Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:18][CH3:19])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16])=O.CC1(C)C2C(=C(OC)C=C(C)C=2)C(C)(C)CC1.C(O)(=O)C.P(=O)(O)(O)O.[ClH:46].C=O>C1C=CC=CC=1>[Cl:46][CH2:1][C:3]1[C:4]([O:18][CH3:19])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16]
Reactant: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Reactant: Cl
Agent: C=O
Agent: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1c(CCl)c(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 95 °C

Procedure:
To prepare the corresponding 6-carboxaldehyde, 6-formyl-1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene, 1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (23.2 g, 0.1 mol) is added to a stirred solution of acetic acid (18.2 g, 0.3 mol), 85% phosphoric acid (17.6 g, 0.15 mol), hydrochloric acid (28.7 g, 0.3 mol) and paraformaldehyde (7.3 g, 0.24 mol). The mixture is stirred and heated at 95° C. for 16 hr. The reaction mixture is then cooled to 25° C., benzene (50 ml) added, and stirred vigorously. The organic layer is separated, washed with water (2×25 ml), neutralized with 5% sodium bicarbonate solution, and dried (Na2SO4). The solvent is removed by distillation to provide 6-chloromethyl-1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(N(C(C)C)CC)(C)C.[NH2:55][CH:56]([CH2:59][OH:60])[CH2:57][OH:58]>C(O)(C)C>[OH:44][C@H:43]([CH2:45][NH:55][CH:56]([CH2:59][OH:60])[CH2:57][OH:58])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(CO)CO
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CNC(CO)CO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.6 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and serinol (0.1 mL, 1.09 mmol) was microwaved at 130° C. for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(2-hydroxy-1-hydroxymethyl-ethylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide (14.2 mg, 28.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C36H46Cl2F2N6O5S+H [(M+H)+]: 751.2948. found: 751.2943.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:21]4[N:20]=[N:19][CH:24]=[CH:23][CH:22]=4)=[CH:30][N:29]=3)=[O:18])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(CC(=O)O)cnc1-c1ccnc(F)c1
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)cnc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the mixture of 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetic acid 193-2 (25 mg, 0.1 mmol) and 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (17 mg, 0.1 mmol) in DCM (1 mL) was added N,N′-Diisopropylcarbodiimide (22 μL, 0.15 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DMSO and then purified by reverse-phase HPLC to give 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 221 as white solid. MS m/z 401.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.09 (s, 1H), 9.17 (dd, 1H), 9.07 (d, 1H), 8.51 (dd, 1H), 8.46 (d, 1H), 8.28 (d, 1H), 8.25 (dd, 1H), 8.18 (d, 1H), 7.76 (m, 1H), 7.71 (d, 1H), 7.51 (m, 1H), 7.31 (s, 1H), 3.83 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(N(CC)CC)C>[C:14]([O:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC1C(=O)C=CC1(C)O
Solvent: CCN(CC)CC
Product: CCCCCC1C(=O)C=CC1(C)OC(C)=O

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g), triethylamine (0.1 g) and acetic anhydride (36 g) were charged, and the resultant mixture was stirred at 60°-80° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 11, followed by purification to give 21.9 g of dl-3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone. Yield, 98%. B.P., 100°-110° C./0.1-0.3 mmHg.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[N:3]=1.[CH2:32]([Sn](CCCC)(CCCC)C=C)[CH2:33]CC.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[O:29]1[CH2:30][CH2:31][N:26]([C:22]2[CH:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:4]5[CH:5]=[N:6][C:2]([CH:32]=[CH2:33])=[N:3]5)=[CH:8][CH:9]=4)[N:19]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ncn(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=Cc1ncn(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Temperature: 120 °C

