Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][NH2:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.C[O:27][C:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:40][N:35]([S:36]([CH3:39])(=[O:38])=[O:37])[C:32]1[CH:31]=[CH:30][C:29]([C:28]([NH:21][CH2:20][CH:9]2[CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:27])=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Reactant: NCC1CN(c2ccccc2)CCN1Cc1ccccc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(c1ccc(C(=O)NCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
To 4-phenyl-1-(phenylmethyl)-2-piperazinemethanamine (6.95 g, 24.7 mmol) in toluene (130 mL) at 0° C. add trimethylaluminum (2.0M in toluene, 16.2 mL, 32.4 mmol). Allow the reaction to warm to room temperature and add 4-[(methyl)(methylsulfonyl)amino]benzoic acid methyl ester (6.91 g, 28.4 mmol). Heat the reaction and monitor the progress by thin-layer chromatography. Upon completion make the solution basic with aqueous NaOH and extract with EtOAc. Remove the solvent in vacuo. Flash chromatograph the residue on silica gel with EtOAc/hexane (2/1) to obtain the title compound.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]1(=[O:13])[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1.Br[CH2:15][C:16]1[C:25]([F:26])=[C:24]2[C:19]([C:20]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23]2)=[CH:18][CH:17]=1>CN(C=O)C>[O:13]=[C:7]1[CH2:8][CH2:9][C:10](=[O:12])[N:11]1[CH2:15][C:16]1[C:25]([F:26])=[C:24]2[C:19]([C:20]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)c(F)c2n1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (1.745 g, 5.35 mmol) was added to a solution of Succinimide (0.292 g, 2.94 mmol) and methyl 7-(bromomethyl)-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-10 (1.05 g, 2.68 mmol) in DMF (13.39 ml) and the reactant stirred at rt for 30 min. The reaction was quenched with KH2PO4 (saturated) and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The solvent was removed in vacuo and the residue purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-100%) to afford Methyl 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-11 as a white solid, LCMS shows the compound is 90% pure, LRMS m/z (M+H)+ 411.2 found, 411.1 required.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][CH:7]([NH:14][CH2:15][C@@H:16]([C:18]1[CH:19]=CC(O)=[C:22]([NH:24][CH:25]=O)[CH:23]=1)[OH:17])[CH2:6]2)[CH3:2].[BH4-].[Na+].C(O[C:34](=O)[CH3:35])(=O)C.O1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([N:14]([CH:7]1[CH2:8][C:9]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[C:11]([CH2:12][CH3:13])[CH:10]=2)[CH2:6]1)[CH2:15][C@@H:16]([C:18]1[CH:19]=[CH:42][C:41]([O:40][CH2:39][C:38]2[CH:35]=[CH:34][CH:8]=[CH:7][CH:6]=2)=[C:22]([NH:24][CH3:25])[CH:23]=1)[OH:17])[C:3]1[CH:4]=[CH:5][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: C1COCCO1
Reactant: CCc1cc2c(cc1CC)CC(NC[C@H](O)c1ccc(O)c(NC=O)c1)C2
Agent: [BH4-]
Agent: [Na+]
Product: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(NC)c1)C2
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The product of Example 22 (260 mg) is dissolved in dioxan (20 mL). Sodium borohydride (90 mg) is added followed by the dropwise addition of acetic anhydride (142 mg). The reaction mixture is stirred at 90° C. The reaction is shown to be complete by TLC after 4 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane/ethyl acetate 2:1 Rf=0.65).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][CH2:10][CH3:11])[C:5]=1[CH2:12][OH:13].Cl[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1.O>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:13][CH2:12][C:5]2[C:6]([CH2:9][CH2:10][CH3:11])=[N:7][O:8][C:4]=2[CH3:3])=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCCc1noc(C)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a stirred suspension of sodium hydride (2.78 g of a 60% dispersion in mineral oil, 64 mmol) in THF (40 mL) at 0° C. and under argon was added solution of (5-methyl-3-propyl-isoxazol-4-yl)-methanol (7.60 g, 49 mmol) in tetrahydrofuran (40 mL) dropwise. The mixture was warmed to ambient temperature, stirred for 30 min, then cooled to 0° C. and a solution of methyl 6-chloronicotinate (8.40 g, 49 mmol) in THF (40 mL) was added dropwise. The reaction mixture was warmed to room temperature. After 2 h, water was added then the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 20% ethyl acetate in heptane) gave the title compound (8.4 g, 50%) as a light yellow oil. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[CH:4][CH:3]=1.C(O)(=O)C.Cl>O>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(Cl)ccc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(Cl)ccc2c1=O
Temperature: 130 °C
Yield: 88.8 %

