Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:35]=[CH:34][C:8]2[N:9]([CH2:23][CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:30]([O:29][C:27]([N:25]([CH3:26])[CH2:24][CH2:23][N:9]1[C:8]2[CH:34]=[CH:35][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CCN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21)C(=O)OC(C)(C)C
Yield: 92 %

Procedure:
1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1.7 g) was prepared by following General Procedure E starting from 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.9 g) and 2 N NaOH (5 mL) in methanol:THF (1:1, 10 mL).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[CH:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[CH:26])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: C#Cc1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: C#Cc1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 91.7 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-ethynyl-phenol (31 mg, 0.26 mmol) to give the title compound (55 mg, 91%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11](O)O)=[CH:2]1.[C:14]([O:20][CH3:21])(=[O:19])[CH2:15][C:16]([CH3:18])=O.C1C=CC=CC=1.C1(C)C=CC([S:34](O)(=O)=O)=CC=1>O>[CH3:21][O:20][C:14](=[O:19])[CH2:15][C:16]1([CH3:18])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][S:34]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: COC(=O)CC(C)=O
Reactant: OC(O)Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Reaction time: 12 h

Procedure:
Indole-3-ethanediol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70° - 80° C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as a semi-solid, νmaxCHCl3 1715 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]([CH2:9][CH3:10])[CH3:8])=[O:5].[CH:15]([NH2:19])([CH2:17]C)C.[C:20]12[C:26](=CC=CC=1)[NH:25]C(=O)OC2=O>>[CH:7]([NH:6][C:4](=[O:5])[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[NH:1][CH2:17][C:15]1[NH:19][CH2:20][CH2:26][N:25]=1)([CH2:9][CH3:10])[CH3:8]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCC(C)N
Reactant: CCC(C)NC(=O)c1ccccc1N
Product: CCC(C)NC(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-sec-butylbenzamide (prepared from sec-butylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-(sec-butyl)-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]benzamide.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([N:24]([C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:43][CH2:42][O:41][C@@H](COC(OC(C)(C)C)=O)[CH2:39]4)=[CH:34][CH:33]=3)C(=O)OC(C)(C)C)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[CH:20]=2)[CH:12]=[N:11][CH:10]=1)=O)(C)(C)C.[C:60]([OH:66])([C:62](F)(F)F)=O.[CH2:67](Cl)Cl>>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([NH:24][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:43][CH2:42][O:41][C@@H:62]([CH2:60][OH:66])[CH2:39]4)=[CH:34][CH:33]=3)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[CH:20]=2)[CH:12]=[N:11][C:10]=1[CH3:67]
Reactant: CC(C)(C)OC(=O)OC[C@H]1CN(c2ccc(N(C(=O)OC(C)(C)C)c3nc(-c4cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n4)cn4ccnc34)cc2)CCO1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Product: Cc1ncc(-c2cn3ccnc3c(Nc3ccc(N4CCO[C@@H](CO)C4)cc3)n2)nc1N
Reaction time: 5 h

Procedure:
(R)-tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(2-(((tert-butoxycarbonyl)oxy)methyl)morpholino)phenyl)carbamate XX (460 mg, 0.56 mmol) in DCM was added to a round bottom flask, and TFA (1.29 ml, 16.85 mmol) was added. The reaction was partially complete after stirring ˜5 hours. Added an additional 10 eq TFA and stirred overnight, then concentrated under reduced pressure. 10% MeOH/DCM (˜100 mL) and sat.aq. sodium bicarbonate were added and stirred 15 min, separated, extracted with ˜100 mL 10% MeOH/DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and dried under vacuum. The resulting solid was triturated with DCM, collected solids via filtration and dried under vacuum to give compound 3. LCMS-ESI+ (m/z): [M+H]+: 419.2. 1H NMR (300 MHz d6-DMSO) δ: 9.57 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.06-7.90 (m, 2H), 7.87 (s, 1H), 7.62 (d, J=1.1 Hz, 1H), 7.05-6.93 (m, 2H), 6.49 (s, 2H), 4.78 (t, J=5.8 Hz, 1H), 3.98-3.87 (m, 1H), 3.71-3.36 (m, 7H), 2.63 (td, J=11.7, 3.4 Hz, 1H), 2.37 (dd, J=12.1, 10.5 Hz, 1H). The corresponding (S) isomer, or racemic mixture of compounds is prepared similarly, using (S)-(4-(4-aminophenyl)morpholin-2-yl)methanol or a racemic mixture of (4-(4-aminophenyl)morpholin-2-yl)methanol, respectively, in the first step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[CH:15]([N:18](C(C)C)[CH2:19][CH3:20])(C)[CH3:16].C(NCC)C>C(#N)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:13]([NH:12][S:9]([N:18]([CH2:19][CH3:20])[CH2:15][CH3:16])(=[O:11])=[O:10])=[O:14]
Reactant: Nc1ccccn1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CCNCC
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)NC(=O)Nc1ccccn1
Temperature: 25 °C

