Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)=[O:26])=[CH:20][CH:19]=1)[NH:6]C(=O)C1C(C)=CC=CC=1Cl.CCN(C(C)C)C(C)C.[OH:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1>C1COCC1>[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:25](=[O:26])[C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[CH:48]2[C:47]2[CH:50]=[CH:51][C:44]([OH:43])=[CH:45][CH:46]=2)=[CH:22][CH:23]=1)[NH2:6]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)C2CCCCN2)cc1)NC(=O)c1c(C)cccc1Cl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](N)Cc1ccc(N2C(=O)[C@@H]3CCCCN3C2c2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
(S)-N-(2-chloro-6-methylbenzoyl)-4-[[(2-piperidinyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride (100 mg, 0.2 mmol), DIPEA (0.10 mL, 0.54 mmol) and 4-hydroxybenzaldehyde (30 mg, 0.25 mmol) was added to a suspension of activated 3 Å molecular sieves (100 mg) in THF (1.5 mL). The resulting mixture was stirred room temperature overnight and at 60° C. for 3 hr. After it was cooled to room temperature, the mixture was transferred onto a silica gel column and eluted with ethyl acetate:hexane (2:1) to give N-[(2-chloro-6-methylphenyl)carbonyl]]-4-[(8aS)-hexahydro-3-(4-hydroxyphenyl)-1-oxoimidazo[1.5-a]pyridin-2-yl]-L-phenylalanine methyl ester (17.5 mg, 0.031 mmol) as a foam. The methyl ester (17.5 mg, 0.031 mmol) was hydrolyzed with 1N NaOH (0.1 mL, 0.1 mmol) in 0.5 mL of ethanol at room temperature for 6 hr. The reaction mixture was acidified to pH<2 with TFA and was purified on RP-HPLC to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-[(8aS)-hexahydro-3-(4-hydroxyphenyl)-1-oxoimidazo[1.5-a]pyridin-2-yl]-L-phenylalanine (8.3 mg, 0.015 mmol), in 7.5% yield. HRMS: calcd. 548.1952. Obs. 548.1938 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](OC3COC3)[CH:14]=2)[C:6]([O:9][CH:10]([F:12])[F:11])=[N:7][CH:8]=1.BrC1C(OC(F)F)=NC=C(CBr)C=1.[Cl:37]C1C=C(B(O)O)C=CC=1>>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:37])[CH:14]=2)[C:6]([O:9][CH:10]([F:12])[F:11])=[N:7][CH:8]=1
Reactant: FC(F)Oc1ncc(CBr)cc1-c1cccc(OC2COC2)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: FC(F)Oc1ncc(CBr)cc1Br
Product: FC(F)Oc1ncc(CBr)cc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 10, using Intermediate 4 and 3-chlorophenyl boronic acid in Step 1, followed by bromination according to Step 3. [M+H]=348.17350.15
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:15]CCC[CH2:11][C:7]3=[C:8]2[OH:10])=[CH:3][CH:2]=1.C[O:17]C(C1C(=O)COC1)=O.N1NC(N)=CC=1>C(O)(=O)C>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[OH:10])[CH2:11][O:17][CH2:15]3)=[CH:3][CH:2]=1
Reactant: Oc1c2c(nc3ccnn13)CCCCC2
Reactant: COC(=O)C1COCC1=O
Agent: Nc1ccn[nH]1
Solvent: CC(=O)O
Product: Oc1c2c(nc3ccnn13)COC2

Procedure:
Using the method described for the preparation of 6,7,8,9-Tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol, the reaction of 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester and 2H-pyrazol-3-ylamine in acetic acid provided the desired 5H,7H-6-Oxa-1,4,8a-triaza-s-indacen-8-ol.
Reaction SMILES: [C:1]1([CH2:11][NH:12][CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[CH:25]=[N:24][CH:23]=2)[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>C(Cl)Cl>[CH3:48][O:47][C:45]([N:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)[CH:25]=[N:24][CH:23]=1)[C@@H:15]([CH3:18])[CH2:16][CH3:17])=[O:46]
Reactant: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(Cc1cccc2ccccc12)C(=O)OC)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 2 (40 mg, 0.083 mmol) in CH2Cl2 (1 ml) and triethylamine (24 μl, 0.17 mmol) at 0° C. was added methyl chloroformate (39 μl of a 2.1 M solution in CH2Cl2, 0.082 mmol). The reaction was stirred at room temperature for 3 hr, the solvent evaporated in vacuo and the residue purified by preparative HPLC (C-18; 95:5 to 5:95 water:CH3CN containing 0.1% trifluoroacetic acid; gradient elution). Lyophilisation of the collected fractions afforded the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1>>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:21][C:22]2[CH:30]=[CH:29][C:25]3[N:26]=[CH:27][S:28][C:24]=3[CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1B(O)O
Reactant: Nc1ccc2ncsc2c1
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1ccc2ncsc2c1

