Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[C:11]1([NH:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.N1C=CC=CC=1.C(OCC)C>C(OC(O)C)C>[C:11]1([NH:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][C:6]4[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Agent: CCOC(C)O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#Cc1cnc(N)cc1Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
2-Amino-4-chloro-5-cyanopyridine (200 mg, 1.30 mmol, Production example 215-3) was dissolved in ethoxyethanol (13.0 ml); 5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol, Production example 201-2) and pyridine hydrochloride (315 mg, 2.73 mmol) were added thereto; and the reaction mixture was heated and stirred at 130° C. for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=2:3, ethyl acetate, ethyl acetate:methanol=95:5 in this order). The pale yellow oil obtained was solidified with diethyl ether; the crystals were suspended with diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (171 mg, 0.464 mmol, 35.7%) as colorless crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:7]([C:20](O)=[O:21])=[CH:6]2.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:33][N:32]([CH3:34])[C:29]1[N:28]=[CH:27][C:26]([NH:25][C:20]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([Si:2]([CH3:23])([CH3:24])[CH3:1])=[CH:11][CH:10]=3)=[O:21])=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)c1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(F)c1
Reactant: CN(C)c1ccc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)c1ccc(NC(=O)c2cc3cc([Si](C)(C)C)ccc3n2Cc2cccc(F)c2)cn1
Yield: 49.3 %

Procedure:
Compound No. 7 was prepared according to a process similar to that described in stage 5.4, by reacting 0.3 g (0.88 mmol) of 5-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in stage 3.6, with 181 mg (1.32 mmol) of 3-amino-6-(dimethylamino)pyridine in the presence of 185 mg (0.97 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and of 131 mg (0.97 mmol) of 1-hydroxybenzotriazole (HOBT) in 10 ml of dimethylformamide. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and acetone. The solid obtained after evaporation of the solvent under reduced pressure is recrystallized from isopropyl alcohol. 200 mg of the expected product are thus isolated.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>C(O)COCCO.O>[CH3:25][C:20]1[CH:19]=[C:18]([F:17])[CH:24]=[CH:23][C:21]=1[N:22]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: OCCOCCO
Solvent: O
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccc(F)cc1C
Temperature: 250 °C
Yield: 78.9 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and (278 μl, 2.5 mmol) of 4-fluor-2-methylaniline (278 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent according to silica gel chromatography to obtain 256 mg of desired compound as solid in 79% of yield.
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][C:6]1=[O:19].O.NN>CCO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:19])[N:5]([CH2:4][CH3:3])[C:11]=2[CH:12]=1
Reactant: COCCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN1C(=O)CCCc2ccc(N)cc21
Yield: 113.1 %

Procedure:
To a solution of 1-(2-methoxy-ethyl)-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (1.00 g, 3.9 mmol) in EtOH (13 mL) was sequentially added 10% Pd/C (155 mg) and hydrazine-monohydrate (3 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine to afford 8-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (901 mg, 98%) that had the following properties: LC/MS (ESI+): 235 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 6.95 (d, J=7.9, 1H), 6.68 (s, 1H), 6.51 (d, J=7.9, 1H), 3.95 (br s, 2H), 3.67 (br s, 2H), 3.56 (m, 2H), 3.32 (d, 3H, J=2.2), 2.75 (br s, 2H), 2.30 (m, 2H), 2.10 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[S:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:13]=3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.[CH:41]1[CH:42]=[CH:43][C:44]2[N:49](O)N=[N:47][C:45]=2[CH:46]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:47][C:45]1[CH:46]=[CH:41][CH:42]=[CH:43][C:44]=1[NH:49][C:20]([C:18]1[S:17][C:14]2[CH2:15][CH2:16][N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH2:12][C:13]=2[CH:19]=1)=[O:22]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCc3sc(C(=O)O)cc3C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCc3sc(C(=O)Nc4ccccc4N)cc3C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (1.0 eq) obtained from step IV in DMF was added Et3N (2.2 eq.), EDCI (1.2 eq) and HOBt ((1.2 eq) and reaction was stirred for 1 h Phenylene diamine was added and reaction was stirred for overnight. Reaction was then quenched with water and extracted with ethyl acetate. Organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[N-:25]=[N+:26]=[N-:27].[Na+]>O.CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]=[N+:26]=[N-:27])=[CH:4][CH:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CN=[N+]=[N-])cc1
Reaction time: 12 h

