2, Steps A-E; 0.20 g, 0.4 mmol), Pd(OH)2/C (30% by weight, 0.06 g) and EtOH (3.7 mL). The mixture was submitted to 60 psi H2 with shaking for 36 h. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated to afford the desired compound (0.12 g). MS: 316.1. 1H NMR (400 MHz, CD3OD) δ ppm 4.47-4.29 (m, 2H), 4.25-4.07 (m, 2H), 3.91-3.80 (m, 1H), 3.54-3.38 (m, 3H), 2.97-2.84 (m, 2H), 2.69-2.61 (m, 2H), 2.41-2.29 (m, 1H), 2.14-2.02 (m, 1H), 2.02-1.86 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[C:29](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:32])[CH2:30][CH3:31].C(O)(=O)CC>>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]([O:18][CH3:19])[C:29](=[O:32])[CH2:30][CH3:31])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CCC(=O)On1nnc2ccccc2c1=O
Solvent: CCC(=O)O
Product: CCC(=O)N(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)OC
Yield: 31 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl propionate prepared from propionic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-amino)-methyl]-benzamide (35.0 mg, 31%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>CC#N>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:39][CH2:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[N:5]=2)[CH:26]=1
Reactant: NCc1cccnc1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CC#N
Product: O=C(Nc1cn(CCNCc2cccnc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (150 mg, 0.29 mmol) and pyridin-3-ylmethanamine (158 mg, 1.46 mmol) in MeCN (3 mL) was stirred at 70° C. for 12 h. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-2): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=30:42 within 12 min; Detector, UV 254 nm. This resulted in 57.7 mg (37%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-3-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 25) [M+H]+=539.1, RT=0.87 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.50 (d, 1H, J=1.8 Hz), 8.41 (dd, 1H, J=1.5, 4.8 Hz), 8.38 (s, 1H), 7.73-7.70 (m, 1H), 7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.33-7.28 (m, 2H), 6.99 (t, 1H, J=73.2 Hz), 4.24 (t, 2H, J=6.0 Hz), 3.75-3.72 (m, 2H), 3.01-2.94 (m, 2H), 2.27 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([CH3:12])[N:6]2[CH3:11].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:12][C:5]1[N:6]([CH3:11])[C:7]2[C:3]([C:4]=1[C:13]([O:15][CH3:16])=[O:14])=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)n(C)c2cccc(Cl)c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)n(C)c2cccc(Cl)c12
Temperature: 85 °C
Yield: 48 %

Procedure:
Methyl 4-chloro-1,2-dimethyl-1H-indole-3-carboxylate (9.70 mmol, 1.0 equiv.) was dissolved in CCl4 (97 ml), and NBS (9.70 mmol, 1.0 equiv.) and benzoyl peroxide (0.19 mmol, 0.02 equiv.) were added. The mixture was heated for 1 h at 85° C. The resulting succinimide was filtered out, the filtrate was concentrated, and the residue was purified by column chromatography (20% ethyl acetate in hexane). Yield: 48%
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.Br>C(O)(=O)C>[ClH:1].[OH:3][C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc2c1ncn2-c1ccccc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cccc2c1ncn2-c1ccccc1
Yield: 77 %

Procedure:
Demethylation of 4-methoxy-1-phenylbenzimidazole hydrochloride with HBr in glacial acetic acid as described for synthesis of Example 2 gave Example 11 as the HCl salt, (77%): mp (MeOH/Et2O) 238-240° C.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].N1C=CN=C1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=2[CH:19]=[CH:18]1>>[CH:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][NH:17]2)([CH3:3])[CH3:2]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Product: CC(C)[Si](Oc1cccc2[nH]ccc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Tri-isopropylsilyl chloride (TIPS-Cl, 15.86 mL) and imidazole (5.62 g) were added to 1H-indol-4-ol (10 g) in DMC (200 mL), and stirred at RT overnight. The resulting solid was filtered and washed with DCM. The filtrate was concentrated and purified on a column with 100% hexane to 25% EtOAc/hexane, and the fractions collected, concentrated, triturated with cold hexane, and the resulting solid was filtered and dried at 50° C. to yield 4-(triisopropylsilyl-oxy)-1H-indole (17 g, ˜80%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].OC(C(F)(F)F)=O.[O:14]=[C:15]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19].[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42]Br>CN(C=O)C>[F:38][C:39]([F:48])([F:49])[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][N:35]1[CH2:36][CH2:37][N:32]([C:15](=[O:14])[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[O:19])[CH2:33][CH2:34]1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(Cc2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Yield: 55.4 %

