Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOC(C)=O.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>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)=[CH:35][CH:34]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (I4) (0.069 g, 0.394 mmol) in dimethylformamide (2 mL) and triethylamine (0.183 mL, 1.31 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (0.150 g, 0.328 mmol), Pd(PPh3)2Cl2 (0.023 g, 0.033 mmol), Cu(I)I (0.0090 g, 0.049 mmol) and triphenylphosphine (0.013 g, 0.049 mmol) in dimethylformamide (2 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 15 minutes. The reaction was cooled and the mixture diluted with EtOAc and passed through a plug of celite and washed through with ethyl acetate (50 mL). Water (50 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-20% EtOAc in cyclohexane) to yield the title compound (I46) (0.157 g, 80%) as a brown viscous oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[C:12]([F:30])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:2][CH2:3][CH:4]4[O:8][CH2:7][CH2:6][O:5]4)=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[C:12]([F:30])[CH:11]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCC1OCCO1
Temperature: 100 °C
Yield: 16.6 %

Procedure:
A solution of 2-(2-bromoethyl)-1,3-dioxolane (258 mg, 1.4 mmol) in DMF (0.5 ml) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (329 mg, 1.02 mmol) and potassium carbonate (264 mg, 2 mmol) in DMF t2 ml). The mixture was heated at 100° C. for 3 hours and allowed to cool. The volatiles were removed by evaporation, and the residue partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic phase was separated and passed through phase separating paper. The solvent was removed by evaporation, and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluoroanilino)-7-(2-(1,3-dioxolan-2-yl)ethoxy)6-methoxyquinazoline (71 mg, 17%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:15]1[C:16]2[N:17]([N:21]=[C:22]([Cl:24])[N:23]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:24][C:22]1[N:23]=[C:16]2[C:15]([NH:1][C:2]3[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:19]=[CH:18][N:17]2[N:21]=1
Reactant: CN(c1ncccc1N)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][C:37](O)=[O:38]>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCC(=O)O
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Product: CN(C)CCC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 18.3 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.183 mmol) was coupled to N,N-dimethyl-beta-alanine hydrochloride (29 mg, 0.189 mmol) following the procedure described in step 1 of Example 120. The product was purified via HPLC using a Sunfire Prep C18 OBD 5 micron, 30×75 mm column. The compound was eluted using a gradient 10-70% acetonitrile/water with 0.1% TFA over 20 minutes to yield (17 mg, 18%) title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.92 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.36-7.32 (m, 4 H), 7.14 (d, 1 H), 6.68 (d, 1 H), 5.64 (s, 2 H), 4.00-3.30 (m, 9 H), 2.45-2.05 (m, 2H), 2.07 (s, 6 H); ES-MS m/z 509.2 [M+H]+, HPLC RT (min) 2.11.
Reaction SMILES: [C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6])(O)=[O:2].Cl.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(N(C(C)C)C(C)C)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[CH:5]([CH3:7])[CH3:6])=[O:2])=[CH:38][CH:39]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)NCCc1ccc(O)cc1)C(C)C
Reaction time: 1 h

Procedure:
0.5 g of the compound from Example 16, 0.21 g of tyramine hydrochloride, 0.225 ml of N-ethyldiisopropylamine, 0.164 g of 1-hydroxybenzotriazole and 0.296 g of dicyclohexylcarbodiimide are stirred at room temperature in 4 ml of DMF for 48 h. After evaporating the solvent in vacuo, the residue is stirred in a mixture of 4 ml of CH2Cl2 -MeOH-AcOH 94:3:3 for 1 h. After evaporating, the mixture is separated by means of flash chromatography (100 g, system N6). After lyophilizing from t-BuOH, the product is obtained as an amorphous powder. FAB-MS: m/e=555 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:29])[C:16](=[O:28])[C:17]([CH3:27])=[C:18](OS(C(F)(F)F)(=O)=O)[C:13]=2[C:12](=[O:30])[N:11]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:10]1=[O:40].[NH2:41][C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=1)[NH:45][C:46](=[O:48])[CH3:47].CN(C)C(=O)C.N1C(C)=CC=CC=1C>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:29])[C:16](=[O:28])[C:17]([CH3:27])=[C:18]([NH:41][C:42]3[CH:43]=[C:44]([NH:45][C:46](=[O:48])[CH3:47])[CH:49]=[CH:50][CH:51]=3)[C:13]=2[C:12](=[O:30])[N:11]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:10]1=[O:40]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)C(F)(F)F)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(NC(C)=O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Yield: 94.5 %

