Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[F:31][C:32]([F:37])([F:36])[CH:33]([NH2:35])[CH3:34].CC(C)([O-])C.[Na+]>C1COCC1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:35][CH:33]([CH3:34])[C:32]([F:37])([F:36])[F:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: CC(N)C(F)(F)F
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: C1CCOC1
Product: CC(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
To a solution of 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (0.5 g, 0.96 mmol) in anhydrous THF (5 mL) was added 1,1,1-trifluoropropan-2-amine (0.13 g, 1.2 mmol), t-Bu-X-Phos precatalyst (0.1 g, 0.14 mmol) and sodium-t-Butoxide (0.27 g, 2.8 mmol). The contents were heated to 80° C. in a sealed reaction vessel under inert atmosphere. After 4 h, the reaction mixture was brought back to ambient temperature, the reaction was quenched with H2O (10 mL) and the organic contents were extracted with EtOAc (2×50 mL), dried over Na2SO4 and concentrated. The residue thus obtained was purified by flash column chromatography, to afford the title compound (0.32 g, 67% yield). MS ESI calc'd. for C28H22ClF3N4 [M+H]+ 507. Found 507.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH2:12]1[CH2:18][O:17][CH2:16][CH2:15][NH:14][CH2:13]1>CN1C(=O)CCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:14]3[CH2:13][CH2:12][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: C1CNCCOC1
Solvent: CN1CCCC1=O
Product: Fc1ccc2nnc(N3CCCOCC3)n2c1
Yield: 24.9 %

Procedure:
A solution of Intermediate 24b (429 mg, 2.50 mmol) and homomorpholine (939 mg, 9.30 mmol) in NMP (10 mL) was heated in the microwave at 170° C. for 10 h. The cooled mixture was applied to an SCX-2 cartridge (70 g), washing with methanol then eluting basic components with 0.4-2 M NH3 in MeOH. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give impure product. Further purified by FCC, using 0-12% MeOH in EtOAc gave the title compound as a pale brown gum (147 mg, 25%). LCMS (Method 3): Rt 2.11 min, m/z 237 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:6]2[CH2:17][CH2:16][CH2:15][CH2:14][C:7]=2[S:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11].N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOC(C)=O>ClCCl>[CH3:13][O:12][C:10]([C:9]1[S:8][C:7]2[CH2:14][CH2:15][CH2:16][CH2:17][C:6]=2[C:5]=1[C:4]#[C:3][CH2:2][O:1][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])=[O:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1sc2c(c1C#CCO)CCCC2
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1sc2c(c1C#CCO[Si](C)(C)C(C)(C)C)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of methyl 3-(3-hydroxyprop-1-yn-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate (8.5 g, 34 mmol) in Dichloromethane (DCM) (50 mL) was added 1H-imidazole (5.8 g, 85 mmol) and TBSCl (7.7 g, 50.9 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography column on silica gel chromatography eluted with PE:EtOAc=50:1˜20:1 to afford title product (11.9 g, 96% yield). 1HNMR: (400 MHz, CDCl3) δ 0.161 (s, 6H), 0.929 (s, 9H), 1.79-1.85 (m, 4H), 2.60-2.63 (m, 2H), 2.72-2.75 (m, 2H), 3.85 (s, 3H), 4.62 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:27])[CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:26].[N+]([O-])(O)=O.CC1([C:39]([NH2:41])=[NH:40])C=C(C)N=N1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[CH3:8][O:9][C:10](=[O:27])[CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:22][CH2:23][CH2:24][NH:25][C:39]([NH2:41])=[NH:40])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:26]
Reactant: COC(=O)CC1Cc2ccc(OCCN)cc2NC1=O
Reactant: CC1=CC(C)(C(=N)N)N=N1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1Cc2ccc(OCCNC(=N)N)cc2NC1=O
Yield: 85.4 %