Procedure:
A mixture of ethyl 7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.114 g, 3.237 mmol), acetic acid (8 ml) and concentrated hydrochloric acid (4 ml) was heated under reflux for 2 hours in an oil bath at 130° C. After then adding water (40 ml) and cooling with ice, the crystals formed were filtered out and washed with water (5 ml×2), 5% aqueous ethanol solution (5 ml×2), and diethyl ether (5 ml×2), thereby obtaining 909 mg (89%) of the title compound as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1.CS(C)=O>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nc(N)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 2.0 g (7.7 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 1.7 g (8.47 mmol) piperidin-4-yl-carbamic acid tert-butyl ester using 1.07 ml (7.7 mmol) triethylamine in 3 mL NMP and 12 mL DMSO. 200 mL ethyl acetate and 100 mL half concentrated aqueous Na2CO3 solution are added and the phases are separated. The aqueous phase is extracted 2 times with ethyl acetate (100 mL each). The combined organic layers are dried over sodium sulfate and the solvent is removed under reduced pressure. The crude product is used without further purification in the next step.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.C=CC(=O)CCC.[CH2:28]([CH:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36])[CH3:29]>[OH-].[K+]>[CH2:28]([C:30]1([CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36])[CH3:29]
Reactant: CCC1C(=O)CCC1=O
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Agent: C=CC(=O)CCC
Agent: [K+]
Agent: [OH-]
Product: CCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCC1=O

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride a 70°C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)=O>ClCCCl.C(O)(=O)C>[CH3:26][CH:25]([CH3:27])[CH2:24][C@@H:16]([NH:15][CH2:28][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)C[C@@H](N)C(=O)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(C)C)C(=O)N3CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and (R)-2-amino-4-methyl-1-(pyrrolidin-1-yl)pentan-1-one (91 mg, 0.493 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100mg, 0.329 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (160 mg, 93%). [M+H] calc'd for C25H36N4O5, 473; found, 473.7.
Reaction SMILES: O.[I-].[I:3][C:4]1[CH:5]=[C+:6][C:7]2[NH:8][C:9]3[C:14]([Se:15][C:16]=2[CH:17]=1)=[CH:13][C:12](I)=[CH:11][CH:10]=3.[I-].C(N([C:27]1[CH:28]=[CH:29][C:30]2[NH:31][C:32]3[C:37]([SeH+]C=2[CH:40]=1)=[CH:36][C:35](N(CCC)CCC)=[CH:34]C=3)CCC)CC.C(N(CC)CC)C.[CH2:55]([NH:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:56][CH2:57][CH2:58][CH3:59]>CO>[I-:3].[CH2:61]([N:60]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([SeH+:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH3:40])[CH2:32][CH2:37][CH2:36][CH2:35][CH3:34])=[CH:11][CH:10]=3)[CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: IC1=CC2=C([C+]=C1)Nc1ccc(I)cc1[Se]2
Reactant: CCCCCNCCCCC
Reactant: CCCN(CCC)c1ccc2c(c1)[SeH+]c1cc(N(CCC)CCC)ccc1N2
Agent: [I-]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCN(CCCCC)c1ccc2c(c1)[SeH+]c1cc(N(CCCCC)CCCCC)ccc1N2
Reaction time: 48 h
Yield: 17 %