Procedure:
To a mixture of 2.97 g of 4-(hydroxymethyl)phenol, 4.90 g of tert-butyl bromoacetate, and 25 ml of DMF was added 4.96 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to obtain a pale yellow oily substance. This oily substance was subjected to methanesulfonylation in accordance with Production Example 15, and then reacted with sodium azide to obtain 4.03 g of tert-butyl[4-(azidomethyl)phenoxy]acetate as a pale yellow oily substance.
Reaction SMILES: [C:1]([C:4]1C(I)=C(NC(=O)CN2CCNCCNCCNCC2)C(I)=CC=1I)([OH:3])=[O:2].Cl.Cl.Cl.[O:32]=[C:33]([NH:55][C:56]1[C:57]([I:67])=[C:58]([C:62]([I:66])=[CH:63][C:64]=1[I:65])[C:59]([OH:61])=[O:60])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:54])[CH2:41][N:42]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.Br[CH2:69][C:70]([OH:72])=[O:71]>CCO.O>[C:70]([CH2:69][N:45]1[CH2:46][CH2:47][N:48]([CH2:4][C:1]([OH:3])=[O:2])[CH2:49][CH2:50][N:51]([CH2:4][C:1]([OH:3])=[O:2])[CH2:52][CH2:53][N:42]([CH2:41][C:40]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C:33]([NH:55][C:56]2[C:57]([I:67])=[C:58]([C:62]([I:66])=[CH:63][C:64]=2[I:65])[C:59]([OH:61])=[O:60])=[O:32])=[O:54])[CH2:43][CH2:44]1)([OH:72])=[O:71]
Reactant: O=C(O)CBr
Reactant: O=C(CN1CCNCCNCCNCC1)NCCCCCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: O=C(CN1CCNCCNCCNCC1)Nc1c(I)cc(I)c(C(=O)O)c1I
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)NCCCCCC(=O)Nc2c(I)cc(I)c(C(=O)O)c2I)CCN(CC(=O)O)CC1
Yield: 73.5 %

Procedure:
According to the procedure described in Example 3, 142.4 g of compound (B) 3-[[1-oxo-6-[[(1,4,7,10-tetraazacyclododec-1-yl) acetyl]amino]hexyl]amino]-2,4,6-triiodobenzoic acid trihydrochloride (0.15 mol ) are reacted with 83.4 g of bromoacetic acid (0.60 mol) in 750 ml of 96% EtOH and 250 ml of H2O. 72.7 g of 3-[[6-[[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetyl]amino]-1-oxohexyl]amino]-2,4,6-triiodobenzoic acid (0.072 mol) are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])[CH3:10].C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:16][CH2:15][N:14]([S:11]([CH2:9][CH3:10])(=[O:12])=[O:13])[CH2:19][CH2:18]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
2,5-Dibromopyridine (1 g) was heated in dimethylacetamide (2.5 ml) with ethanesulfonylpiperazine (0.752 g) and diisopropylethylamine (1.84 ml) at 120° C. for 18 h. After cooling, the reaction mixture was poured into water (30 ml) and the precipitated solid was collected by filtration. The product was purified by column chromatography eluting with dichloromethane (0.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([NH2:13])=O)=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]#[N:13])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(N)=O)cc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
To a slurry of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxamide (0.4488 g, 1.43 mmol) in tetrahydrofuran (20 ml) at 5° C. is added triethylamine (0.5 ml, 3.58 mmol) and trifluoroacetic acid anhydride (0.26 ml, 1.79 mmol). The cooling bath is removed and the reaction allowed to warm to room temperature and stir for 16 hours. The contents are partitioned between water and methylene chloride, and the organic layer is separated, dried over magnesium sulfate, filtered and concentrated to a solid, which is chromatographed on silica gel (9:1 dichloromethane:toluene) to afford 386.9 mg (92%) of title compound as a solid: mp 141.7-142.9° C. IR (KBr) 2985, 2214, 1610, 1498, 1479, 1260, 1033 cm-1 ; 1H NMR (CDCl3): δ7.82 (d, 2 H, J=8.9 Hz), 7.81 (d, 1 H, J=8.8 Hz), 7.28 (d, 1 H, J=2.2 Hz), 7.12 (dd, 1 H, J=8.9, 2.2 Hz), 7.02 (d, 2 H, J=8.9 Hz), 3.90 (s, 3 H), 3.88 (s, 3 H); 13C NMR (CDCl3): d 161.1, 158.5, 155.5, 131.0, 138.5, 133.1, 129.4, 124.3, 123.0, 115.8, 114.7, 104.9, 100.2, 55.8, 55.5. Anal. Calcd. for C17H13NO2S: C, 69.13; H, 4.44; N, 4.74; S, 10.85. Found: C, 68.86; H, 4.66; N, 4.52; S, 10.76.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](O)=[O:28])=[CH:23][NH:24]2)=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:27]([C:22]4[C:21]5[C:25](=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=5)[NH:24][CH:23]=4)=[O:28])[CH2:14][CH2:15]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Reactant: O=C1Nc2ccc(Br)cc2C12CCNCC2
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)C(=O)Nc1ccc(Br)cc12