Procedure:
A mixture of N-(4-(3-bromo-1H-1,2,4-triazol-1-yl)phenyl)-4-(3-morpholinophenyl)pyrimidin-2-amine (0.024 g, 0.05 mmol), tributyl(vinyl)stannane (0.032 g, 0.10 mmol), Pd(PPh3)4 (0.012 g, 0.01 mmol), toluene (0.4 mL) and DMF (0.1 mL) was heated in a sealed tube at 120° C. with microwave irradiation for 1 h. The reaction mixture was cooled down to room temperature. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided the desired product as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.43 (d, 1H), 8.36 (s, 1H), 7.80 (d, 2H), 7.59 (d, 2H), 7.37 (m, 4H), 7.14 (d, 1H), 7.01 (dd, 1H), 6.75 (dd, 1H), 6.27 (d, 1H), 5.51 (d, 1H), 3.84 (m, 4H), 3.20 (m, 4H). MS (ESI) 426.29 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([N+:41]([O-])=O)[C:38]([NH2:44])=[C:37]([CH3:45])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1.[H][H]>C1COCC1.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:36]=[C:37]([CH3:45])[C:38]([NH2:44])=[C:39]([NH2:41])[CH:40]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N

Procedure:
260 mg (0.37 mmol) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 25 mL THF and combined with 130 mg 10% Pd/C. The mixture was hydrogenated for 4.5 h in a Parr apparatus at 50° C. under 50 psi hydrogen pressure. Then the catalyst was filtered off, the filtrate was evaporated down i.vac., the residue was dissolved in a little DCM, combined with diethyl ether, the precipitate was suction filtered and dried.
Reaction SMILES: [Cr+6:1].N([O-])=O.[Cr+3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8]>>[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8].[Cr+3:1].[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8].[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8]
Reactant: CCC(=O)O
Reactant: [Cr+6]
Agent: [Cr+3]
Agent: O=N[O-]
Product: CCC(=O)[O-]

Procedure:
adding to said solution of chromium(VI) source in aqueous propionic acid, a nitrite source selected from alkali metal and ammonium nitrites, employing sufficient nitrite source to effectively reduce said chromium(VI) source to chromium(III) and allowing sufficient time at sufficient temperature to produce a clear green solution of stabilized chromium(III) propionate; and
Reaction SMILES: CN1CCOCC1.Cl[S:9]([C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[C:13]=1[N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=[O:11])=[O:10].Cl.[CH:41]1([CH2:45][NH2:46])[CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[NH2:25][C:13]1[C:14](=[O:24])[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:17][C:12]=1[S:9](=[O:10])(=[O:11])[NH:46][CH2:45][CH:41]1[CH2:44][CH2:43][CH2:42]1
Reactant: NCC1CCC1
Reactant: CCOC(=O)Cn1ccc(S(=O)(=O)Cl)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)Cn1ccc(S(=O)(=O)NCC2CCC2)c(N)c1=O
Temperature: 25 °C

Procedure:
NMM (1.43 mL, 13.0 mmol) was added to a stirred mixture of 4-chlorosulfonyl-3-(N,N-di-t-butoxycarbonylamino)-1-ethyloxycarbonylmethyl-2-pyridinone (as a mixture from Step H, 0.84 g) and cyclobutylmethylamine hydrochloride (348 mg, 2.86 mmol) in methylene chloride (15 mL). After 16 h the reaction was diluted with methylene chloride and washed with 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica (40% ethyl acetate/hexanes). HCl gas was bubbled through a stirred solution of the resulting compound in ethyl acetate (10 mL) at 0° C. for 15 min. The reaction was warmed to rt and after a further 3 h it was evaporated to give the title compound as a solid;
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:10][CH2:9][C@@H:8]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (S)-3-cyclohexyl-1-hydroxypropan-2-ylcarbamate (3.02 g, 11.7 mmole) in CH2Cl2 (50 mL) and triethylamine (4.0 mL, 28.6 mmol) was cooled to −20° C. (internal temperature). Neat methanesulfonyl chloride (2.0 mL, 25.7 mmol) was added dropwise, maintaining the internal temperature at −20° C. (+/−5° C.). The reaction mixture was stirred at −20° C. for an additional 30 min and at 0° C. for 1 h. Reaction progress was followed by TLC and LC-MS. The reaction was quenched with ice-cold water, extracted with CH2Cl2 (3×20 mL), washed with water (3×10 mL), dried (Na2SO4), decanted, and stripped to give 4.13 g (quant) of product. 1H NMR (CDCl3) δ 0.80-1.40 (10H), 1.40 (s, 9H), 1.65 (t, 2H), 1.75 (d, 1H), 2.95 (s, 3H), 3.94 (m, 1H), 4.10 (m, 1H), 4.24 (m, 1H), 4.60 (m, 1H). MS ESI +ve m/z 236 (M(−BOC)+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccccc23)CC1
Temperature: 107.5 °C
Yield: 66 %

