Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[CH2:34]([O:36][C:37](=[O:40])[C:38]#[N:39])[CH3:35]>O=P(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:39]=[C:38]([C:37]([O:36][CH2:34][CH3:35])=[O:40])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: O=C(CCN1C(=O)c2ccccc2C1=O)Nc1ccccc1
Reactant: CCOC(=O)C#N
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(CCN2C(=O)c3ccccc3C2=O)nc2ccccc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-phenylpropanamide (40 g, 135.91 mmol, 1.00 equiv) in POCl3 (300 mL). This was followed by the addition of PCl5 (30 g, 144.06 mmol, 1.06 equiv). The mixture was stirred for 2 h at 65° C. The resulting mixture was concentrated under vacuum. The residue was poured into chlorobenzene (500 mL). To this was added SnCl4 (53 g) and 2-ethoxy-2-oxoacetonitrile (26 g, 262.39 mmol, 1.93 equiv) dropwise with stirring. The resulting solution was stirred for 2 h at 120° C. in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 7.0 g (14%) of ethyl 2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]quinazoline-4-carboxylate as a white solid. MS (ESI) m/z 376 ([M+H]+).
Reaction SMILES: C(O)=O.C([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1
Reactant: C#CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: C1CCOC1
Product: C#CCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 60 °C
Yield: 7.2 %

Procedure:
50% Formic acid (41 ml.) was added to a solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 8.2 g.) and tetrahydrofuran (41 ml.), and stirred at 60° C. for an hour. The resultant solution was concentrated to a half of initial volume under reduced pressure, and the precipitates were collected by filtration and washed with diisopropyl ether. The filtrate and washing solution were combined together and concentrated in vacuo. The residue was added to ethyl acetate (200 ml.) under stirring. The insoluble substance was collected by filtration, and washed with diethyl ether to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 0.3 g.). The filtrate and ethyl acetate washing solution were combined together, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride twice in turn, and dried over magnesium sulfate. The solution was treated with activated charcoal and concentrated in vacuo. The residue was dried in vacuo after adding benzene. The residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn. The eluate was concentrated in vacuo, and the residue was triturated with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether to give the same compound as mentioned above (syn isomer, 2.658 g.). The I.R. spectrum and N.M.R. spectrum are the same as those of the compound obtained in Example I-(3).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].C(N(CC)CC)C>O1CCCC1>[CH2:38]([O:37][C:35]([CH2:34][N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=2)[C@H:9]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (1.5 g), benzyl 2-bromoacetate (0.79 g), triethylamine (0.55 ml) and tetrahydrofuran (15 ml) was stirred overnight at room temperature. The resulting insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (30:1) to give (2R)-4-(benzyloxycarbonylmethyl)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (1.92 g).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4]/[N:5]=[CH:6]\[C:7]1[S:11][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:9][CH:8]=1.[SH:27][C@@H:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29](O)=[O:30]>C1(C)C=CC=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[S:11][C:7]([CH:6]3[N:5]([CH2:4][CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1])[C:29](=[O:30])[C@H:28]([CH2:32][C:33]([OH:35])=[O:34])[S:27]3)=[CH:8][N:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)C[C@H](S)C(=O)O
Reactant: CC(C)(C)CC/N=C\c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 110 °C
Yield: 100.3 %

Procedure:
A mixture of (Z)-tert-butyl 4-(5-((3,3-dimethylbutylimino)methyl)thiazol-2-yl)piperidine-1-carboxylate (290 mg, 0.76 mmol, 1 eq) and (S)-2-mercaptosuccinic acid (138 mg, 0.92 mmol, 1.2 eq) in toluene (20 mL) was heated at 110° C. for 18 hr. The excess solvent was concentrated in vacuo and the solids were collected by filtration. The solids were washed with water, toluene and dried to give 2-((5S)-2-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazol-5-yl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (390 mg, 90% yield). (M+1) 512. 1H NMR (CDCl3) δ 7.15 (m, 1H), 5.68 (m, 1H), 4.58-4.11 (m, 3H), 3.62 (m, 1H), 3.39-3.09 (m, 2H), 2.93-2.74 (m, 3H), 2.09 (m, 2H), 1.71-1.64 (m, 2H), 1.47 (s, 9H), 1.44 (m, 1H), 0.85 (s, 9H) ppm.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl-].[Li+].COP([CH:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:21]([O:23][CH3:24])=[O:22])(OC)=O.