Procedure:
This example was prepared according to the general procedure described by Karady et al. in Heterocycles, 1979, 12, 815-818. To a solution of 2-aminopyridine (5.0 g, 0.053 mol) in acetonitrile (17.5 mL) cooled to 0° C. was added chlorosulfonylisocyanate (4.5 mL) while maintaining the temperature between -5 and +5° C. A very thick precipitate formed. The cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. The mixture was re-cooled to 0° C., and diisopropylethylamine (8 mL, 0.046 mol) was added dropwise with stirring while maintaining the internal temperature between -5 and +5° C. An additional 0.85 mL of diisopropylethylamine was added, and the mixture was allowed to warm to room temperature and stirred overnight. The solid that formed was filtered, washed with cold acetonitrile, and dried in vacuo; yield 6.0 g. To a mixture of this 1,2,4,6-thiatriazene-1,1-dioxide (2.0 g, 0.010 mol) in acetonitrile (60 mL) was added diethylamine (0.97 mL, 9.38 mmol). The reaction mixture was stirred overnight at room temperature and evaporated. The resulting solid was triturated with methanol, filtered, washed with diethyl ether, and dried in vacuo; yield 1.6 g (55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1N1CCOCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cnc1N1CCOCC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 4-(5-bromo-3-nitropyridin-2-yl)morpholine (1.02 g, 3.54 mmol) in EtOAc (30 mL) was added tin(II) chloride dihydrate (4.01 g, 17.77 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 2 h, the reaction was cooled to rt and diluted with ethyl acetate, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as 5-bromo-2-morpholinopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.59 (1H, d, J=2.0 Hz), 7.12 (1H, d, J=2.0 Hz), 5.19 (2H, s), 3.80 (4H, m), 3.02 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:16](=[O:17])[C:11]=3[CH:10]=2)[CH:5]=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1.CC(=O)OCC.O>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]([OH:46])[C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:14](=[O:28])[N:13]([CH3:29])[C:12]=3[N:30]=[CH:31][C:9]=2[O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:43][CH:42]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(F)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 0.35 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 0.7 mL, 1.40 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 4-chlorobenzaldehyde (98 mg, 0.70 mmol) in THF (2 mL) was added. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 25.1% yield) as an oil. LCMS: [MH+-THP] 487 and TR=1.423 min. Used without further purification.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH2:11].Cl[CH2:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH3:21]>CO>[CH3:18][C:19](=[C:20]([CH3:22])[CH3:21])[CH2:23][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH2:11]
Reactant: CC(C)=C(C)CCl
Reactant: C=C(c1ccccc1O)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccccc1OCC(C)=C(C)C)n1ccnc1
Yield: 63 %

Procedure:
9.2 g (0.23 mol) of sodium hydroxide are added to a mixture of 39.1 g (0.21 mol) of 1-[1-(2-hydroxyphenyl)-vinyl]-imidazole and 200 ml of methanol at room temperature, with stirring. When the addition has ended, the mixture is stirred at 50° C. for a further 30 minutes and is then concentrated under reduced pressure by stripping off the solvent. The solid residue which remains is taken up in 200 ml of dimethylformamide. 24.9 g (0.21 mol) of 1-chloro-2,3-dimethyl-but-2-ene are added to the solution formed at a temperature of 25° C., with stirring. The reaction mixture is stirred at 20° C. for a further 12 hours and then worked up by being concentrated by stripping off the diluent. The residue obtained is chromatographed over silica gel. 35.5 g (63% of theory) of 1-[1-(2-(2,3-dimethyl-but-2-en-1-yl-oxy)phenyl)-vinyl]-imidazole in the form of an oil are obtained in this manner.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][O:3]1.[C:8](=[S:10])=[S:9].N1C=CC=CC=1.C([O-])(=O)C.[Zn+2:21].C([O-])(=O)C>C(Cl)(Cl)Cl.C(O)C>[CH3:1][C:2]1([CH3:7])[N:6]([C:8]([S-:10])=[S:9])[CH2:5][CH2:4][O:3]1.[CH3:1][C:2]1([CH3:7])[N:6]([C:8]([S-:10])=[S:9])[CH2:5][CH2:4][O:3]1.[Zn+2:21]
Reactant: S=C=S
Reactant: CC1(C)NCCO1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)OCCN1C(=S)[S-]
Reaction time: 8 h