Procedure:
A suspension of [7-(2-amino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester trifluoroacetate (1.49 g, 3.8 mmol), 3,5-dimethylpyrazole carboxamidine nitrate (0.84 g, 4.18 mmol) and diisopropylethylamine (1.45 mL, 8.32 mmol) in 3:1 dioxane-water (11 mL) were heated at reflux for 22 h. The cooled solution was concentrated in vacuo to yield a viscous yellow syrup. Washing the syrup with ice-cold water (3×5 ml) gives the title compound as a dried white solid (1.04 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:21][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CS(=O)(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared following Example 46, was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester via General Procedure A. Purification on silica yielded 130. NMR (DMSO): 1.61-1.68 (2H, m), 2.01-2.08 (2H, m), 2.12-2.18 (2H, m), 2.94 (3H, s, Me), 3.02-3.11 (3H, m), 3.76-3.80 (4H, m, CH2), 3.89 (2H, s, CH2), 3.96-3.99 (4H, m, CH2), 7.02 (2H, s, NH2), 7.32 (1H, s, Ar) and 9.10 (2H, s, Ar). MS: (ESI+): MH+=490.34
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:43][C@@H:44]1[CH2:49][CH2:48][CH2:47][N:46]([C:50]2[N:55]=[C:54]([NH:56][CH3:57])[N:53]=[C:52]([C:58]3[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[C:60]([F:66])[CH:59]=3)[CH:51]=2)[CH2:45]1>CN(C=O)C.O>[C:62]([C:61]1[CH:64]=[CH:65][C:58]([C:52]2[N:53]=[C:54]([NH:56][CH3:57])[N:55]=[C:50]([N:46]3[CH2:47][CH2:48][CH2:49][C@@H:44]([NH:43][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:45]3)[CH:51]=2)=[CH:59][C:60]=1[F:66])#[N:63]
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@@H](N)C2)n1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To benzoic acid (30.6 mg, 0.250 mmol) in DMF (2 mL) was added HATU (105 mg, 0.275 mmol) followed by Hunig's base (0.18 mL, 1.00 mmol). After 15 minutes, 4-[6-[(3R)-3-amino-1-piperidinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (100 mg, 0.250 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Water was added (˜10 mL), and a solid precipitated. The mixture was filtered, and the solid was washed with water and air dried to afford the crude title compound (83 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31](N2C=CN=C2)=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[N:4]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21
Reactant: N#Cc1cccc(NC(=O)n2ccnc2)c1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc(C#N)c2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
3-Amino-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2,4-dioxo-1H-1,5-benzodiazepine (360 mg) was suspended in dry THF (10 ml) under nitrogen. N-(3-cyanophenyl)-1H-imidazole-1-carboxamide (326 mg) was added, and the mixture stirred at room temperature for 2 h. The mixture was filtered to give the title compound (510 mg) as a white solid m.p.>250°.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C(O)C>[CH2:2]([O:4][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[CH3:1]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ncccc1C(=O)O
Temperature: 170 °C
Yield: 8.6 %

Procedure:
A solution of potassium t-butoxide (44.9 g, 0.40 mol) in absolute ethanol (300 mL) was added slowly to a solution of 2-chloronicotinic acid (30 g, 0.19 mol) in ethanol (100 mL), and the reaction heated in a sealed vessel at 170° C. for 20 h. On cooling, the reaction mixture was concentrated under reduced pressure, the residue dissolved in water (200 mL) and acidified to pH 3 with aqueous hydrochloric acid. The aqueous solution was extracted with dichloromethane (4×200 mL), the organic phases combined, dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (27.4 g, 16.4 mmol) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[OH:23])[CH3:8].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[O:23][CH:25]([CH3:27])[CH3:26])[CH3:8]
Reactant: CCOCOc1ccc(O)c(OCOCC)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCOc1ccc(OC(C)C)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
Potassium carbonate (2.85 g, 20.7 mmol) was added to 3a (500 mg, 2.07 mmol) in N,N-dimethylformamide (4.10 mL) at room temperature. After 10 minutes, 2-iodopropane (2.06 mL, 20.7 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×20 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 5:1→1:1 Hexane:EtOAc) to afford 4c as a yellow oil (0.32 g, 55%): 1H NMR (CD2Cl2, 400 MHz) δ 6.87 (s, 1H), 6.86 (d, J=4.9 Hz, 1H), 6.66 (dd, J=11.6, 3.4 Hz, 1H), 5.23 (s, 2H), 5.17 (s, 2H), 4.44-4.38 (m, 1H), 3.83-3.72 (m, 4H), 1.33 (s, 3H), 1.31 (s, 3H), 1.27-1.23 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 152.4, 149.1, 143.2, 118.6, 109.5, 107.5, 94.4, 93.9, 72.8, 64.3, 64.1, 22.2 (2C), 15.1, 15.1; IR (film) νmax 2976, 1591, 1504, 1528, 1391, 1258, 1217, 1107, 1011, 847 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C15H24O5, 285.1702. found, 285.1746; [M+Na]+ calcd for C15H24O5, 307.1522. found, 307.1310.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Li+].[CH3:20][CH:21]([N-]C(C)C)[CH3:22].C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1[N:3]([CH:13]([CH2:22][CH:21]=[CH2:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: C=Cc1c(C(F)(F)F)nc(C)n1CC(=O)OCC
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCC)n1c(C)nc(C(F)(F)F)c1C=C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
To a cooled (−78° C.) solution of ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]acetate (790 mg, 3.01 mmol) in THF (6 mL) under nitrogen atmosphere was added LDA (2 M, 3 mL, 6.03 mmol) drop wise. After stirring the reaction mixture at −78° C. for 15 min, allyl bromide (521 μL, 6.03 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. A saturated NH4Cl solution (20 mL) was added to the reaction mixture at 0° C. and the mixture was then extracted with EtOAc (2×100 mL). The combined EtOAc layers were then washed with brine (50 mL), dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to obtain ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]pent-4-enoate (127 mg, 0.42 mmol, 14% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[C:13]3[C:14]2=[C:9]([C:10]([CH3:30])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=[O:5].CO.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([C:10]([CH3:30])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cnc42)CN([C@@H](C(=O)O)C(C)(C)C)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc2[nH]cc3c2c1CN([C@@H](C(=O)O)C(C)(C)C)C3=O
Temperature: 50 °C
Yield: 42 %