[F:33][C:34]([F:76])([F:75])[C:35]1[CH:36]=[C:37]([C@H:45]([N:47]([CH3:74])[C:48]([N:50]2[CH2:55][CH2:54][C@@:53]([NH:59][S:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])([CH2:56][CH:57]=O)[CH2:52][C@@H:51]2[C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=2[CH3:73])=[O:49])[CH3:46])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])=[CH:57][CH2:56][C@:53]1([NH:59][S:60]([C:62]([CH3:64])([CH3:63])[CH3:65])=[O:61])[CH2:54][CH2:55][N:50]([C:48]([N:47]([C@@H:45]([C:37]2[CH:36]=[C:35]([C:34]([F:33])([F:75])[F:76])[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=2)[CH3:46])[CH3:74])=[O:49])[C@@H:51]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=2[CH3:73])[CH2:52]1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@](CC=O)(NS(=O)C(C)(C)C)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)P(=O)(OC)OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(=CC[C@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 7 h
Yield: 37.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.12 mL, 0.80 mmol, Aldrich) was added dropwise to a suspension of Lithium chloride (35.9 mg, 0.847 mmol, Aldrich) and Methyl [bis(methyloxy)phosphoryl]{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}acetate (Tetrahedron Lett. 1981, 22, 663-666) (265 mg, 0.847 mmol) in dry Acetonitrile (16 mL) and the mixture was maintained at 0° C. for 1 h. A solution of (2R,4S)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-(2-oxoethyl)-1-piperidinecarboxamide (Intermediate 9, 378 mg, 0.58 mmol) in Acetonitrile (5 mL) was added dropwise at 0° C. The mixture was stirred for 7 hours while the temperature was allowed to increase to 25° C. Saturated aqueous NaHCO3 and EtOAc were added to the reaction mixture and the two phases were separated. The combined organic phases were dried (Na2SO4) and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the title compound (186 mg, 0.22 mmol, 38% yield) as a white foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (m, 1H) 7.68 (s, 2H) 7.12-7.20 (m, 1H) 6.92 (d, 1H) 6.79 (t, 1H) 5.66 (t, 1H) 5.26-5.35 (m, 1H) 5.00 (s, 1H) 4.33 (d, 1H) 3.71 (s, 3H) 2.70 (s, 3H) 2.60-3.4 (m, 4H) 2.27 (s, 3H) 1.48 (d, 3H) 1.35-2.10 (m, 4H) 1.05-1.13 (m, 9H) 0.84-0.98 (m, 9H) 0.06 (s, 6H). The sample consists of two species ratio ˜3:1 most probably E and Z isomers (see the signals of OMe at 3.71 ppm). UPLC: 2 close peaks Rt 0.86 and 0.89 mins, m/z=838 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:21]>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:21][C:12]1[CH:13]=[C:14]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: COc1ccc(CC(=O)O)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC(=O)O)cc1CBr
Yield: 96.2 %

Procedure:
N-Bromosuccinimide (1.0 g) and 2,2′-azobis(2-methylpropionitrile) (20 mg) were added to a solution of (4-methoxy-3-methyl-phenyl)-acetic acid (1.1 g) in chloroform (25 mL) and heated to reflux for 4 hours. On cooling, the mixture was evaporated, the residue dissolved in ethyl acetate, washed sequentially with 2M aqueous hydrochloric acid (2×50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated to give the subtitle compound as an oil (1.4 g).
Reaction SMILES: CN(C([C@@H]1C[C@@H](SCC2C=CC(OC)=CC=2)CN1S(C1C=CC2C(=CC=CC=2)C=1)(=O)=O)=O)NS(C1C=CC(C)=CC=1)(=O)=O.[CH3:44][N:45]([C:64]([C@@H:66]1[CH2:70][C@@H:69]([S:71]CC2C=CC(OC)=CC=2)[CH2:68][N:67]1[S:81]([C:84]1[CH:93]=[CH:92][C:91]2[C:86](=[CH:87][CH:88]=[CH:89][CH:90]=2)[CH:85]=1)(=[O:83])=[O:82])=[O:65])[N:46]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[S:47]([C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1)(=[O:49])=[O:48].C(Br)C1C=CC=CC=1>>[CH3:44][N:45]([C:64]([C@@H:66]1[CH2:70][C@@H:69]([SH:71])[CH2:68][N:67]1[S:81]([C:84]1[CH:93]=[CH:92][C:91]2[C:86](=[CH:87][CH:88]=[CH:89][CH:90]=2)[CH:85]=1)(=[O:82])=[O:83])=[O:65])[N:46]([CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[S:47]([C:50]1[CH:51]=[CH:52][C:53]([CH3:56])=[CH:54][CH:55]=1)(=[O:49])=[O:48]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)N(Cc3ccccc3)S(=O)(=O)c3ccc(C)cc3)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Agent: BrCc1ccccc1
Agent: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)NS(=O)(=O)c3ccc(C)cc3)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Product: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N(C)C(=O)[C@@H]2C[C@@H](S)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1

Procedure:
(step 25,26) According to procedure (Scheme 4, step 16) was prepared from (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N-methyl-N′-(4-methyl-benzenesulfonyl)-hydrazide and benzyl bromide (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N-methyl-N′-benzyl-N′-(4-methyl-benzenesulfonyl)-hydrazide which was directly deprotected according to Scheme 2 (step 4) to give (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N-methyl-N′-benzyl-N′-(4-methyl-benzenesulfonyl)-hydrazide as white solid, mp 82.5° C., MS: 610 (MH+).