Procedure:
According to the experimental procedure of Example 234, Example 235 was obtained by reacting 234b with 6-aminobenzothiazole. tR=7.344 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H22N3OS [M+H]+. found 376.
Reaction SMILES: CN.[NH2:3][CH2:4][C:5]([OH:7])=O.C([N:10]([CH2:13][CH3:14])[CH2:11]C)C.[CH3:15][C@H:16]1[CH2:22]C(=O)[C@H:19]([CH:23](C)[CH3:24])[CH2:18][CH2:17]1>>[CH:16]([C@@H:17]1[CH2:18][CH2:19][C@@H:23]([CH3:24])[CH2:14][C:13]21[N:10]([CH3:11])[C:5](=[O:7])[CH2:4][NH:3]2)([CH3:22])[CH3:15]
Reactant: CCN(CC)CC
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Reactant: NCC(=O)O
Agent: CN
Product: CC(C)[C@@H]1CC[C@@H](C)CC12NCC(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
156 ml of a commercially obtainable 8M ethanolic methylamine solution are added to 62.8 g glycine.imethyl ester hydrochloride (500 mmol) in 160 ml ethanols. at room temperature and the mixture is stirred overnight with exclusion of moisture. 40.5 g triethylamine (400 mmol) and 61.6 g (-)-menthone (400 mmol) are then added to the suspension and the mixture is boiled under reflux for 18 h under an inert gas (argon) using a Soxhlet attachment which is filled with 100 g molecular sieve 3A (capacity: 14%). Thereafter, the solvent is removed and the residue is taken up in a two-phase system of water/diethyl ether. After the organic phase has been separated off, extraction is carried out twice more with diethyl ether and the extract is dried over sodium sulphate. After the yellow solution has been evaporated, the residue can be recrystallized from cyclohexane/diethyl ether =8:2. During distillation of the mother liquor in vacuo, the content of the desired compound can be increased by cyclizing the chain tautomer. Unreacted menthone passes over as the first fraction (70° .C/1 mbar), followed by a mixture of the desired product and chain tautomer (140-150° C., 1 mbar). After cyclohexane has been added to the product fraction, further product can be obtained as a crystalline solid with a melting point of 125° C. The yield is 65%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7](I)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(I)c1
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(C(C)(C)C)ccc3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-t-butyl-2-iodophenol [38941-98-9] (1.0 g, 3.6 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with MeOH, filtered to give 84 as a solid.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-:20].[Na+]>>[CH2:13]([O:12][C:10]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:20])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCCCCN1
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
5 g (44.2 mmol) of ε-caprolactam was dissolved in 19.4 g of 20 wt % NaOH and heated to reflux for 3-5 hours. After ε-caprolactam was hydrolyzed completely, the mixture was cooled down to 5-10° C. and 25 g of benzyl chloroformate was added. The mixture was stirred 1 hour at 5˜10° C. and then washed with 25 g of ethyl acetate twice. The pH of the aqueous layer was adjusted to 1-2 by adding 16% HCl and extracted with ethyl acetate twice. Combined ethyl acetate layer was washed with brine. The organic layer was dried by sodium sulfate and concentrated to obtain 6-benzyloxycarbonylamino-hexanoic acid. Purity was 95.0%.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[Cl:27])=O)(=O)OC.O.[NH2:29][NH2:30]>>[Cl:27][C:20]1[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=1[C:17]1[N:29]=[N:30][C:2]2[CH:1]3[CH2:7][CH:4]([C:3]=2[CH:16]=1)[CH2:5][CH2:6]3
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cc(F)c(F)cc1Cl)OC
Solvent: O
Product: Fc1cc(Cl)c(-c2cc3c(nn2)C2CCC3C2)cc1F

Procedure:
yellow solid. MS (EI): 292.1 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(2-Chloro-4,5-difluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:8][C:7]=12
Reactant: CCCCCCCCCC(=O)O
Reactant: Cc1ccnc(N)c1N
Product: CCCCCCCCCc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and decanoic acid (0.35 g, 2 mmol) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (20:1) to give the pure product (0.38g, 72%) as a tan colored solid. 1H NMR (300 MHz, CDCl3): 8.16 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz), 3.03 (t, 2H, J=7.8 Hz), 2.69 (s, 3H), 1.25-2.0 (m, 14H), 0.90 (t, 3H, J=7.5 Hz).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[N:16]=[C:15]1[CH:26]=CN(C)C>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[N:16]=[C:15]1[CH:26]=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Yield: 101.1 %