Procedure:
(R)-3,3-Dimethyl-2-(6-methyl-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (36 mg, 0.079 mmol)) was dissolved in THF (3 mL), MeOH (3 mL) and aqueous NaOH (1N, 3 mL) in a 50 mL round bottom flask. The reaction mixture was heated at 50° C. for 30 min in an oil bath then cooled to room temperature. The solution was concentrated and purified by preparative HPLC (10-35% AcCN/H2O with 0.035% TFA) to give the title compound (10 mg, 42%). 1H NMR (500 MHz, CD3OD) δ 1.25 (s, 9H), 2.29 (s, 3H), 4.87 (s, 1H), 5.21 (d, J=19.5 Hz, 1H), 5.37 (d, J=19.5 Hz, 1H), 7.87 (s, 1H), 8.23 (s, 1H). [M+H] calc'd for C16H19N3O3, 302; found, 302.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[C:7]([C:13]([OH:15])=[O:14])[C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.CC1C(C)=CC2N=CNC=2C=1>>[N:3]1[C:4]2[CH:9]=[C:8]3[C:10](=[O:12])[O:15][C:13](=[O:14])[C:7]3=[CH:6][C:5]=2[NH:1][CH:2]=1
Reactant: O=C(O)c1cc2nc[nH]c2cc1C(=O)O
Agent: Cc1cc2nc[nH]c2cc1C
Product: O=C1OC(=O)c2cc3[nH]cnc3cc21
Temperature: 250 °C
Yield: 81.5 %

Procedure:
Benzimidazole-5,6-dicarboxylic acid (8.2 g), prepared from 5,6-dimethylbenzimidazole as described in J.Org.Chem. 1987, 52, 2934., was heated at 250° C. under vacuum (0.01 mm Hg) for 1 h. The solid was extracted with hot acetone and the acetone extracts were evaporated to give the title compound (6.1 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([Br:18])=[CH:16][N:15]=[C:14]([Cl:19])[N:13]=1)(C)(C)C.Cl>C(#N)C.O1CCOCC1>[ClH:19].[Br:18][C:17]1[C:12]([NH:11][CH2:10][CH2:9][CH2:8][NH2:7])=[N:13][C:14]([Cl:19])=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: NCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.0 g (13.7 mmol) of [3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propyl]-carbamic acid-tert-butyl-ester in 150 ml of acetonitrile is mixed with 25 ml of a 4 molar solution of hydrochloric acid in dioxane and stirred at room temperature. After 4 hours, the solvent is drawn off in a rotary evaporator, and the residue is dried in a drying oven. 4.1 g (13.7 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:26]O>>[OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:26])=[O:18]
Reactant: CO
Reactant: CCCCCC(C)(O)C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O
Product: CCCCCC(C)(O)C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC

Procedure:
In the same manner but using the appropriate choice of the compound of formula 1 and lower alkanol, other corresponding esters of formula 1 (R1 = lower alkyl) are prepared; for example, the corresponding lower alkyl esters of the products of Table IV. More specifically exemplified, the choice of trans-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]heptanoic acid, described in Example 68, as the compound of formula 1 and methanol as the lower alkanol in the procedure of this example give methyl trans-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]heptanoate, γmaxfilm 3475, 1730 cm-1, nmr (CDCl3) δ 0.89 (t, 3H), 3.64 (s, 3H), 5.61 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>C(O)C>[CH3:12][C:11]1[C:3]([CH2:2][S:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(O)CS
Reactant: Cc1cc2c(cc1CCl)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(cc1CSCC(=O)O)OCO2
Yield: 20.5 %

