Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1cccc(Cl)c1)c1ccccc1[N+](=O)[O-]
Yield: 98 %

Procedure:
Using the procedure described in Example 93, Part A, 3-chloroaniline (9.4 mmol) and 2-nitrobenzoyl chloride (10.4 mmol) yielded 2.55 g (98%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2=[CH:17][C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[N:15]2[CH:14]=[CH:13][NH:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Br:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([N:12]2[CH:13]=[CH:14][N:15]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=[C:16]3[C:11]2=[O:24])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: O=c1[nH]ccn2c3c(cc12)CCCC3
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Br)cncc1-n1ccn2c3c(cc2c1=O)CCCC3
Temperature: 100 °C
Yield: 35.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 3,5-dibromoisonicotinaldehyde (604 mg, 2.28 mmol), 6,7,8,9-tetrahydropyrazino[1,2-a]indol-1(2H)-one (142 mg, 0.76 mmol) and cesium carbonate (485 mg, 1.5 mmol). CuI (143 mg, 0.76 mmol) and 4,7-dimethoxy-1,10-phenanthroline (127 mg, 0.52 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time, the reaction was cooled to room temperature. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with EtOAC/PE (1:2) to afford 126a (100 mg, 35%) as a yellow solid. MS: [M+H]+ 372.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:9]([CH2:20][CH3:21])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:20][CH3:21])[C:10]([OH:12])=[O:11])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Under an atmosphere of argon, (S)-benzyl 2-(dibenzylamino)butanoate (84 g, 191 mmol, Eq: 1.00) was combined with methanol (136 ml) to give a light yellow solution. Then cold (0° C.) NaOH solution (15.3 g in 150 ml water, 382 mmol, Eq: 2) was added at once to the reaction mixture. The reaction was stirred at 90° C. for 4 h. Upon cooling to RT, the reaction mixture was poured into water (75 ml) and extracted with tert-butyl methyl ether: heptane=1:1 (2×150 ml), to remove the benzylalcohol formed in the hydrolysis. The basic aqueous layer was acidified to pH 2 with HCl (conc.). The aqueous layer was then extracted with ethyl acetate (2×250 ml). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residual solvent was removed under vacuum. The title compound was obtained as a white solid (68.13 g, quant., MS (m/e)=284.1 [M+H+], MS (m/e)=282.3 [M−H+]).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24](Br)CC>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:24][CH2:23]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1O
Reactant: CCC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccccc21
Yield: 80.6 %

Procedure:
A solution of dry acetone (100 mL) containing N-(tertbutoxycarbonyl)-2-aminophenol (0.722 g, 3.69 mmol), potassium carbonate (10.2 g, 73.8 mmol) and 1,2-dibromobutane (2.54 mL, 29.6 mmol) was refluxed for 18 h. The reaction was monitored by TLC (petrol/ether 8/2). After cooling, the mixture was filtered through celite. After concentration and hydrolysis, the aqueous layer was extracted with EtOAc (3×40 mL), dried over MgSO4 and the solvent was removed under reduce pressure. The crude product was purified by flash chromatography on silica gel (petrol/EtOAc 95/5) to yield the title compound as a white solid (0.70 g, 82%). m.p=78-79° C.; Rf=0.44(petrol/ether 8/2); LCMS m/z 236 ([M+1]+); 1H NMR (300 MHz, CDCl3): δ 1.59 (9H, s); 3.87 (4H, m); 4.26 (4H, m); 6.86-7.02 (4H, m); 13C NMR (75 MHz, CDCl3): δ 27.4 (3C); 41.1; 64.6(2C); 80.6 (2C); 116.0; 119.2; 122.6; 123.4; 125.2; 144.9; 151.6. IR (film): 2975; 1696; 1494; 1143 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:25])([CH3:24])[CH2:13][NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[O:8][CH:7]([C:26]([F:29])([F:28])[F:27])[C:6]([C:30]([O:32]CC)=[O:31])=[CH:5]2.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:25])([CH3:24])[CH2:13][NH:14][C:15](=[O:23])[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[O:8][CH:7]([C:26]([F:28])([F:29])[F:27])[C:6]([C:30]([OH:32])=[O:31])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CNC(=O)c3ccc(Cl)cc3)cc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)c1ccc(Cl)cc1)c1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Reaction time: 2 h