Reaction SMILES: Br[C:2](Cl)(Cl)[C:3]([Br:6])(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C@H](O)C)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.CCCCCC>C1(C)C=CC=CC=1>[Br:6][C@H:3]([C:32]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([C:29]([F:28])([F:44])[F:43])[CH:31]=1)[CH3:2]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C[C@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), the solution was added with triphenylphosphine (6.1 g, 23.2 mmol) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was added dropwise with a solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (5.0 g, 19.4 mmol, >99.5% ee) in toluene (12.5 mL) at 0° C. over 10 minutes or more, and then the mixture was warmed to room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was added with n-hexane (25 mL), and the mixture was filtered through Celite. The filtrate was washed successively with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was distilled under reduced pressure (56° C., 0.7 mmHg) to obtain 5.45 g of (S)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][NH:5][CH:6]1[CH2:23][CH:22]([OH:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:32])[C:11]4[CH:12]=[CH:13][CH:14](CC)[C:15]5(OCCO5)[C:16]=4[C:17]3=[O:25])=[C:8]([OH:33])[C:7]1=2.Cl.[CH3:36][C:37](C)=[O:38]>>[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH:6]1[CH2:23][C:22]([C:37](=[O:38])[CH3:36])([OH:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:32])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:25])=[C:8]([OH:33])[C:7]1=2
Reactant: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(NCCN(C)C)CC(O)C4)C12OCCO2
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)C1(O)Cc2cc3c(c(O)c2C(NCCN(C)C)C1)C(=O)c1ccccc1C3=O

Procedure:
7-(2-Dimethylaminoethyl)amino-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (60 mg) prepared in Example 13 (2) was added to a mixture of acetone (60 ml) and conc. hydrochloric acid (24 ml), and the resultant mixture was heated under reflux for 1 hour. After removal of acetone by distillation under reduced pressure, the water layer was washed with dichloromethane, adjusted to pH 8.0 with aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was purified by silica gel chromatography using a mixture of chloroform and methanol (9:1) to give 7-(2-dimethylaminoethyl)amino-9-acetyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (55 mg). M.P., 170°-172° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][O:7][C:8](=[O:19])[CH2:9][CH2:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O.C1COCC1.CCOCC>[CH3:3][CH:4]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][O:7][C:8](=[O:19])[CH2:9][CH2:10][CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(=O)CCC(=O)OCCC(C)CCC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(O)CCC(=O)OCCC(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.0 g sodium borohydride in 30 ml of water was cooled to 5° C. A solution of 4-oxo-decanoic acid 3,7-dimethyl-oct-6-enyl ester in 75 ml of THF was added to the reaction during 12 minutes and the resulting reaction mixture was stirred at room temperature for 5 hours. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3, brine and water. The organic phase was dried, filtered and evaporated to dryness. The resulting liquid was purified by chromatography to yield 7.6 g of a liquid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.C(Cl)Cl.[CH2:10]([O:12][C:13]([C:15]1[NH:16][C:17]2[C:22](C=1)=[CH:21][C:20]([Br:24])=[CH:19][CH:18]=2)=[O:14])[CH3:11].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:10]([O:12][C:13]([C:15]1[NH:16][C:17]2[C:18]([C:2]=1[CH:1]=[O:5])=[CH:19][C:20]([Br:24])=[CH:21][CH:22]=2)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (3.43 mL, 39.9 mmol) was added with stirring to DMF (30 mL) and CH2Cl2 (80 mL) at 0° C. After 20 min at 0° C., 5-bromoindole-2-carboxylic acid ethyl ester (10 g, 37.3 mmol) in DMF (80 mL), was added. The mixture was stirred at rt for 24 h and poured into NaHCO3 (aq, sat) and extracted with CH2Cl2. The combined extracts were washed with H2O and brine, dried (Na2SO4) and concentrated. Crystallisation from EtOH gave the sub-title compound. Yield 8.9 g (81%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[N:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20]([C:17]3[CH:16]=[N:15][C:14]([CH3:13])=[CH:19][N:18]=3)=[O:21])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cn1