Procedure:
K2CO3 (50.5 mg, 0.37 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (80 mg, 0.18 mmol) in DMF (3 mL). 2-Trifluoromethyl benzyl bromide (52.2 mg, 0.22 mmol) was then added, and the resulting mixture was heated to 90° C. overnight. The product was extracted with ethyl acetate and the ethyl acetate layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 48 mg (45.7% yield) of biphenyl-4-carboxylicacid {2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 94.3%, 1H NMR: (CDCl3) δ 7.9 (d, 2H), 7.8-7.7 (d, 1H), 7.7-7.6 (m, 5H), 7.55 (m, 1H), 7.5 (m, 2H), 7.4 (m, 3H), 4.3 (d, 2H), 3.7 (s, 4H), 3.5 (t, 2H), 2.5 (q, 4H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][O:5][CH2:4][O:3][CH2:2]1>[Pd].C(O)C.C(OCC)(=O)C>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:2][O:3][CH2:4][O:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2COCOC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2COCOC2)cc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of 1-(3,5-dioxapiperidin-1-yl)sulphonyl-4-nitrobenzene (Method 8) (500 mg, 1.82 mmol) and 10% palladium on charcoal catalyst (150 mg) in ethanol (25 ml) and ethyl acetate (25 ml) was stirred under an atmosphere of hydrogen for 3 hours. The catalyst was removed by filtration through diatomaceous earth and the filter pad was washed with ethanol and ethyl acetate. The volatiles were removed from the filtrate by evaporation and the residue triturated with ether and hexane to give the tide compound (395 mg, 88%). NMR: 4.90 (s, 2H) 5.10 (s, 4H), 6.02 (s, 2H), 6.58 (d, 2H), 7.50 (d, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20]([CH2:22]P(OC)(OC)=O)=[O:21]>O>[CH3:18][O:19][C:20](=[O:21])/[CH:22]=[CH:1]/[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)/C=C/c1ccc(C(=O)O)cc1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
4-Formylbenzoic acid (20 g, 0.133 mol) and K2CO3 (55 g, 0.398 mol) were added to water (350 mL) and cooled to 0-5° C. Trimethyl phosphonoacetate (26 mL, 0.160 mol) was charged dropwise maintaining the reaction temperature below 15° C. The reaction was then warmed and stirred at RT for 1.5 h before acidifying to pH˜1. The resulting precipitate was filtered and dried in vacuo to afford the title product as a pale yellow solid (29.5 g, quant). 1H NMR (300 MHz, d6-DMSO) δ: 7.89-7.52 (5H, m), 6.59 (1H, d, J=16.2 Hz), 3.7 (3H, s).
Reaction SMILES: C([O:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[O:7][CH:6]=1)(=O)C>Cl.CO.O>[CH3:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5](=[O:4])[CH2:6][O:7][C:8]=2[CH:13]=1
Reactant: CC(=O)Oc1coc2cc(C)ccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A solution of 6-methyl-1-benzofuran-3-yl acetate (3.8 g, 19.98 mmol) in HCl (4 mL, conc), methanol (160 mL), and water (40 mL) was heated under reflux for 1.5 h, the reaction mixture was cooled to room temperature, dissolved in water (200 mL) and filtered to give 6-methyl-2,3-dihydro-1-benzofuran-3-one as a white solid (2.5 g, 82%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CC1C=CC(S(O[CH2:18][C@@H:19]2[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>>[CH3:24][C:21]1([CH3:25])[O:20][C@H:19]([CH2:18][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:23][O:22]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2cc(I)cn2)O1
Temperature: 100 °C