Procedure:
The title product of Example 130 Step 2 was dissolved in 5 mL of MeOH, and a solution of 244 mg of 50% aqueous NaOH in 1 mL of water was added. After stirring for 2 h, the mixture was acidified, extracted with DCM, the combined organic extracts dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using 25% EtOAc—heptane—1% HOAc gave the title compound, 65 mg, as a pure white crystalline solid. 1H NMR (DMSO-d6) 8.34 (t, 1H, J=4.6 Hz), 7.86 (s, 1H), 7.72 (d, 2H, J=8.8 Hz), 7.60 (s, 1H), 7.48 (d, 2H, J=8.8Hz), 7.03 (s, 1H), 5.93 (q, 1H, J=7.2 Hz), 3.78 (m, 2H), 1.44 (s, 6H). LCMS m/z=488.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:38]=[C:37]([F:39])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH2:32][CH2:33][S:34]([CH3:36])=[O:35])=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:40])[CH:5]=1)[CH3:2].OO.CC[O:45]C(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:40])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[C:21]([O:31][CH2:32][CH2:33][S:34]([CH3:36])(=[O:45])=[O:35])=[CH:20][N:19]=3)=[N:10]2)=[C:37]([F:39])[CH:38]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: OO
Solvent: C1CCOC1
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)(=O)=O)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-[2-(methylsulfinyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (36-1, 0.177 mmol, 1.0 eq.) were dissolved in 0.9 ml of anhydrous tetrahydrofuran. 0.09 ml of aqueous hydrogen peroxide (30%, 0.886 mmol, 5.0 eq.) and 37.0 mg Diethylazodicarboxylate were added. The reaction mixture was stirred at 50° C. for 2 h. A white precipitate was filtered off and purified by flash chromatography to yield 18.1 mg (0.03 mmol, 17.6%) of the analytically pure target compound.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[Ca+2].C(#N)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:32]=[C:33]([Cl:36])[C:34]=1[OH:35])[C:16]([N:19]1[CH2:23][C:22]([CH3:24])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:31])([CH3:18])[CH3:17]>O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:32]=[C:33]([Cl:36])[C:34]=1[O:35][CH2:1][CH3:2])[C:16]([N:19]1[CH2:23][C:22]([CH3:24])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:31])([CH3:18])[CH3:17]
Reactant: CCI
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)c(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Product: CCOc1c(Cl)cc(C(C)(C)N2CC(C)=C(c3ccccc3)C2=O)cc1Cl
Yield: 90.7 %

Procedure:
0.6 g (0.004 mol) of ethyl iodide and 0.6 g (0.004 mol) of anhydrous calcium carbonate were added to an acetonitrile solution of 1.2 g (0.003 mol) of 1-(3,5-dichloro-4-hydroxy-α,α-dimethylbenzyl)-4-methyl-3-phenyl-3-pyrrolin-2-one prepared in Example 11, and the mixture was refluxed for about 30 minutes under stirring. After completion of the reaction, the reaction mixture was poured into a large amount of water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The solid thereby obtained was washed with isopropyl ether to obtain 1.1 g (yield: 91.6%) of the desired compound as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 37 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 39.1) and 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester. UPLC-MS (Condition 3) tR=0.87 min, m/z=434.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 2.59-2.68 (m, 1H) 3.47 (d, J=6.02 Hz, 2H) 3.53-3.61 (m, 2H) 3.77-3.87 (m, 2H) 6.45 (d, J=1.88 Hz, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.79 (br. s, 1H) 7.86 (d, J=9.03 Hz, 2H) 8.10 (s, 1H) 8.69 (d, J=1.69 Hz, 1H) 10.28 (s, 1H).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22]([Cl:24])Cl>>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][C:4]2[CH:11]=[CH:12][C:22]([Cl:24])=[CH:6][CH:5]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: ClCCl
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc(Cl)cc2)C1