Procedure:
1-Chloro-isoquinoline (176 mg, 1.07 mmol), piperazine-1-carboxylic acid tert-butyl ester (420 mg, 2.26 mmol) and DBU (0.25 mL, 1.61 mmol) were added into DMP (2 mL). The mixture was heated to 105-110° C. for overnight. The residue was diluted with water and extracted with ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to dryness. The resulting residue was purified by column chromatography (5% to 10% ethyl acetate/hexane) to give 222 mg of the desired product 4-isoquinolin-1-yl-piperazine-1-carboxylic acid tert-butyl ester (yield: 66%).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:15]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: COC(=O)C1CCCCN1
Product: COC(=O)C1CCCCN1CCC(=O)c1ccc(F)cc1
Yield: 92 %

Procedure:
N-[3-(4-Fluorophenyl)-3-oxopropyl]pipecolic acid methyl ester was prepared in 92% yield by alkylation of methyl pipecolinate with 3chloro-4′-fluoropropiophenone (Aldrich) as described in Example 20A (Step 1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16]1=[CH:22][C:23]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])=[N:24][C:25](=[O:26])[N:15]1[CH2:14][CH2:13]2.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16]1=[CH:22][C:23]([N:27]([C:37](=[O:39])[CH3:38])[C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])=[N:24][C:25](=[O:26])[N:15]1[CH2:14][CH2:13]2
Reactant: COc1cc2c(cc1OC)-c1cc(Nc3c(C)cc(C)cc3C)nc(=O)n1CC2
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)-c1cc(N(C(C)=O)c3c(C)cc(C)cc3C)nc(=O)n1CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 ml of triethylamine are added first to an ice-cold solution of 9,10-dimethoxy-2-(2,4,6-trimethyl-anilino)-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one (1.6 g) in chloroform (40.0 ml), and then a solution of acetyl chloride (0.64 ml) in chloroform (10.0 ml) is added dropwise. The mixture is stirred for 2 hours. The chloroform solution is washed successively with water, sodium carbonate solution and water, and is then dried over anhydrous sodium sulfate. The solution is filtered and the filtrate evaporated to dryness in vacuo. The residue is triturated with diethyl ether to yield the desired compound in solid form. Yield 1.6 g, m.p. 210°-212° C. (dichloromethane-petroleum ether b.p. 60°-80° C.).
Reaction SMILES: [N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]([NH2:12])[CH2:3][C:2]=1[NH2:13].CS(C)=O.[CH3:18][N:19]1[CH2:24][CH2:23]N[CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:12]([C:4]2[CH2:3][C:2]([N:13]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[N:1][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: NC1=Nc2ccccc2N=C(N)C1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CCN(C2=Nc3ccccc3N=C(N3CCN(C)CC3)C2)CC1
Temperature: 120 °C
Yield: 74 %

Procedure:
3H-[1,5]Benzodiazepine-2,4-diamine (32.50 g, 160 mmol, 86%) was added to a solution of dimethyl sulfoxide (220 ml), toluene (220 ml) and 1-methylpiperazine (165 ml). The mixture was heated for 16 h at 120° C. After cooling the product precipitated. It was filtered off and washed with isopropyl ether (80 ml) to give 40.1 g (74%) of the title compound as off-white needles. The second crop was obtained by adding isopropyl ether (410 ml) to the filtrate. The mixture was allowed to stand overnight at 4° C., the crystallised product was filtered off to give additional 4.25 g (8%) of the title compound. For analytical purposes the product was recrystallised from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(OC)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(4-methoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[C:6]([F:23])=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15](I)=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:22]=1>CN(C=O)C.[Cu]I>[Br:4][C:5]1[C:6]([F:23])=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:1]#[N:2])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:22]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: [C-]#N
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Temperature: 150 °C