Procedure:
Following the general procedure I as described above, the acylation of 5-bromospiro[indole-3,4′-piperidin]-2(1H)-one with 6-chloro-1H-indole-3-carboxylic acid (preparation described in example 5 above), gave the title compound. ES-MS m/e (%): 458.3(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.[CH3:23][NH2:24]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:24]([CH3:23])[CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: CN
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Solvent: CO
Product: CN1CCN2c3ccc(Cl)cc3C(c3ccco3)=NCC2C1
Yield: 45.3 %

Procedure:
1 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine in 40 ml of methanol is left to react with 0.8 g of methylamine at 50° C. for 3 hours. The reaction mixture is then worked up as described in Example 7. On purification by chromatography, the fractions containing the more highly polar title compound are separated off. 0.4 g of 1,2,3,4,4a,5-hexahydro-9-chloro-3-methyl-7-(2-furyl)-pyrazino[1,2-a][1,4]benzodiazepine is obtained therefrom.
Reaction SMILES: [F:1][C:2]([F:19])([CH:8]([OH:18])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:19])([CH:8]([O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(F)(F)C(OS(=O)(=O)c1ccc(C)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
To a solution of ethyl 2,2-difluoro-3-hydroxy-3-(4-nitrophenyl)propanoate (800 mg, 2.91 mmol) in pyridine (20 mL) was added dropwise p-toluenesulfonyl chloride (665 mg, 3.49 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (1.09 g, yield 99%) as a colorless oil.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:37])[C:35]=1[F:36])[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:33]=[C:34]([F:37])[C:35]([F:36])=[C:28]([F:27])[CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCc1cc(F)c(F)c(F)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cc(F)c(F)c(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), 3,4,5-trifluorobenzylamine (0.66 g, 4.0 mmol) and MeOH (0.2 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and the mixture is purified by chromatography on silica gel; gradient elution with heptane: EtOAc (70:30-50:50) gives 0.44 g of the product 83. 1H NMR (CDCl3) δ 7.59 (s, 1H), 7.20-7.05 (m, 2H), 7.05-6.90 (m, 8H), 6.80-6.70 (m, 2H), 5.45-5.30 (m, 2H), 4.70-4.50 (m, 2H), 1.16 (s, 9H); MS: m/z 482 (M++1).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C(F)F)=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.C(O)(C)(C)C.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)N(C)C1CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(OC(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: COC(=O)N(C)C1CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(O)cc1