Procedure:
A similar procedure starting with 3-(S)-(-)-(1-carbamoyl1,1-diphenylmethyl)pyrrolidine (0.64 g--see Preparation 10B) gave 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-l-(4-chlorophenethyl)pyrrolidine, yield 0.2 g, [α]25D -7.4° (c 1.0, CH2Cl2).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH3:47][C:48]1([CH3:57])[C@H:53]2[CH2:54][C@@H:49]1[CH2:50][CH2:51][C@H:52]2[CH2:55][OH:56]>>[Cl:17][C:18]1[C:19]([O:56][CH2:55][C@@H:52]2[CH2:51][CH2:50][C@H:49]3[CH2:54][C@@H:53]2[C:48]3([CH3:57])[CH3:47])=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with ((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]-heptan-2-yl)methanol, the title compound was obtained as a colorless solid (0.12 g, 29%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.72 (d, J=6.1 Hz, 1H), 7.26 (d, J=13.2 Hz, 1H), 4.12-4.05 (m, 2H), 2.87 (s, 6H), 2.38-2.37 (m, 1H), 2.13-1.90 (m, 6H), 1.56 (m, 1H), 1.18 (s, 3H), 1.00-0.92 (m, 4H); MS (ES−) m/z 431.1, 433.1 (M−1).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:38]=[CH:37][C:23]2/[C:24](=[C:33](/[CH3:36])\[C:34]#[N:35])/[C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[O:27][CH2:28][C:22]=2[CH:21]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:38]=[CH:37][C:23]3/[C:24](=[C:33](/[CH3:36])\[C:34]#[N:35])/[C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[O:27][CH2:28][C:22]=3[CH:21]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CCl)cc2COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
[step 1] 2-Ethylbenzimidazole (163 mg, 1.12 mmol) was dissolved in DMF (5.0 mL), potassium carbonate (0.700 g, 5.07 mmol) was added, and the mixture was stirred for 15 min. To this mixture was added (E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and the mixture was stirred at 60° C. for 3 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/5) to give (E)-2-[8-(2-ethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (318 mg, 70%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=O)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl-].[NH4+].C[N:20](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH2:20])[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.4 %

Procedure:
In a round-bottomed flask, (1R,3R)—N-Boc-1-aminocyclopentane-3-carboxylic acid (300 mg, 1.31 mmol) and ammonium chloride (210 mg, 3.93 mmol) were suspended in DMF (6 ml). HATU (547 mg, 1.44 mmol) and N,N-diisopropylethylamine (0.80 ml, 4.58 mmol) were added and the yellow suspension was stirred at room temperature for 72 h. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 97 mg (33%) of ((1R,3R)-3-carbamoyl-cyclopentyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8]>[Fe].O>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]=[C:6]([CH3:5])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccccc1N
Reaction time: 1 h