Procedure:
While cooling and stirring, 20 g. (0.20 mole) of 2,2-dimethyloxazolidine (preparation described by E. Bergmann et. al., J. Am. Chem. Soc. 75, 358 (1953)) was added to a solution of 15.2 g. (0.20 mole) carbon disulfide in 150 g. pyridine. To the stirring solution was added 18.3 g. (0.10 mole) of anhydrous zinc acetate at 25°-30° C. After standing overnight at room temperature, filtration gave 15.2 g. of the crude product; vacuum-concentration of the filtrate and ethanol-dilution of the residue gave an additional 10.4 g. After combining and vacuum-drying of the crude product at 100° C there was obtained 17.8 g. of the desired carbodithioate melting at 188°- 190° C (decomp.). A small sample, dissolved in hot chloroform and precipitated by hexane (m. 192°-3° C decomp.) had the following analysis: Found: C, 34.22; H, 4.47; N, 6.84; Zn, 15.20%. Calcd for C12H20N2O2S4Zn: C, 34.50; H, 4.79; N, 6.71; Zn, 15.67%.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:8]([N:10]2[CH:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC=C)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCOCC1>ClCCl.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>[CH:1]1([CH2:6][C@H:7]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCOC(=O)N1CCC(C(=O)Nc2ncccn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ncccn1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
Pd(Ph3P)4 (4.63 mg, 4.01 μmol) was added to a solution of 2-propen-1-yl 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-[(2-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (32 mg, 0.057 mmol) and morpholine (15.87 μl, 0.182 mmol) in dichloromethane (DCM) (0.8 ml). The mixture was stirred at ambient temperature for 15 min. The solvent was removed to give a residue which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-2-pyrimidinyl-3-pyrazolidinecarboxamide (13 mg, 0.027 mmol, 60% yield). MS (ES+) m/z 475.1 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2)[CH3:2].[B-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]([C:14]#[N:15])[CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2)[CH3:2]
Reactant: CCN1c2ccccc2C=C(C#N)c2ccccc21
Agent: [B-]
Agent: [Na+]
Solvent: CCO
Product: CCN1c2ccccc2CC(C#N)c2ccccc21

Procedure:
To a solution of approximately 49 parts of 5-ethyl-5H-dibenz[b,f]azepine-10-carbonitrile in 1,600 parts of absolute ethanol at 70°-75° is added, portionwise with stirring, 76 parts of sodium tetrahydroborate (1-). When the addition is conplete, the reaction mixture is maintained at 70°-75° with stirring for a further 1 1/2 hours, whereupon it is cooled and solvent is then removed by vacuum distillation. Approximately 2,000 parts of water is mixed with the residue. Insoluble solids are filtered out, washed on the filter with water, dried in air, and recrystallized from ethanol to give 5-ethyl-10,11-dihydro-5H-dibenz[b,f]azepine-10-carbonitrile as a yellow solid melting at 127°-129°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (R)-tert-butyl piperidin-3-ylcarbamate (10.00 g, 49.93 mmol) and triethylamine (20.88 mL, 149.8 mmol) in CH2Cl2 (100 mL) at 0° C. (ice bath) was treated dropwise with benzyl carbonochloridate (10.54 mL, 74.90 mmol) and stirred at 0° C. After 2 hours, the mixture was diluted with CH2Cl2 (50 mL) and successively washed with ice cold 10% HCl (2×30 mL), water (1×30 mL), saturated NaHCO3 (1×30 mL), and brine (1×30 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 60) eluting with 20% EtOAc/hexane (3 L). The fractions containing the product were pooled, concentrated in vacuo and dried under high vacuum for 18 hours to provide (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate as a solid. LCMS (APCI+) m/z 335 (M+H)+.
Reaction SMILES: CCO.Cl.[CH2:5]([NH:12]/[C:13](/[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[CH:14]\[C:15](=O)[C:16]([F:19])([F:18])[F:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.N.CCOC(C)=O>[Br:27][C:25]1[CH:26]=[C:21]2[C:22](=[CH:23][CH:24]=1)[O:28][C:15]([C:16]([F:18])([F:19])[F:17])=[CH:14]/[C:13]/2=[N:12]/[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(/C=C(\NCc1ccccc1)c1cc(Br)ccc1O)C(F)(F)F
Agent: Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)c1c/c(=N/Cc2ccccc2)c2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a cooled (ice bath) EtOH (96 ml) was bubbled through hydrogen chloride gas for 30 min. (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-1,1,1-trifluorobut-3-en-2-one (24.0 g, 60 mmol) was then added in one portion to this solution. The reaction was stirred at RT for 36 h. The resulted mixture was diluted with 900 ml of cool water, 28% aq NH3 (96 ml) was then added. The precipitate formed was filtered and washed with water to give a brown sticky solid. The solid was dissolved in EtOAc, washed with 1N HCl and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was crystallized from hexane to give the title compound as a brown solid. MS m/z: 382.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: ClCc1ccccc1Br
Solvent: CCO
Product: Brc1ccccc1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Product: Cl
Temperature: 25 °C
Yield: 110.7 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-bromobenzyl chloride (327 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 400 mg of the product 235. 1H NMR (DMSO-d6) δ 11.52 (s, 2H), 7.86 (d, 1H), 7.78 (d, 1H), 7.55-7.30 (m, 2H), 7.20-7.00 (m, 6H), 7.00-6.85 (m, 4H), 5.83 (s, 2H), 4.95 (s, 2H); MS: m/z 424 (M++1).
Reaction SMILES: CN(C=O)C.C(N(CC)CC)C.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[Si:20](Cl)([CH3:23])([CH3:22])[CH3:21]>CCCCC>[O:13]1[CH2:18][CH:17]=[C:16]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCOCC1
Solvent: CCCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=CCOCC1
Temperature: 140 °C
Yield: 58.1 %