Procedure:
To a well stirred mixture of sodium periodate (2.24 g, 10.47 mmol) in pH 7 buffer (10 mL) and tetrahydrofuran (10 mL) was added 3-(2-chloro-phenyl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (0.90 g, 2.62 mmol) all at once. The mixture warmed slightly to the touch and was stirred 1 h at ambient temperature. The reaction was filtered through celite and the pad was rinsed with ethyl acetate. The phases were separated from the filtrate and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated to afford 0.802 g (97%) of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as a 1:2 mixture of free aldehyde and hydrate which had: 1H NMR δ 9.52 (s,) [CHO], 8.20-7.45 (m, 7H), 6.75 (d, J=7.4 Hz) [hydrate OH] and 6.49 (d, J=8 Hz) [hydrate OH], 5.14 (t, J=7.5 Hz) [hydrate methine CH].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.Cl[Mg][CH2:26][CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](=[O:9])[CH2:26][CH3:27])[CH:7]=1
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a solution of 8-chloro-5-(3-fluorophenyl)-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide (300 mg, 0.91 mmol) in tetrahydrofuran (3.0 mL) cooled at 0° C., a 2 M solution of chloro(ethyl)magnesium in tetrahydrofuran (1.6 mL, 3.2 mmol) was added slowly and the mixture was stirred for 3 hours at 0° C. The reaction was quenched with acetic acid (0.5 mL), poured into saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-60%) gave the desired compound (130 mg, 49%). LCMS calculated for C16H13ClFN2O (M+H)+: m/z=303.1. found: 302.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:20])[C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[C:46]([NH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH2:60])([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:20])[C:15]([C:17](=[O:19])[NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[NH:53][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(C(=O)O)cc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
To a solution of compound 5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.0 eq) in DMF was added DCC (1.3 eq.), and HOBt (1.3 eq) and stirred for 1 hr. Monoboc phenylene diamine was added and reaction was stirred for 48 hrs. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford 2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-1-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester which was then reacted with hydrochloric acid saturated diethyl ether to get N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[CH:15]1([NH:18]C)[CH2:17][CH2:16]1.[C:20]([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:18]([CH:15]1[CH2:17][CH2:16]1)[CH:12]2[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: CNC1CC1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1c2cc(Br)cc(Cl)c2C(=O)N1C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.684 g, 2.00 mmol), cyclopropyl methyl amine (0.22 mL, 2.6 mmol), and K2CO3 (0.552 g, 4.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-cyclopropyl methyl-2,3-dihydro-isoindol-1-one (0.173 g, 29%). GC-MS: m/z 301 (M)+, 286 (M−15)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 0.34 (m, 2H), 0.59 (m, 2H), 1.05 (m, 1H), 3.47 (d, 2H) 4.44 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.36 g) in methanol (10 ml) was added a solution of 1-[5-fluoro-2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (0.58 g) and triethylamine (0.65 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.17 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[CH:42]5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[CH:42]5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4ccnc4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4ccnc4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[2-(imidazol-1-yl)ethyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) was dissolved in methylene chloride (15 ml), and a solution of m-chloroperbenzoic acid (0.20 g) in methylene chloride (10 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[2-(imidazol-1-yl)ethyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 266) (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.[C:20]([NH:22][C:23]([NH2:25])=[NH:24])#[N:21].[OH-].[Na+].[C:28]([O:31]CC)(=[O:30])C>CS(C)=O>[CH:28]([OH:31])=[O:30].[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]2[N:24]=[C:23]([NH2:25])[N:22]=[C:20]([NH2:21])[N:15]=2)[N:6]=1
Reactant: N#Cc1nc(Cc2ccccc2F)n2ncccc12
Reactant: N#CNC(=N)N
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1nc(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)n1
Product: O=CO

Procedure:
100 mg (0.4 mmol) of 7-(2-fluorobenzyl)imidazo[1,5-b]pyridazine-5-carbonitrile (Example 6A) and 60 mg (0.71 mmol) of 1-cyanoguanidine in 1.3 ml of DMSO were stirred with 4.8 mg (0.12 mmol) of sodium hydroxide at 150° C. in a microwave reactor for 40 minutes. At 20° C., the reaction mixture was then diluted with ethyl acetate (50 ml) and washed twice with in each case 20 ml of water. Purification by HPLC (acetonitrile:water (+0.1% formic acid) gradient) and concentration of the product-containing fractions gave 37.2 mg (25% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:14]=2[CH:33]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:43])[N:15]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:14]=2[CH:33]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccc(C)cc3)c2c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCCOc1ccc2nc(S(=O)Cc3ccccc3)n(-c3ccc(C)cc3)c2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
500 mg of 6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 9 ml of dichloromethane, mixed with 303 mg of m-chloroperbenzoic acid (about 60%), and the mixture was stirred for 2 hours at 20° C. It was mixed with sodium disulfite solution, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 232 mg of 6-[[1-(4-methylphenyl)-2-(phenylmethanesulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was obtained.