Procedure:
Into 160 ml of acetic acid, 10 g (42.5 mmol) of (E) ethyl 2-methyl-3-(2-nitrophenyl)-2-propenate were dissolved. While the solution was stirred, 10.9 g (195.2 mmol) of iron powder (Koso Chem. Co.) and 12 ml of distilled water were added thereto at room temperature; and temperature was raised, so that reflux was carried out for 1 hour at 100° C. After the end point of the reaction was verified by TLC, the reaction liquid was cooled, and acetic acid was evaporated under a reduced pressure. Ethyl acetate was added to the residue, and insoluble matters were filtered out. With water being added thereto, the filtrate was fractionated. The resulting organic layer was successively washed with water and a saturated aqueous sodium hydrogencarbon ate solution, and then was dried for one night with sodium sulfate being added thereto. After sodium sulfate anhydride was filtered out, the filtrate was concentrated under a reduced pressure; and the resulting oily product was refined by a silica gel column chromatography (silica gel; developing solvent: ethyl acetate/hexane=1/3), whereby 6.4 g of the aimed compound were obtained as an oily product (yield: 71.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:16](Br)([CH3:18])[CH3:17]>>[CH:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])([CH3:18])[CH3:17]
Reactant: CC(C)Br
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(C(C)C)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=240.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and isopropylbromide.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]3)[C:12]2=O)=[CH:8][CH:7]=1.[CH3:23][C:24]([S:27]([NH2:29])=[O:28])([CH3:26])[CH3:25].O>CC1CCCO1.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9](=[CH:8][CH:7]=1)[CH2:10][C:11]1([CH2:16][CH2:17][CH:18]([O:21][CH3:22])[CH2:19][CH2:20]1)[C:12]2=[N:29][S:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28]
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=NS(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
6′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 65, 611 mg, 1.99 mmol) and 2-methylpropane-2-sulfinamide (435 mg, 3.59 mmol) were dissolved in 2-methyl-tetrahydrofuran (40 mL). Titanium(IV) ethoxide (0.84 mL, 3.99 mmol) was added and the resulting mixture was heated to 80° C. over a weekend. The reaction mixture was cooled to r.t. and diluted with EtOAc (85 mL). Water (3 mL) was added under vigorous stirring and then the mixture was allowed to stand for 1 h. The mixture was filtered, the solvent was evaporated, and the residue was purified by flash chromatography using a gradient of EtOAc (0-70%) in heptane to give 244 mg (30% yield) of the title compound: MS (ES+) m/z 410 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH:30]1([NH:33][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C22H18ClN5O2, 419.9
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[N:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[N:13]=[C:12]([CH3:19])[C:11]=2/[C:10](=[N:25]/[NH:24][C:21]([NH2:23])=[NH:22])/[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1nc(C)c2c(n1)CC(c1ccccc1Cl)CC2=O
Agent: Cl
Solvent: CCO
Product: Cc1nc(C)c2c(n1)CC(c1ccccc1Cl)C/C2=N\NC(=N)N
Temperature: 90 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinazolin-5-one (0.20 g) and aminoguanidine hydrochloride (77 mg) were added ethanol (14 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 3 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-7-(2-chlorophenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinazoline hydrochloride (Compound 90) (0.14 g).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:15]3=[CH:16][N:17]=[CH:18][C:19]([Br:20])=[C:14]3[CH:13]=2)=[O:11])[CH2:4][O:3]1>ClCCl>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])[C:15]2=[CH:16][N:17]=[CH:18][C:19]([Br:20])=[C:14]2[CH:13]=1)=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc3c(Br)cncc3n2Cc2ccc(I)cc2F)O1
Solvent: ClCCl
Product: O=C(NOC[C@H](O)CO)c1cc2c(Br)cncc2n1Cc1ccc(I)cc1F
Yield: 13.4 %

Procedure:
A solution of 4-bromo-1-(2-fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (40 mg, 66 μmol) in dichloromethane (1.5 ml) was loaded onto a SCX-2 SPE cartridge. The desired compound was eluted from the cartridge with a solution of ammonia in methanol to afford a residue. The residue was further purified by flash chromatography (Si-SPE, ethyl acetate, dichloromethane:methanol 90:10 to 80:20) afforded the title compound as a pale yellow gum (5 mg, 13%). LCMS (Method A): RT=3.51 min, (M−H)−=562, 564, M+H+=564, 566. 1H NMR (CD3OD): 3.62 (2H, m), 3.89 (1H, m), 3.94 (1H, dd, J=10.2, 6.4 Hz), 4.05 (1H, dd, J=10.2, 3.7 Hz), 5.92 (2H, s), 6.63 (1H, t, J=8.0 Hz), 7.04 (1H, s), 7.40 (1H, dd, J=8.0, 1.6 Hz), 7.49 (1H, dd, J=9.7, 1.6 Hz), 8.29 (1H, s), 8.79 (1H, s).
Reaction SMILES: [C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[N:16]1[C:20]([CH2:21]Cl)=[N:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:17]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)C[N:29]1C3>C(O)C>[CH3:14][C:13]1[C:9]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:29][CH2:21][C:20]3[N:16]([N:17]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=3)[C:10]=2[S:11][C:12]=1[CH3:15]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CCOC(=O)c1nc(CCl)n(-c2sc(C)c(C)c2C(=O)c2ccccc2)n1
Solvent: CCO
Product: CCOC(=O)c1nc2n(n1)-c1sc(C)c(C)c1C(c1ccccc1)=NC2

Procedure:
A mixture of ethyl 1-(3-benzoyl-4,5-dimethyl-2-thienyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate, hexamethylenetetramine and ethanol is refluxed for 4 hours in the same manner as in a) to give ethyl 7,8-dimethyl-6-phenyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxylate as colorless plates melting at 173° to 174° C.