Procedure:
To a solution of 3,7-diiodo-phenoselenazin-ylium iodide hydrate (2.49 g) (prepared as above for Compound 2) in methanol (300 cm3) was added triethylamine (1.0 cm3) followed by dipentylamine (10 cm3). The reaction was stirred for 48 hours. The residue remaining after removal of the methanol was taken up in dichloromethane and washed with dilute hydriodic acid (5% w/w) followed by water. The organic phase was isolated and dried (MgSO4). Flash column chromatography over silica gel 60A was performed on the crude material using a mobile phase of 85/15 methanol/water containing 3% w/v ammonium acetate. After isolation of the desired fractions and removal of the methanol, the product was extracted from the aqueous phase using dichloromethane. Concentration of the dichloromethane in vacuo and addition of an excess of diethyl ether resulted in precipitation of the product. The product was collected by filtration, washed with diethyl ether and dried to give 3,7-bis-(N,N-dipentylamino)-phenoselenazin-5-ylium iodide as a dark blue powder in 17% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:31]3[C:26](=[CH:27][N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[CH:30]=3)[CH2:25][O:24][C:21]=2[C:22]=1[CH3:23]>>[C:33]([NH:32][C:29]1[CH:30]=[C:31]2[C:20]3[CH:19]=[CH:18][C:17]([O:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:4][CH:5]([CH3:7])[CH3:6])=[C:22]([CH3:23])[C:21]=3[O:24][CH2:25][C:26]2=[CH:27][N:28]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(Cl)c1C
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1C
Yield: 11 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (S)-tert-butyl (1-((2-acetamido-7-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (168 mg, 0.037 mmol, 11% yield) as a brown oil. LCMS (ESI) m/e 470.3 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method F): tR=0.96 min.
Reaction SMILES: C([O:4][C:5](=[O:75])[C@@H:6]([NH:25][C:26](=[O:74])[C:27]1[C:32]([F:33])=[CH:31][C:30]([CH2:34][NH:35][CH2:36][C:37]2[CH:42]=[C:41]([F:43])[C:40]([C:44](=[O:71])[NH:45][C@H:46]([C:65]([O:67]CCC)=[O:66])[CH2:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]4[C:55](=[O:64])[N:56]([CH3:63])[C:57](=[O:62])[N:58]([CH3:61])[C:59]=4[CH3:60])=[CH:50][CH:49]=3)=[C:39]([F:72])[CH:38]=2)=[CH:29][C:28]=1[F:73])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)CC.C1COCC1.[Li+].[OH-]>O>[F:73][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([F:33])[C:27]=1[C:26](=[O:74])[NH:25][C@H:6]([C:5]([OH:75])=[O:4])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]([NH:45][C@@H:46]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[C:55](=[O:64])[N:56]([CH3:63])[C:57](=[O:62])[N:58]([CH3:61])[C:59]=3[CH3:60])=[CH:50][CH:49]=2)[C:65]([OH:67])=[O:66])=[O:71])=[C:39]([F:72])[CH:38]=1
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(CNCc2cc(F)c(C(=O)N[C@@H](Cc3ccc(-c4c(C)n(C)c(=O)n(C)c4=O)cc3)C(=O)OCCC)c(F)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNCc4cc(F)c(C(=O)N[C@@H](Cc5ccc(-c6c(C)n(C)c(=O)n(C)c6=O)cc5)C(=O)O)c(F)c4)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a 200 mL flask containing (S)-2-[4-[[3,5-difluoro-4-[(S)-1-propoxycarbonyl-2-[4-[1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]phenyl]ethylcarbamoyl]benzylamino]methyl]-2,6-difluorobenzoylamino]-3-[4-[1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]phenyl]propionic acid propyl ester (1004 mmg, 0.97 mmol) was added THF (25 mL), water (25 mL) and LiOH (193 mg, 4.6 mmol) and the reaction stirred at room temperature overnight. The reaction was concentrated, dried from acetonitrile yielding a white solid that was mixed with DMSO (13 mL) and water (12 mL). This mixture was heated minimally, filtered and to the filtrate was added TFA (0.25 mL) resulting in a precipitate. The precipitate was diluted with water (50 mL), filtered, washed with water and hexanes and dried on high vacuum yielding the title compound as a white solid (696 mg, 75%). ES(+)-LRMS m/e calcd. for C48H45F4N7O10 (M+H)+ 956, obsd 956.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[Cl:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37]([Sn](CCCC)(CCCC)CCCC)=[N:38][N:39]2[CH3:42])=[CH:35][CH:34]=1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[C:36]5[C:40](=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=5)[N:39]([CH3:42])[N:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (0.135 g, 0.27 mmol) and 6-chloro-1-methyl-3-tributylstannyl-1H-indazole (crude from step 3, 342 mg, 0.38 mmol) were dissolved in DMF (2.4 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) and copper(I) iodide (11 mg, 0.058 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3 h. The reaction mixture was cooled to room temperature, 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. The residue was absorbed on silica gel and purified by chromatography with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2.5% MeOH) to afford 157 mg (90%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([CH3:15])[CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[C:4]([CH2:15][Br:16])[CH:3]=1
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1CBr)C(F)(F)F
Yield: 67.5 %

Procedure:
A solution of Example 478A (2.5 g, 8.9 mmol) and N-bromosuccinimide (1.58 g, 8.9 mmol) in carbon tetrachloride (25 mL) was irradiated with a 100-watt incandescent bulb overnight. The solution was filtered and the filtrate was concentrated. The concentrate was purified by flash chromatography on silica gel using 3-4% ethyl acetate/hexanes to give 2.17 g (68% yield) of the desired product. MS (ESI(−)) m/e 360, 362 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[N:23]=[C:22]([C:24]([O:26]C)=[O:25])[CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[Na+].C(O)C.Cl>O.C(OCC)(=O)C>[CH3:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[N:23]=3)[N:17]=2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C(=O)OC)n3)cs2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2nc(-c3cccc(C(=O)O)n3)cs2)cc1OCC
Reaction time: 4 h

Procedure:
First, methyl 6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]pyridin-2-carboxylate (49 g; 127 mmol) and 10% sodium hydroxide (100 ml) were added to ethanol (1.4 L), and the obtained mixture was then stirred for 4 hours under heating to reflux. A majority of solvent was eliminated from the obtained solution, and water and ethyl acetate were then added to the residue for separation. The water layer obtained as a result of the separation was changed to acidic by addition of 10% hydrochloric acid, followed by extraction with ethyl acetate. Thereafter, the extract was quickly washed with a saturated sodium chloride aqueous solution, and was then dried over an excessive amount of magnesium sulfate. The obtained mixture was recrystallized from ethyl acetate, so as to obtain an anhydrous tetomilast type B crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Oc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and 2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated with cesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to 120° C. for 20 min by microwave irriadation (normal). The mixture was treated with water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan solid. The solid was purified by silica gel chromatography (12 g ISCO, 30% EtOAc in hexanes 30 ml/min) to give the title compound (340 mg, 58%) as a tan solid LCMS (M−H)−=362.