Procedure:
A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 g of mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of 50% aqueous ethanol was heated under reflux for one hour and concentrated, followed by the addition of water. The mixture was washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent. The residue was chromatographed over a silica gel column and eluted with chloroform to obtain a crude crystal. This crude crystal was recrystallized from diisopropyl ether to obtain 1.6 g of the title compound as a colorless crystal.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=[C:15]3[N:16]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)C.O>[N:9]1([C:12]2[N:16]=[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[N:13]=2)[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCN(c2nc3cccccc-3n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc2nc(N3CCNCC3)nc-2cc1
Yield: 126.2 %

Procedure:
A mixture of 4-(2-cycloheptimidazolyl)-piperazine-1-carboxylic acid ethyl ester (2.86 g, described in Example 1) and potassium hydroxide in ethanol (20 ml) and water (1.5 ml) was refluxed for 20 hr. Water was added and the ethanol was evaporated. Additional water was added and the solution was extracted with chloroform. The organic extract was dried and evaporated to give the title compound (2.7 g). To a solution of the title compound in chloroform and diethyl ether, a solution of hydrogen chloride in diethyl ether was added. The precipitate was collected and crystallized from methanol-diethyl ether to obtain the hydrochloride salt of the title compound (2.4 g): mp>280° C.; ir(nujol) 2600, 1630 and 1584 cm-1 ; uv max (MeOH) 285(ε7540), 261(ε26,930) and 236 nm(ε18,310) and nmr(DMSO-d6)δ 3.37(4H,t), 4.3(4H,t), 8.4(5H,m) and 10.0(2H,s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.[Br:23]N1C(=O)CCC1=O>C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:23][C:9]1[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[C:6]2=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCn2c(Br)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (10 g, 32.74 mmol) in methylene chloride (73.5 mL) at 0° C. was added N-bromosuccinimide (5.53 g, 31.10 mmol) portionwise. The reaction was stirred at 0° C. After 30 minutes, additional N-bromosuccinimide (291.4 mg, 1.64 mmol) was added and the reaction was stirred for 1 hour. The reaction was diluted with 0.5 M Na2S2O3 (135 mL) and the aqueous phase was removed. The organic layer was washed with brine (135 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield tert-butyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate as a red viscous liquid that was used in the next step without further purification. 1H NMR (400 MHz, DMSO) δ 6.09 (d, J=3.7 Hz, 1H), 5.99 (d, J=3.7 Hz, 1H), 3.78-3.65 (m, 4H), 3.27 (t, J=6.0 Hz, 2H), 3.17-2.92 (m, 2H), 2.21 (s, 3H), 2.03-1.93 (m, 2H), 1.65-1.53 (m, 2H), 1.40 (s, 9H). ESI-MS m/z calc. 383.1, found 386.0 (M+1)+; Retention time: 1.13 minutes (3 minute run).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+].O.[N+:12]([CH3:15])([O-:14])=[O:13]>C(O)C>[N+:12]([CH2:15][C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:14])=[O:13]
Reactant: O=C1CCCC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of cyclopentanone (40.0 mL, 452 mmol) in nitromethane (36 mL) and ethanol (14 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 8.5 mL, 23 mmol). The solution was stirred for 5 days at room temperature. Water (400 mL) was added and the mixture was extracted with ethyl acetate (2×350 mL). The combined organic extracts were washed with water (2×200) and brine (200 mL), dried over MgSO4, filtered, and concentrated. The starting materials and solvent were removed from the product by distillation under reduced pressure to yield 8.3 g of 1-(nitromethyl)cyclopentanol as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18](O)=[O:19])=[CH:8][C:9]=1[NH:10]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C1COCC1.C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:18]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[O:19])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:15]([NH2:16])=[O:17])=[CH:13][CH:14]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(=O)O)ccc12
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.1 %

Procedure:
A suspension of 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid (Intermediate 49-1, 1.84 g, 4.97 mmol), EDC (1.334 g, 6.96 mmol), and HOBT (1.066 g, 6.96 mmol) in THF-DCM-DMF (4:1:1) (124 mL) was treated with 1-methylpiperazine (1.656 mL, 14.91 mmol) and the mixture was stirred at rt for 3 days. The mixture was concentrated and the residue was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to afford an oil. This was purified by column chromatography (DCM-2 M methanolic ammonia, 100:0 to 95:5 to 92.5:7.5). The resulting solid was suspended in EtOAc, collected by filtration and dried to provide 4-bromo-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (1.57 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H) 8.57 (d, J=8.13 Hz, 1H) 8.20 (br. s., 1H) 7.84 (d, J=8.35 Hz, 1H) 7.79 (s, 1H) 7.56 (br. s., 1H) 7.42 (d, J=8.13 Hz, 1H) 7.22 (d, J=8.13 Hz, 1H) 3.30-3.70 (m, 4H) 2.19-2.39 (m, 4H) 2.16 (s, 3H). Mass spectrum m/z 415, 417 (M+H)+.