Yield: 61.5 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (300 mg, 1.30 mmol, Example 1, Step H), 5-methylpyrazine-2-carboxylic acid (378 mg, 2.74 mmol), BOP—Cl (697 mg, 2.74 mmol), and triethylamine (0.909 mL, 6.52 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamide (280 mg, 61% yield).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19].[NH2:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[N:46]1([NH-:52])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl>[NH:16]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:17]([C:21]([NH:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:23])[CH:18]([CH3:19])[CH3:20].[N:46]1([NH-:52])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH-]N1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.75 g of DCC are added to a solution of 2.14 g of Z-(L)-Val-OH in 80 ml of absolute ice-cooled methylene chloride and after stirring for 20 minutes at that temperature a solution of 2 g of H-(L)-Phe-morpholin-4-ylamide is added dropwise thereto over a period of 15 minutes. The reaction mixture is stirred for a further 24 hours at room temperature and the urea that forms is filtered off. The filtrate is washed in succession with aqueous sodium hydrogen carbonate solution and brine and, after drying over sodium sulfate, concentrated. Stirring with ether and removal of the insoluble residue by filtration yields, after concentration, the title compound which is processed further without additional purification. TLC Rf (D )=0.7.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6](OCC)[C:7]2[C:8](=[CH:10][S:11][CH:12]=2)[N:9]=1)[CH3:2].[CH2:16]([NH2:19])[CH2:17][CH3:18]>C(O)C>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([NH:19][CH2:16][CH2:17][CH3:18])[C:7]2[C:8](=[CH:10][S:11][CH:12]=2)[N:9]=1)[CH3:2]
Reactant: CCCN
Reactant: CCOc1nc(OCC)c2cscc2n1
Solvent: CCO
Product: CCCNc1nc(OCC)nc2cscc12

Procedure:
A solution of 2.3 g (0.01 mole) of 2,4-diethoxy-thieno[3,4-d]pyrimidine and 3.6 g (0.06 mole) of n-propylamine in 50 ml absolute ethyl alcohol is heated under reflux for 10 hours. The solution is then evaporated to dryness. The solid is drained off, washed with water and dried. After recrystallization from toluene, 14 g (59% of theory) of 2-ethoxy-4-n-propylamino-thieno[3,4-d]pyrimidine are obtained. M.P. 140°-142°C.
Reaction SMILES: C1(C[O:5]C2C=C(C=CC=2O)C=O)CC1.ClC(F)F.[OH-].[Na+].[CH:21]1([CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[O:34][CH:35]([F:37])[F:36])[CH:29]=[O:30])[CH2:23][CH2:22]1.Cl([O-])=O.[Na+].S(=O)(=O)(O)N>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH:21]1([CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[O:34][CH:35]([F:36])[F:37])[C:29]([OH:5])=[O:30])[CH2:23][CH2:22]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=Cc1ccc(O)c(OCC2CC2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: FC(F)Cl
Agent: NS(=O)(=O)O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
In WO9501338 the reaction of 3-(cyclopropylmethoxy)-4-hydroxy-benzaldehyde with chlorodifluoromethane in the presence of sodium hydroxide and benzyl-trimethylammonium chloride (BTMA) in dioxane/water leads to 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde, which by oxidation with sodium chlorite and sulphamic acid yields 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid. Chlorination of this acid with thionyl chloride in reflux toluene provides the corresponding acyl chloride, which is finally condensed with 3,5-dichloropyridine-4-amine in the presence of sodium hydride in tetrahydrofuran to thus reach roflumilast (I). These procedures are set out in Scheme 1.
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C@H:27]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=4)[C@@H:28]([NH2:30])[CH3:29])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.N>C1COCC1.CO.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C@H:27]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=4)[C@@H:28]([NH:30][C:5](=[O:4])[CH2:6][OH:7])[CH3:29])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2ccccc2c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)CO)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
Acetoxyacetyl chloride (13 μL, 0.12 mmol) was added to a stirred mixture of (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(naphthalen-2-yl)propan-2-amine hydrochloride (20a) (50 mg, 0.11 mmol) and N,N-diisopropylethylamine (60 μL, 0.34 mmol) in THF (2 mL). The reaction mixture was stirred at r.t. 45 min. Water (0.5 mL), 28% (aq) NH3 (0.5 mL) and MeOH (0.5 mL) was added to give a clear one-phase solution, the mixture was stirred over night at r.t.