Procedure:
Potassium Cyanide (0.8 eq) and Copper (I) Iodide (0.2 eq) were added to solution of 10-bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.05 g) in DMF (3 ml/mmol). The reaction was heated overnight at 150° C., filtered and purified by reverse phase hplc to give 10-bromo-3-cyano-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 12 mg of 3-cyano-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 355 (M)+. 1H NMR (400 MHz, DMSO) δ 8.69-8.56 (m, 1H), 8.04 (s, 1H), 7.64 (s, 1H), 7.14-7.00 (m, 1H), 5.51 (d, J=10.2 Hz, 1H), 4.63-4.57 (m, 2H), 4.56-4.49 (m, 2H), 1.49 (s, 6H).
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[CH2:5](O)[CH3:6]>>[S:1]([CH2:6][CH2:5][S:1]([OH:4])(=[O:3])=[O:2])([OH:4])(=[O:3])=[O:2]
Reactant: O=S(=O)=O
Reactant: CCO
Product: O=S(=O)(O)CCS(=O)(=O)O

Procedure:
The second method relates to a process for the direct sulfonation of ethanol with gaseous sulfur trioxide. A two stage process is described by Breslow et al (J. Am. Chem. Soc., 1954, Vol 76, pp 5361-5363). First, ethanol is reacted with the first mole of sulfur trioxide at a lower temperature of 0-5° C., then with the second mole of sulfur trioxide at a higher temperature of 50-70° C. Ethionic acid is obtained as a viscous, pale amber liquid. This two stage process is difficult to implement on an industrial scale, since the reaction heat from the exothermic sulfonation is inherently difficult to remove in the first stage at a temperature of 0-5° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[C:9]([Cl:27])=[CH:10][C:11]([F:26])=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])[CH:13]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:27][C:9]1[C:8]([NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:13][C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[NH:16][C:15]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chloroformate (2.58 g) was dropwise added into a solution of 3-(5-amino-4-chloro-2-fluorophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (XLVI) in pyridine (25 ml) at 0° C., and stirred at room temperature for one hr. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid followed by water, and dried over sodium sulfate. After concentration, the crystals (5.46 g) were collected by filtration. 1H NMR (CDCl3, 300 MHz) 1.31 (3H, t, J=7.1 Hz), 4.22 (2H, q, J=7.1 Hz), 6.20 (1H, s), 7.14 (1H, br), 7.29 (1H, d, J=8.8 Hz), 7.36 (1H, d, J=6.0 Hz), 8.26 (1H, bd, J=6.4 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Li])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C1(OC(Cl)=O)C=CC=CC=1.[N].N1C=CC=CC=1>>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:11]=1
Reactant: Clc1ccncc1
Reactant: [Li]c1cccc(Br)c1
Agent: O=C(Cl)Oc1ccccc1
Agent: [N]
Solvent: c1ccncc1
Product: Clc1ccnc(-c2cccc(Br)c2)c1

Procedure:
Starting from 3-bromophenyllithium, 4-chloropyridine and chloroformic acid phenyl ester (for the acylation of the pyridine nitrogen), the title compound is prepared analogously to J. Org. Chem. 50, 4410 (1985). A corresponding 1-acyl-1,2-dihydropyridine is formed as intermediate and is aromatised by reaction with o-chloroanil (=3,4,5,6-tetrachloro-1,2-benzoquinone) to form the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][N:6]([C:8](=[O:16])[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1.[CH3:25][NH2:26]>C(Cl)Cl.CO>[CH3:24][C:2]1([CH3:1])[CH2:7][N:6]([C:8](=[O:16])[CH:9]([NH:26][CH3:25])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1
Reactant: CCOC(=O)C=CC(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CC(NC)C(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 36.6 %

Procedure:
In 3 ml of methylene chloride was dissolved 0.5 g of ethyl 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)-4-oxo-2-butenoate followed by addition of 0.116 g of methylamine in methanol. The mixture was stirred at room temperature for 4 days, at the end of which time the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crude crystals were washed with ethanol-hexane to give 0.2 g of ethyl 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)-3-methylamino-4-oxobutanoate.