Procedure:
To a flame-dried sealed tube was added DMF (3 ml) and triethylamine (3.34 ml, 23.97 mmol), followed by tetrahydro-4H-pyran-4-one (0.923 ml, 9.99 mmol) and TMS-Cl (1.532 ml, 11.99 mmol). The mixture was heated at 140° C. for 16 hours, allowed to cool to room temperature, diluted with pentane and decanted into ice cooled saturated sodium bicarbonate and extracted with pentane (50 ml×3). The combined pentane layers were washed with brine and dried over sodium sulfate, filtered and concentrated to give 1.0 g of the product as a liquid (5.80 mmol, yield 58.1%). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.63-4.61 (m, 1H), 3.95-3.93 (m, 2H), 3.60-3.58 (m, 2H), 1.94-1.90 (m, 2H), 0.01 (b, 9H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:21]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2)(=[O:23])[CH3:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:21]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:29]2)(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 74.2 %

Procedure:
398 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 485 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:4]=2[N:5]=[C:6]([CH2:8][CH3:9])[N:7]=1.[NH2:15][CH2:16][CH:17]([OH:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][N:12]1[C:3]2[C:2]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[N:7][C:6]([CH2:8][CH3:9])=[N:5][C:4]=2[C:10]([CH3:14])=[N:11]1
Reactant: CCc1nc(Cl)c2c(n1)c(C)nn2C
Reactant: CC(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(NCC(C)O)c2c(n1)c(C)nn2C
Temperature: 25 °C
Reaction time: 60 h
Yield: 76 %

Procedure:
A mixture of 10.5 g (0.05 mol) of 7-chloro-5-ethyl 1,3-dimethylpyrazolo[4,3-d]pyrimidine (Ex. 11) 7.5 g (0.1 mol) of 1-amino-2-propanol and 8 ml of triethylamine in 75 ml of methylene dichloride is stirred at room temperature for 60 hours and filtered. The hygroscopic solid is stirred in 50 ml of saturated sodium bicarbonate solution to give 9.5 g (76%) of 1-[1,3-dimethyl-5-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]amino-2-propanol, a hemihydrate melting at 116°-119° C. from ethyl acetate-pet ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[Cl:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:11][C:8]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Fc1ccc2nncn2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc2nnc(Cl)n2c1
Yield: 71.2 %

Procedure:
A solution of Intermediate 24a (789 mg, 5.98 mmol) and N-chlorosuccinimide (878 mg, 6.57 mmol) in chloroform (15 mL) was heated at 65° C. overnight. The cooled mixture was washed with sat. aq. NaHCO3 solution (2×15 mL) and dried (Na2SO4). The solvent was evaporated, then the residue suspended in diethyl ether (10 mL) and filtered to give the title compound (730 mg, 76%). LCMS (Method 1): Rt 1.83 min, m/z 172 [MH+].