Procedure:
A mixture of 4-iodopyrazole (1.00 g, 5.16 mmol), ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.624 g, 5.671 mmol), Cs2CO3 (2.52 g, 7.73 mmol) and DMF (5 mL, 60 mmol) was heated to 100° C. for 2 h. The solution was extracted with EtOAc, and washed with water (2×). The organic layer was concentrated in vacuo and purified via column chromatography, eluting with 2-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.34 (d, J=8.8 Hz, 6H), 3.76 (dd, J=8.6, 6.1 Hz, 1H), 4.08 (dd, J=8.6, 6.3 Hz, 1H), 4.23-4.37 (m, 2H), 4.39-4.46 (m, 1H), 7.50-7.55 (m, 1H), 7.77 (s, 1H). MS (ES+): m/z=309.01 (100) [MH+]. HPLC: tR=1.34 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20](NC1SC=CN=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.Cl>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 1, Part E (300 mg, 1.02 mmol) was taken up in 4 mL CH2Cl2 and cooled to 0° C. Oxalyl chloride (0.1 mL, 1.22 mmol) was added slowly and stirring continued for 0.5 h. A slurry of 6-aminonicotinic acid (211 mg, 1.53 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) was added slowly and stirring continued at room temperature for 16 h. Three drops of conc. HCl was added and the organic phase was washed with brine. The organic phase was dried (Na2SO4), filtered and evaporated. The product was purified by silica gel chromatography (12 mg, 3%). 1H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.70 (m, 1H), 8.32 (m, 1H), 7.87 (m, 1H), 7.52 (m, 3H), 7.34 (m, 6H), 5.46 (m, 1H), 4.60 (br s, 1H), 4.31 (m, 1H), 2.54 (m, 2H), 2.09 (m, 2H). MS: m/z (MH+) 416.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].CO>CN(C=O)C>[C:3]1([C:9]2[N:10]=[CH:11][N:12]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:35])[C:13]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.7 g (70.8 mmol) sodium hydride are placed in 130 ml DMF and 1.0 g (54.5 mmol) 4,5-diphenylimidazole are added under cooling. The suspension is stirred for four hours at RT and, subsequently, 15.4 g (54.5 mmol) N-(4-bromobutyl)-phthalimide dissolved in DMF is added dropwise under cooling. After complete addition, the reaction mixture is stirred for 12 hours at RT, 18 ml methanol are carefully added dropwise and the suspension is filtered. The filtrate is concentrated under vacuum and the residue is distributed between 500 ml chloroform and 170 ml water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dry dried. The residue is purified by chromatography on silica gel with CHCl3/CH3OH (95/5) and subsequently crystallized from methanol: Yield 16.5 g (72%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[C:20]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn(COCCO)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: O
Product: O=c1ccn(COCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Yield: 20 %

Procedure:
1-(2-hydroxy-ethoxymethyl)uracil (0.50 g, 2.69 mmol) and triphenylmethyl chloride (0.82 g, 2.96 mmol) were stirred in dry pyridine (20 ml) overnight at 50° C. under an atmosphere of nitrogen. H2O (10 ml) was added and the mixture was extracted with CHCl3 (2×50 ml), dried (Na2SO4) and reduced in vacuo to obtain a crude product, which was purified by column chromatography eluting with 0→3% MeOH/CHCl3 to obtain the title compound as a white solid (0.23 g, 20%).
Reaction SMILES: [C:1]([C:3]([C:20]#[N:21])=[CH:4][NH:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[Cl:19])#[N:2].C>C(OCCO)C>[NH2:2][C:1]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: N#CC(C#N)=CNNc1c(Cl)cc(SC(F)(F)F)cc1Cl
Solvent: CCOCCO
Product: N#Cc1cnn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Yield: 69.4 %

Procedure:
14.1 g (0.04 mole) of 1-(2,2-dicyanethen-1-yl)-2-(2,6-dichloro-4-trifluoromethylthio-phenyl)-hydrazine in 30 ml of ethylene glycol monoethyl ether are heated under reflux for 2 hours. Active charcoal is added to the hot solution, the mixture is filtered and the filtrate is diluted with 60 ml of water. The precipitate which has separated out is filtered off with suction and dried. 9.8 g (70% of theory) of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-phenyl)-pyrazole of melting point 185° C. to 187° C. are obtained. ##STR121##
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20](=O)[CH3:21]>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH:20]([NH:4][CH2:3][CH:2]([OH:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:21]
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cc1ccc(C)cc1C
Product: Cc1ccc(CC(C)NCC(O)c2ccccc2)c(C)c1

Procedure:
The title compound was reprepared as a 49:51 mixture of diastereoisomers m.p. 58-63 in the manner described in Example 3 using 2-hydroxy-2-phenylethanamine and (2,4-dimethylphenyl)propanone. 'Hnmr identical with that of Example 32.