Procedure:
To trifluoromethanesulfonic acid 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl ester 86 (1.10 g) and 3′-aminoacetanilide 57 (285 mg) were added, N,N-dimethylacetamide (2.20 ml) and 2,6-lutidine (221 μl), and the mixture was stirred at 130° C. for 2 hrs. After allowing to return to room temperature, methanol (12.0 ml) was added dropwise with stirring. The precipitated crystals were collected by filtration, washed with methanol and dried to give N-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide 87 (1.04 g, yield 94.6%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2.C([BH3-])#N.[Na+]>>[F:34][C:31]1[CH:32]=[CH:33][C:24]([NH:23][CH2:14][C:13]([OH:20])([C:16]([F:17])([F:19])[F:18])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)([CH3:21])[CH3:22])=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:35])[CH:27]=[CH:26]2
Reactant: Cc1ccc2c(N)ccc(F)c2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)ccc(F)c2n1

Procedure:
Analogously to Example 1, the corresponding imine is produced starting from 45 mg of 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 25 mg of 5-amino-8-fluoro-2-methylquinoline. After reaction with sodium cyanoborohydride, the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20]([C:22]1[C:23]2[S:31][CH:30]=[C:29]([CH2:32]Br)[C:24]=2[C:25]([Cl:28])=[N:26][CH:27]=1)=[O:21])[CH3:18]>C1COCC1.CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[S:31][CH:30]=[C:29]([CH2:32][O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]=2[C:25]([Cl:28])=[N:26][CH:27]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc([N+](=O)[O-])c3)csc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 3-nitrophenol (457 mg, 3.29 mmol) (Aldrich) and potassium carbonate powder (498 mg, 3.60 mmol) in dry THF (10 mL) and DMF (5 mL) was stirred at 50° C. for 15 minutes before a solution of 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (1.00 g, 2.99 mmol) (from Example 1 supra) in THF (8+2 mL) was added. The reaction was stirred at 50° C. for 3 hours and the resulting mixture was concentrated to remove most of the solvent. The residue was dissolved in EtOAc (200 mL), washed with water (2×25 mL) and brine (25 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (CH2Cl2/MeOH, 98/2 to 90/10) to give 4-chloro-3-(3-nitro-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 911 mg, 78%).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH2:9]([C@@:12]1([CH3:37])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N+:14]2[C@@H:32]([CH2:35][CH3:36])[CH2:33][O:34][C:13]1=2)[CH:10]=[CH2:11].[CH2:38]([S-:40])[CH3:39].[Na+]>CN(C=O)C>[CH2:9]([C@@:12]1([CH3:37])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:14]([C@@H:32]([CH2:35][CH3:36])[CH2:33][S:40][CH2:38][CH3:39])[C:13]1=[O:34])[CH:10]=[CH2:11]
Reactant: CC[S-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2CC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSCC)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium trifluoromethanesulfonate (86 mg, 0.15 mmol; Example 339, Step A) in DMF (0.74 ml) was added sodium ethanethiolate (38 mg, 0.45 mmol). After being stirred at 25° C. for 1.5 h, the reaction was quenched (sat. aq. NH4Cl), extracted (2×EtOAc), and washed (2×brine). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 10% and 20% EtOAc/hex) provided the title compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][C:24](=[O:49])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:46][CH2:47][CH3:48])([CH3:22])([CH3:21])[CH3:20]>CC#N.CCOC(C)=O.O>[C:19]([O:23][C:24](=[O:49])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)(=[O:37])=[O:38])[CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:46][CH2:47][CH3:48])([CH3:22])([CH3:21])[CH3:20]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc2cc(N(Cc3cccc(C(F)(F)F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Trifluoromethylbenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5])[CH2:26]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C(O)(c1ccco1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccco1)C1CCCCC1