Procedure:
To 25.5 g (50.8 mmole) of N-(4-trifluoromethoxyphenyl)-3-(4-difluoromethoxyphenyl)-4-(N-methyl-N-(methoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide dissolved in 25 g of tetrahydrofuran and 25 g of t-butanol was added 10 g of potassium t-butoxide. The mixture was refluxed for 1 hour and an additional 3.5 g of potassium t-butoxide was added. After refluxing an additional hour the mixture was acidified with acetic acid, concentrated in vacuo, and partitioned between methylene chloride and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel using hexane and diethyl ether to yield the expected compound, a white solid, mp 228°-233° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[OH:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:16]
Reactant: Cc1cc(Br)cc2c(O)c(C(=O)O)cnc12
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(Br)cc2c(O)ccnc12
Temperature: 260 °C
Yield: 94.4 %

Procedure:
A mixture of 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid (1.80 g, 6.36 mmol) and Dowtherm A (10 mL) was heated at 260° C. for 1.0 h. The reaction was cooled, triturated with hexanes, filtered and dried in a Buchner funnel to give the title compound (1.43 g, 95%) as a tan solid. MS (ES)+ m/e 238 [M+H].
Reaction SMILES: [Na].[S:2]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])(O)(=[O:4])=[O:3].S(Cl)([Cl:16])=O>CN(C)C=O.C(OCC)C.O>[CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:2]([Cl:16])(=[O:4])=[O:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccccc1S(=O)(=O)O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1ccccc1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 38.2 %

Procedure:
To a solution of 2-sulfobenzaldehyde sodium salt (2.0 g, 9.6 mmol) in 0.8 mL of dry N,N-dimethylformamide was added thionyl chloride (7.0 mL, 96 mmol) under nitrogen at 0° C. After being stirred at 100° C. for 3 min, the reaction mixture was diluted with diethyl ether and water at 0° C., successively. The separated organic layer was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 2-formylbenzenesulfonyl chloride (0.75 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](Br)[C:5]=1[NH2:6])([O-:3])=[O:2].C[Sn](C)(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=2)[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: Nc1c(-c2ccccc2)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 75.8 %

Procedure:
A solution of 2,4-dinitro-6-bromoaniline (2.5 g, 9.5 mmol), tetramethyltin (6.1 g, 14.3 mmol) and Cl2Pd(PPh3)2 (100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reaction mixture was concentrated in vacuo, yielding an oil which was purified on silica gel column chromatography (CH2Cl2, neat) to provide 1.0 g (3.6 mmol, 41%) of 2,4-dinitro-6-phenylaniline, which was converted to the diamine (0.72 g, >95%) on hydrogenation (H2/Pd-C).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH2:27][O:28][CH2:29][CH:30]=[CH2:31])[CH:16]=[CH2:17]>>[CH2:15]([O:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:21][C:20]=1[CH2:27][O:28][CH2:29][CH:30]=[CH2:31])[CH:16]=[CH2:17]
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: C=CCOCc1cc(C=O)ccc1OCC=C
Product: C=CCOCc1cc(/C=C/C(=O)c2cc(C)cc([N+](=O)[O-])c2O)ccc1OCC=C
Yield: 44.8 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (500 mg, 2.56 mmol) and 4-(allyloxy)-3-[(allyloxy)methyl]benzaldehyde (760 mg, 3.27 mmol) were reacted according to the same procedure as Preparation 22 to give 470 mg (Yield 45%) of the title compound.
Reaction SMILES: C([Li])CCC.[CH:6]1[N:7]=[CH:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=12.[CH2:15]=[O:16].Cl>CCOCC>[OH:16][CH2:15][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:6][N:7]=1
Reactant: C=O
Reactant: c1ncn2c1CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OCc1ncc2n1CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.58 molar n-butyl lithium in N-hexane (49 ml.) was added over 0.5 hour to a stirred solution of 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (8.9 g.) in dry ether at -60° under nitrogen. After 3 hours, gaseous formaldehyde generated by the thermal condensation of paraformaldehyde (6.9 g.) was passed into the red solution. The mixture was allowed to warm to room temperature overnight, acidified with hydrochloric acid and extracted with chloroform. The aqueous layer was basified with an excess of saturated sodium carbonate solution and extracted with chloroform. Concentration and recrystallisation of the residue from ethanol-ethyl acetate-petroleum ether afforded 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (7.7 g.), m.p. 188°-199°.