Procedure:
Prepared using the same method as for Intermediate I-1, but from 13.73 g (0.057 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester (Intermediate I-11) dissolved in 350 ml of toluene, 8.6 g (0.067 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.37 g (0.0342 mol) of HNa (60% dispersion in mineral oil). The oil obtained (10.33 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 97:3:0.3. Appropriate fractions were combined and evaporated to obtain the two diastereomers: I-4a and I-4b.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([O:17]CC)=[O:16])[C:5]1=[O:20])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]1=[O:20])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)cccc2n(C(C)C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2c1cc(C(=O)O)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of ethyl 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (15.0 g, 54.9 mmol), 2N aqueous sodium hydroxide (41 mL, 82 mmol), and ethanol (150 mL) was stirred at room temperature for 2 h. Then, 2N aqueous hydrochloride (41 mL, 82 mmol) was added, and the white precipitate was collected by filtration. This solid was washed with water to give 12.6 g (93%) of the title compound as a pale yellow solid.
Reaction SMILES: C[O:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[N:23]2CC2C=CC(OC)=CC=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[O:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[NH:23]2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[O:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCCCCCC(C)=CC(=O)O3)O2)cc1
Agent: C/C1=C/C(=O)O[C@@H]2C[C@@H](CCCCCCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CC1=CC(=O)O[C@@H]2C[C@@H](CCCCCCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,13R,15R,Z)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-4-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH:1]([O:12][CH:13]([CH2:15][CH3:16])[CH3:14])(OC(CC)C)OC(CC)C.[C:17]1(=O)[CH2:22][CH2:21]C[CH2:19][CH2:18]1.CC(O)CC>[Fe](Cl)(Cl)Cl>[CH3:14][CH:13]([O:12][C:1]1[CH2:21][CH2:22][CH2:17][CH2:18][CH:19]=1)[CH2:15][CH3:16]
Reactant: O=C1CCCCC1
Reactant: CCC(C)OC(OC(C)CC)OC(C)CC
Agent: Cl[Fe](Cl)Cl
Solvent: CCC(C)O
Product: CCC(C)OC1=CCCCC1
Temperature: 50 °C
Yield: 89.4 %

Procedure:
A mixture containing 116.2 g (0.5 mol) of tri(2-butyl) orthoformate, 49.10 g (0.5 mol) of cyclohexanone and 3.7 g (0.05 mol) of 2-butanol was stirred at room temperature (25° C.) and 0.2 g (1 mmol) of reagent grade iron (III) chloride was added. The temperature of the reaction mixture rose to about 35° C. due to the exotherm and was heated and maintained at about at 50° C. until gas-chromatographic analysis indicated that the reaction was complete. After removing the by-products 2-butyl formate and 2-butanol by distillation under reduced pressure, the resulting residue was subsequently distilled to provide 1-(2-butoxy)-1-cyclohexene (bp 86° C. @2 mm Hg) as a colorless liquid; the yield was 89.4% with a purity exceeding 99%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[C:15]([C:24](O)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[C:15]([C:24]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccccn2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccccn3)n2)CN1

Procedure:
75 mg (0.18 mmol) of the compound of Example 37A is reacted analogously to the synthesis of the compound of Example 1 with 24 mg (0.19 mmol) of 4-imidazolinone-hydrochloride. 75 mg (87% of theory) of the title compound is obtained.
Reaction SMILES: IC1C2N=CN=C(N)C=2N(C2C=CC([N+]([O-])=O)=CC=2)N=1.CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.[NH2:43][C:44]1[C:45]2[N:52]([C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[C:55](OC)[CH:54]=3)[N:51]=[C:50]([C:64]3[CH2:65][CH2:66][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:68][CH:69]=3)[C:46]=2[N:47]=[CH:48][N:49]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[NH2:43][C:44]1[C:45]2[N:52]([C:53]3[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=3)[N:51]=[C:50]([C:64]3[CH2:65][CH2:66][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:68][CH:69]=3)[C:46]=2[N:47]=[CH:48][N:49]=1
Reactant: COc1cc(-n2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c32)ccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Nc1ncnc2c(I)nn(-c3ccc([N+](=O)[O-])cc3)c12
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2nn(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc23)CC1

Procedure:
The title compound was prepared from 3-iodo-1-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate in the manner described for the preparation of tert-butyl 4-[7-amino-1-(3-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate: 1H NMR (DMSO-d6, 400 MHz) δ 8.44 (m, 3H), 7.76 (d, 2H), 7.53 (m, 1H), 7.05 (bs, 2H), 4.13 (m, 2H), 3.58 (m, 2H), 2.67 (m, 2H), 1.44 (s, 9H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 21.70 min; MS: MH+ 438.1, M−H+ 436.1
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[C:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)C=CC=CC=1.Cl>O1CCCC1>[CH3:22][C:18]1[N:17]=[C:16]([NH:15][C:10]2[C:9]([NH2:8])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(Nc2ccccc2N=C(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(Nc2ccccc2N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
42.1 g (0.11 mol) of N1-(diphenylmethylene)-N2-(6-methylpyridine-2-yl)benzene-1,2-diamine was dissolved in tetrahydrofuran (100 ml), and 10% hydrochloric acid (45 ml) was added thereto, and was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure, and water was added to the residue thus obtained and washed with ethyl acetate. Then, the aqueous layer was adjusted to pH >11, and the aqueous layer was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 19.8 g (yield: 83%) of N-(6-methylpyridine-2-yl)benzene-1,2-diamine.